WO2024211745A1

WO2024211745A1 - Human pd1, pd-l1, and ctla-4 combination peptide vaccines and uses thereof

Info

Publication number: WO2024211745A1
Application number: PCT/US2024/023320
Authority: WO
Inventors: Pravin Kaumaya
Original assignee: Ohio State Innovation Foundation
Current assignee: Ohio State Innovation Foundation
Priority date: 2023-04-05
Filing date: 2024-04-05
Publication date: 2024-10-10
Anticipated expiration: 2025-10-05

Abstract

Disclosed are compositions related to combination peptide therapies comprising PD-1 peptides, PD-L1 peptides, CTLA-4 peptides, anti-PD-1 antibodies, anti-PD-L1 antibodies, and/or anti-CTLA-4 antibodies and methods of treating cancers, autoimmune diseases, and Alzheimer's disease using said peptides or antibodies.

Description

HUMAN PD1, PD-L1, AND CTLA-4 COMBINATION PEPTIDE VACCINES AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/494,360, filed on April 5, 2023, which is incorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING

The sequence listing submitted on April 5, 2024, as an .XML file entitled "103361 - 479WO1 ST26.XML’⁷ created on April 2, 2024, and having a file size of 52.703 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).

I. BACKGROUND

1. Cancer is now the primary cause of death in developed countries and world-wide. The financial burden of this disease, and more importantly, the suffering it causes, is immense. There is an obvious and urgent need to speed the development and application of new, more efficacious anti-cancer therapies. The field of oncology is vast and comprises several indications, including some rare / orphan forms. Although oncology’ continues to be one of the most active areas in terms of drug development, there is still a significant unmet need.

2. Recent advances in cancer immunology have documented the importance of T cell- mediated anti-tumor immunity' against human cancers, and inhibitory' receptors expressed by T cells have become important targets for cancer immunotherapy. Checkpoint inhibitors act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been greatly successful in the treatment of cancer either as monotherapy or in combination, have revolutionized the treatment landscape of cancer patients. The success of immune checkpoint inhibitors (ICIs), notably anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as well as inhibitors of CTLA-4, programmed death 1 (PD-1), and programmed death ligand- 1 (PD-L1), has revolutionized treatment options for solid tumors. The advent of immune checkpoint receptors has been one of the most fruitful, stimulating, and studied strategies in immune-oncology' and vaccine immunotherapy. Currently, several immune checkpoint inhibitors, mostly monoclonal antibodies, have shown significant results; however, major drawbacks exist in that only 10-20% of patient respond to such treatment and severe immune-related adverse effects can occur. Small molecules are being studied extensively as alternative approaches to mAbs. 3. Monoclonal antibodies targeting immunologic checkpoints and especially the PD- 1/PD-L1 axis provided spectacular results in cancer therapy in the recent years. These agents have been approved for use in multiple solid and hematologic malignancies. Improved treatment outcomes and durable responses have been observed after discontinuation of therapy, however their efficacy was limited to a small number of patients. Despite their proven utility, antibodies have specific drawbacks as therapeutics, including poor tissue/tumor penetrance which may be especially pertinent when targeting the PD-1:PD-L1 signaling pathway. This is problematic for antibodies, which are impeded from entering tumors due to their large size. It follows that antibodies may therefore fail to completely antagonize checkpoint signaling at the intended therapeutic site within tumors, leading to suboptimal efficacy.

4. Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. However, a lot of cancer patients failed to respond to the CTLA-4 or PD-1/PD-L1 checkpoint blockades. What are needed are new CTLA-4, PD-1, and PD-L1 checkpoint inhibitors for the treatment of cancer, viral infections, autoimmune diseases and Alzheimer’s disease.

II. SUMMARY

5. Disclosed are methods and compositions related to immune checkpoint therapies comprising combinations of PD-1 peptides, PD-L1 peptides, CTLA-4 peptides, anti-PD-1 antibodies, anti-PD-Ll antibodies, and anti-CTLA-4 antibodies.

6. In one aspect, disclosed herein are immune checkpoint therapies comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor.

7. Also disclosed herein are immune checkpoint therapies of any preceding aspect, w herein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand-1 (PD-L1) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. 8. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

9. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17. SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

10. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20.

11. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22. SEQ ID NO: 23. SEQ ID NO: 24, and SEQ ID NO: 25.

12. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

13. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26. SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

14. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

15. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6). and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13. SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles vims fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

16. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

17. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

18. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

19. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as. for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP -224, AMP-514, CT-011, MK- 3475, and acrixolimab), an anti-PD-Ll antibody (such as. for example, atezolizumab, avelumab. durvalumab, BMS-986189, KN035, cosibehmab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab). 20. In one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintihmab, tislelizumab, INCMGA00012, AMP- 224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C. and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

21. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab. retifanlimab. toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189. KN035, cosibelimab, AUNP12, BMS-936559. MPDL3280A, MSB0010718C, and CA-170), or an anti- CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

22. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example, breast cancer (including, but not limited to triple negative breast cancer), colon cancer, and melanoma), Alzheimer’s disease, or an autoimmune disease in a subject comprising administering to the subject the immune checkpoint therapy of any preceding aspect. For example, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as. for example, breast cancer (including, but not limited to triple negative breast cancer), colon cancer, and melanoma), Alzheimer’s disease, or an autoimmune disease comprising administering to a subject an immune checkpoint therapy comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor.

23. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand- 1 (PD-L1 ) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

24. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11 .

25. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

26. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20. 27. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as. for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

28. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11 .

29. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

30. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

31. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6). and a linker (such as, for example. SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

32. In one aspect disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

33. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

34. In one aspect disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

35. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example. SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, w herein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab. dostarlimab. retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189. KN035, cosibelimab, AUNP12, BMS-936559. MPDL3280A, MSB0010718C, and CA-170), or an anti- CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

36. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti- PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012. AMP-224, AMP-514, CT-011, MK-3475. and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti- CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

37. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis. Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the first therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as. for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab. BMS-986189, KN035. cosibehmab, AUNP12, BMS-936559. MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

38. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the cancer is selected from the group of cancers consisting of lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin’s Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma, neuroblastoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer (including, but not limited to triple negative breast cancer), epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancer; testicular cancer; prostatic cancer, or pancreatic cancer.

39. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the cancer is breast cancer, and wherein the method further comprises administering to the subject one or more one or more HER-2 B cell epitopes (such as for example, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40).

40. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the autoimmune disease is selected from the group consisting of Psoriasis, Alopecia Areata, Primary biliary cirrhosis, Autoimmune poly endocrine syndrome, Diabetes mellitus type 1, autoimmune thyroiditis, Systemic Lupus Erythematosus. Multiple sclerosis, Guillain-Barre syndrome, Grave’s disease, Sjogren’s syndrome, ulcerative colitis, Autoimmune hemolytic anemia, Pernicious anemia, Psoriatic arthritis, rheumatoid arthritis, relapsing polychondritis, myasthenia gravis, Acute disseminated encephalomyelitis, and Granulomatosis with polyangiitis.

III. BRIEF DESCRIPTION OF THE DRAWINGS 41. The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods.

42. Figure 1 shows protocol for assessing combination of PD-1. PD-L1, and CTLA-4 immunizations.

43. Figure 2 shows the immunogenicity of combination of PD-1, PD-L1, and CTLA-4 immunizations.

44. Figure 3 shows the antibody isotypes generated following combination of PD-1, PD- Ll. and CTLA-4 immunizations.

45. Figures 4A, 4B, 4C, 4D, and 4E show the effect of PD-1 and PD-L1 peptide immunizations in a CT26 colon cancer model. Figure 4A shows the scheme of BALB/c mice vaccination and tumor engraftment. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-PD-1 (92)+MVF-PD-L1 (36) or MVF-PD-1(92)+MVF-PD-L1(13O) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with CT26 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti -mouse PD-1 antibody (clone 29F.1A12) plus anti-mouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge. Tumor grow ths were observed and measured by calipers; Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Figure 4B shows the immunogenicity of each peptide in BALB/c mice immunized with various peptide constructs. Sera were tittered against each individual peptide immunogen. Titers are defined as the highest dilution of sera with an absorbance value of 0.2 after subtracting the blank. Figure 4C shows line curves of mean value of tumor growth measured at each time point as indicated. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Two-way ANOVA was used to analyze the whole curves of tumor growth, which shows significant difference with p<0.05. Figure 4D show s plots of tumor volume LWW at day 14 and day 16 for each of group. At day 14, One-w ay ANOVA analysis p<0.01. Betw een two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated, mAbs vs PBS p<0.05; MVF-PD-1(92)+MVF-PD-L1(36) vs PBS with p<0.05; MVF-PD-1(92)+MVF-PD-L1(13O) vs PBS with p<0.01. Figure 4E show-s survival curves comparison Log-rank(Mantel-Cox) test p<0.05; 46. Figures 5A, 5B, 5C, 5D, 5E, and 5F show the effect of PD-1 and PD-L1 peptide immunizations in D2F2 and 4T1 breast cancer models. Figure 5A shows the immunization and challenge protocol. Figure 5B and 5C show the tumor volume in combination immunized mice following D2F2 challenge. Figures 5D and 5E show the tumor volume in combination immunized mice following 4T1 challenge. Figure 5F shows the percent survival in combination immunized mice following D2F2 and 4T1 challenge.

47. Figures 6A, 6B, 6C, 6D, 6E, 6F, and 6G show the effect of PD-1 and CTLA-4 peptide immunizations in CT26, D2F2, and 4T1 breast cancer models. Figure 6A shows the immunization and challenge protocol. Figure 6B and 6CE show the tumor volume in combination immunized mice following CT26 challenge. Figure 6D and 6E show the tumor volume in combination immunized mice following D2F2 challenge. Figures 6F and 6G show the tumor volume in combination immunized mice following 4T1 challenge.

48. Figure 7 shows the percent survival in PD-1 and CTLA-4 peptide combination immunized mice following CT26, D2F2, and 4T1 challenge.

49. Figures 8 A, 8B, 8C, 8D, 8E, and 8F show the effect of PD-L1 and CTL-4 peptide immunizations in D2F2 and 4T1 breast cancer models. Figure 8A shows the immunization and challenge protocol. Figure 8B and 8C show the tumor volume in combination immunized mice following D2F2 challenge. Figures 8D and 8E show the tumor volume in combination immunized mice following 4T1 challenge. Figure 8F shows the percent survival in combination immunized mice following D2F2 and 4T1 challenge.

50. Figures 9A, 9B, 9C, 9D, and 9E show the effect of PD-L1 and CTL-4 peptide immunizations in CT26 colon cancer models. Figure 9A shows the scheme of BALB/c mice vaccination and tumor engraftment. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-CTLA-4(59)+MVF-PD-Ll(36); MVF-CTLA-4(59)+MVF-PD-L 1(130); MVF-CTLA-4( 130)+MVF-PD-L 1 (36); MVF-CTLA- 4(130)+MVF-PD-Ll(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with CT26 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti-mouse CTLA-4 antibody (clone 9H10) plus anti-mouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge. Tumor growths were observed and measured by calipers. Tumor volume was calculated as: Tumor volume (LWW) -(Length X Width X Width)/2. Figure 9B shows the immunogenicity of each peptide in BALB/c mice immunized with various peptide constructs. Sera were tittered against each individual peptide immunogen. Titers are defined as the highest dilution of sera with an absorbance value of 0.2 after subtracting the blank. Figure 9C shows line curves of mean value of tumor growth measured at each time point as indicated. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Two-way ANOVA was used to analyze the whole curves of tumor grow th, which shows significant difference with p<0.01. Figure 9D shows plots of tumor volume LWW at day 14 and day 16 for each of group. All the treatment group with smaller mean value of tumor volume both at day 14 and day 16. At day 14. One-way ANOVA analysis p<0.01. Figure 9E shows survival curves comparison Log- rank(Mantel-Cox) test p<0.01; ** indicates p<0.01, * indicates ?<0.05.

51. Figures 10A, 10B, 10C, and 10D show the effect of PD-L1 and CTL-4 peptide immunizations in CT26 colon cancer models.

52. Figure 10A shows a schematic of immunization and challenging with CT26 tumor cells. 6-8 weeks old BALB/c mice were vaccinated with single peptide vaccine before challenging with CT26 tumor cells, each group indicated as following: PBS; 9H10+10F.9G2; or MVF-PD-1 (92)+MVF-CTLA-4(130). Mice were immunized as 3 weeks interval. 0.1 mg each peptide cancer vaccine w ere used per mouse. Mice were boosted with the designed doses for every 3 weeks intervals. Blood was collected weekly for monitoring antibody titers. After 2 w eeks of the third time immunization (3Y), mice were challenged with 1X10⁵ per mouse CT26 tumor cells. After tumor challenge, the positive control group, we treat the mice with antimouse PD-1 antibody (clone 29F.1A12) combination with anti-mouse CTLA-4 antibody (clone 9H10) twice a week for at least up to three weeks, and the negative control group was treated with PBS. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Figure 10B shows CT26 tumor model. Line curves of mean value of tumor growth measured at each time point as indicated. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Two-way ANOVA w as used to analyze the whole curves of tumor growth, which shows significant difference with p<0.01. Figure 10C shows CT26 tumor model. Plots of tumor volume LWW at day 9 and day 12 for each of group. The immunized group mice with smaller mean value of tumor volume at day 9 and day 12. (Left) At day 9, One-w ay ANOVA analysis p<0.01. (Right) At day 12, One-way ANOVA analysis p<0.01. Figure 10D shows survival curves comparison Log-rank(ManteLCox) test p<0.05.

53. Figures 1 1A, 1 IB, 11C, 1 ID, and 1 IE show the effect of combination PD-1 and PD-L1 peptide vaccines followed by treatment with anti-PD-Ll monoclonal antibody (10F.9G2) in CT26 tumor model. Figure 11 A shows a schematic of immunization and challenging with CT26 tumor cells. 6-8 weeks old BALB/c mice were vaccinated with single peptide vaccine before challenging with CT26 tumor cells, each group indicated as following: MVF-PD-1 (92); MVF- PD-L1 (36); or MVF-PD-L1 (130). Mice were immunized as 3 weeks interval. 0.1 mg each peptide cancer vaccine were used per mouse. Mice were boosted with the designed doses for every 3 weeks intervals. Blood was collected weekly for monitoring antibody titers. After 2 weeks of the third time immunization (3Y), mice were challenged with 1X10⁵ per mouse CT26 tumor cells. After tumor challenge, the positive control group, we treat the mice with antimouse PD-L1 antibody (clone 10F.9G2) twice a week for at least up to three weeks, and the negative control group was treated with PBS. At the same time, all the immunized mice group will be treated with anti-mouse PD-L1 antibody (clone 10F.9G2) twice a week for at least up to three weeks. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Figure 11B show s the immunogenicity of mice from different groups are show ed in the table and bar graph figure as indicated. The highest dilution at the cutoff absorbance 0.2 was determined as the antibody titer. Figure 11C shows line curves of mean value of tumor growth measured at each time point as indicated. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. Two-way ANOVA w as used to analyze the whole curves of tumor growth, which show s significant difference with p<0.01. Figure 1 ID shows plots of tumor volume LWW at day 14 and day 16 for each of group. All the treatment group with smaller mean value of tumor volume at day 14 and day 16 (Left) At day 14, One-way ANOVA analysis p<0.01; between two groups comparison indicated, 10F.9G2 vs PBS p<0.01; MVF-PD-1(92) +10F.9G2 vs PBS p<0.01; MVF-PD-L1(36) +10F.9G2 vs PBS p<0.01; MVF- PD-Ll(130) +10F.9G2 vs PBS p<0.01; (Right) At day 16, One-way ANOVA analysis p<0.01; Between two groups comparison indicated, 10F.9G2 vs PBS p<0.01; MVF-PD-l(92)+10F.9G2 vs PBS p<0.01; MVF-PD-L1(36) +10F.9G2 vs PBS p<0.01; and MVF-PD-Ll(130) +10F.9G2 vs PBS p<0.01. Figure HE shows survival curves comparison Log-rank(Mantel-Cox) test p<0.01; Between groups comparisons all the treatment groups vs PBS with significant difference. ** indicates /?<0.01, * indicates /?<0.05;

IV. DETAILED DESCRIPTION

54. Before the present compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific recombinant biotechnology methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

A. Definitions

55. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.

56. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

57. In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:

58. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

59. The term “administering” refers to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional. intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term ‘'parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.

60. As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. Embodiments defined by each of these transition terms are within the scope of this invention.

61. An "effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages.

62. The terms “treat”, “treating”, “treatment” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, palliatively or remedially. In some instances, the terms “treat”, “treating”, “treatment” and grammatical variations thereof, include partially or completely reducing the size of a tumor, reducing the number of tumors, and reducing the severity/metastatic ability of a tumor as compared with prior to treatment of the subject or as compared with the incidence of such symptom in a general or study population. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

63. As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g. mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.

64. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.

65. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

66. By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is ty pically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.

67. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is ty pically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.

68. References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2: 5, and are present in such ratio regardless of whether additional components are contained in the compound. As used herein, a "wt. %” or "w eight percent"’ or “percent by weight” of a component, unless specifically stated to the contrary, refers to the ratio of the weight of the component to the total weight of the composition in which the component is included, expressed as a percentage.

69. The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.

70. "Biocompatible" generally refers to a material and any metabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause significant adverse effects to the subject.

71. "Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and/or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure.

72. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative."

73. “Effective amount” of an agent refers to a sufficient amount of an agent to provide a desired effect. The amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent or agents, and the like. Thus, it is not always possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

74. A "pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation provided by the disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

75. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various t pes of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well know n in the art for use in pharmaceutical formulations and as described further herein.

76. “Pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

77. “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a non-immunogenic cancer). The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the terms “therapeutic agent'’ is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.

78. “Therapeutically effective amount'’ or “therapeutically effective dose” of a composition (e.g. a composition comprising an agent) refers to an amount that is effective to achieve a desired therapeutic result. In some embodiments, a desired therapeutic result is the control of type I diabetes. In some embodiments, a desired therapeutic result is the control of obesity⁷. Therapeutically effective amounts of a given therapeutic agent will ty pically vary⁷ with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and/or agent formulation to be administered (e.g.. the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary⁷ skill in the art. In some instances, a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years.

79. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

B. Compositions

80. Disclosed are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular chimeric PD-1 peptide, chimeric PD-L1 peptide, or chimeric CTLA-4 peptide is disclosed and discussed and a number of modifications that can be made to a number of molecules including the chimeric PD-1 peptide, chimeric PD-L1 peptide, or chimeric CTLA-4 peptide are discussed, specifically contemplated is each and every combination and permutation of the chimeric PD-1 peptide, chimeric PD-L1 peptide, or chimeric CTLA-4 peptide and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D. B-E, B-F, C- D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

81. The PD-1 gene, which belongs to the immunoglobulin super family, encodes a 55 kDa type I transmembrane protein. Both mouse PD-1 and human PD-1 consist of 288 amino acids, and have signal peptide at N terminal (20 amino acid) and hydrophobic region in the middle part, which is a transmembrane region. Human and murine PD-1 proteins share about 60%-80% amino acid identity⁷ with conservation of four potential N-glycosylation sites, and residues that define the Ig-V domain. PD-1 is expressed on T cells, B cells, and macrophages. The ligands for PD-1 are the B7 family members PD-L1 (B7-H1) and PD-L2 (B7-DC). Signaling through the immune checkpoint programmed cell death protein- 1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand- 1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer and demonstrated impressive activity' across a broad set of cancer subtypes. Disclosed herein, are improvements on traditional PD-1/PD-L1 blockades using smaller, non-antibody peptide therapeutics and peptide vaccines which directly block the interaction of PD-1 and PD-L1 or can stimulate host immune responses to generate antibodies to PD-1 that block the PD-1/PD-L1 interaction.

82. Using computer aided analysis of PD-1 B cell epitopes, sequences corresponding to PD-1 (SEQ ID NO: 1) residues 32-50, 45-64, 73-90, and 92-110 were derived. Thus, in one aspect, disclosed herein are chimeric PD-1 peptides for stimulating an immune response to a PD-1 protein comprising residues 32-50, 45-64, 73-90 and/or 92-100 of PD-1. For example, disclosed herein are chimeric PD-1 peptides for stimulating an immune response to a PD-1 protein comprising VLNWYRMSPSNQTDKLAAF (SEQ ID NO: 2), KLAAFPEDRSQPGQDCRFR (SEQ ID NO: 3), DFHMSVVRARRNDSGTYL (SEQ ID NO: 4), and/or GAISLAPKAQIKESLRAEL (SEQ ID NO: 5). In one aspect, the peptides can be acylated and/or amidated.

83. In one aspect, it is understood and herein contemplated that the disclosed PD-1 peptides can have increased B cell stimulation by linking the PD-1 peptides to a helper T (Th) cell epitope that promotes the release of cytokines that assist in bypassing MHC restriction (i.e., a promiscuous Th cell epitope) to form a chimeric PD-1 peptide. For example, disclosed herein, in one aspect are PD-1 chimeric peptides for stimulating an immune response to a PD-1 protein comprising one or more PD-1 B cell epitopes further comprising a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the resulting sequence being SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively.

84. Similarly, using computer aided analysis of PD-L1 B cell epitopes, sequences corresponding to PD-L1 (SEQ ID NO: 12) residues 36-53, 50-67, 95-112, and 130-147 were derived. Thus, in one aspect, disclosed herein are chimeric PD-L1 peptides for stimulating an immune response to a PD-L1 protein comprising residues 36-53, 50-67, 95-112, and/or 130-147 of PD-L1. For example, disclosed herein are chimeric PD-L1 peptides for stimulating an immune response to a PD-L1 protein comprising L1VYWEMEDKN1IQFVHG (SEQ ID NO: 13), FVHGEEDLKVQHSSYRQR (SEQ ID NO: 14), YRCMISYGGADYKRITVK (SEQ ID NO: 15), and/or VTSEHELTCQAEGYPKAE (SEQ ID NO: 16).

85. As with the PD-1 peptides, in one aspect, it is understood and herein contemplated that the disclosed chimeric PD-L1 peptides can have increased B cell stimulation by linking the chimeric PD-L1 peptides to a helper T (Th) cell epitope that promotes the release of cytokines that assist in bypassing MHC restriction (i.e., a promiscuous Th cell epitope) to form a chimeric PD-L1 peptide. For example, disclosed herein, in one aspect are PD-L1 chimeric peptides for stimulating an immune response to a PD-L1 protein comprising one or more PD-L1 B cell epitopes further comprising a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15. and/or SEQ ID NO: 16, the resulting sequence being SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and/or SEQ ID NO: 20, respectively.

86. Also, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4; CD 152) is one of the inhibitory immune checkpoints expressed on activated T cells and Treg cells. CTLA-4, as a type

1 transmembrane glycoprotein, belongs to the immunoglobulin superfamily. Its gene is located on band q33 of chromosome 2 and encodes for a protein of 223 amino acids. CTLA-4 is a member of CD28-B7 immunoglobulin superfamily of immune regulatory molecules which acts as a negative regulator of T cell activation, especially CD28-dependent T cell responses. The ligands for CTLA-4 are the B7 family members B7-1 (CD80) and B7-2 (CD86). Signaling through the immune checkpoint CTLA-4 enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between CTLA-4 and its ligands B7-1/B7-2 with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer and demonstrated impressive activity across a broad set of cancer subtypes. Disclosed herein, are improvements on traditional CTLA-4 blockades using smaller, non-antibody peptide therapeutics and peptide vaccines which directly block the interaction of CTLA-4 and B7-1/B7-

2 or can stimulate host immune responses to generate antibodies to CTLA-4 that block the B7- 1/B7-2 interaction.

87. Using computer aided analysis of CTLA-4 B cell epitopes, sequences corresponding to CTLA-4 (SEQ ID NO: 21) residues 59-77, 75-92, 92-1 14, and 130-150 were derived. Thus, in one aspect, disclosed herein are chimeric CTLA-4 peptides for stimulating an immune response to a CTLA-4 protein comprising residues 59-77, 75-92, 92-114, and/or 130-150 of CTLA-4. For example, disclosed herein are chimeric CTLA-4 peptides for stimulating an immune response to a CTLA-4 protein comprising EYASPGKATEVRVTVLRQA (SEQ ID NO: 22) (CTLA-4 residues 59-77), RQADSQVTEVCAATYMMG (SEQ ID NO: 23) (CTLA-4 residues 75-92), GNELTFLDDSICTGTSSGNQVNFHMSVVRARRNDSGTYL (SEQ ID NO:

24) (CTLA-4 residues 92-114), and/or KVELMYPPPYYLGIGNGTQIY (SEQ ID NO:

25)(CTLA-4 residues 130-150). In one aspect, the peptides can be acylated and/or amidated.

88. In one aspect, it is understood and herein contemplated that the disclosed chimeric CTLA-4 peptides can have increased B cell stimulation by linking the chimeric CTLA-4 peptides to a helper T (Th) cell epitope that promotes the release of cytokines that assist in bypassing MHC restriction (i.e., a promiscuous Th cell epitope) to form a chimeric CTLA-4 peptide. For example, disclosed herein, in one aspect are CTLA-4 chimeric peptides for stimulating an immune response to a CTLA-4 protein comprising one or more CTLA-4 B cell epitopes further comprising a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6). wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of the SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, the resulting sequence being SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28. and/or SEQ ID NO: 29, respectively.

89. The Th epitope can be from about 14 to about 22, more preferably about 15 to 21, most preferably 16 amino acids in length. Preferably, the Th cell epitope has one of the following amino acid sequences provided in Table 1.

Table 1

To join the chimeric PD-1 peptide and the Th cell epitope, an amino acid linker can be used. Preferably the linker is a peptide of from about 2 to about 15 amino acids, more preferably from about 2 to about 10 amino acids, most preferably from about 2 to about 6 amino acids in length. The most preferred linker comprises the amino acid sequence Gly-Pro-Ser-Leu (SEQ ID NO: 7). Thus, in one aspect, also disclosed herein are chimeric peptides comprising the chimeric peptide of any preceding aspect, further comprising a Th epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the chimeric PD-1, PD-L1, or CTLA-4 peptide to the Th epitope. For example, disclosed herein, in one aspect, are chimeric PD-1 peptides for stimulating an immune response to a PD-1 protein comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), and a linker (such as. for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope; wherein the chimeric PD-1 peptide comprises the amino acid sequence as set forth in KLLSLIKGVIVHRLEGVEGPSLVLNWYRMSPSNQTDKLAAF (SEQ ID NO: 8), KLLSLIKGVIVHRLEGVEGPSLKLAAFPEDRSQPGQDCRFR (SEQ ID NO: 9), KLLSLIKGVIVHRLEGVEGPSLDFHMSVVRARRNDSGTYL (SEQ ID NO: 10), and KLLSLIKGVIVHRLEGVEGPSLGAISLAPKAQIKESLRAEL (SEQ ID NO: 11). Similarly, disclosed herein, in one aspect, are chimeric PD-L1 peptides for stimulating an immune response to a PD-L1 protein comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), and a linker (such as. for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope; wherein the chimeric PD-L1 peptide comprises the amino acid sequence as set forth in KLLSLIKGVIVHRLEGVEGPSLLIVYWEMEDKNIIQFVHG (SEQ ID NO: 17), KLLSLIKGVIVHRLEGVEGPSLFVHGEEDLKVQHSSYRQR (SEQ ID NO: 18), KLLSLIKGVIVHRLEGVEGPSLYRCMISYGGADYKRITVK (SEQ ID NO: 19), and KLLSLIKGVIVHRLEGVEGPSLVTSEHELTCQAEGYPKAE (SEQ ID NO: 20). Also, disclosed herein, in one aspect, are chimeric CTLA-4 peptides for stimulating an immune response to a CTLA-4 protein comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope (for example, a measles virus fusion protein peptide such as SEQ ID NO: 6), and a linker (such as. for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope; wherein the chimeric CTLA-4 peptide comprises the amino acid sequence as set forth in KLLSLIKGVIVHRLEGVEGPSLEYASPGKATEVRVTVLRQA (SEQ ID NO: 26), KLLSLIKGVIVHRLEGVEGPSLRQADSQVTEVCAATYMMG (SEQ ID NO: 27), KLLSLIKGVIVHRLEGVEGPSLGNELTFLDDSICTGTSSGNQVNFHMSVVRARRNDSGTY L (SEQ ID NO: 28), and KLLSLIKGVIVHRLEGVEGPSLKVELMYPPPYYLGIGNGTQIY (SEQ ID NO: 29).

90. Herein it is recognized that combination therapies offer significant therapeutic benefits relative to single peptide vaccines. Accordingly, in one aspect, disclosed herein are immune checkpoint therapies comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor. The combination therapies can comprise any combination of chimeric PD-1 peptides, chimeric PD-L1 peptides, chimeric CTLA-4 peptides, anti-PD-1 antibody, anti-PD-Ll antibody, and/or anti-CTLA-4 antibody. For example, disclosed herein are immune checkpoint therapies, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles vims fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3. SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand-1 (PD-L1) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles vims fusion protein peptide including, but not limited to SEQ ID NO: 6). and a linker (such as, for example. SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. In one aspect, disclosed herein are immune checkpoint therapies wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11. Also disclosed herein are immune checkpoint therapies, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20. For example, disclosed herein are immune checkpoint therapies, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20.

91. Also disclosed herein are immune checkpoint therapies, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4. and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles vims fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25. Thus, in one aspect, disclosed herein are immune checkpoint therapies, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11. Also disclosed herein are immune checkpoint therapies, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29. For example, in one aspect, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

92. Also disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the first therapeutic peptide is a programmed cell death ligand-1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as. for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13. SEQ ID NO: 14. SEQ ID NO: 15. and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25. In one aspect, disclosed herein are immune checkpoint therapies, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17. SEQ ID NO: 18. SEQ ID NO: 19 or SEQ ID NO: 20. Also disclosed herein are immune checkpoint therapies, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29. For example, disclosed herein are immune checkpoint therapies of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

93. Also disclosed herein are immune checkpoint therapies, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as. for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as. for example, pembrolizumab, nivolumab. cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab). 94. In one aspect, disclosed herein are immune checkpoint therapies, wherein the first therapeutic peptide is a programmed cell death ligand-1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody(such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acnxohmab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

95. Also disclosed herein are immune checkpoint therapies, wherein the first therapeutic peptide is a a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab. tislelizumab. 1NCMGA00012. AMP- 224, AMP -514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C. and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

1. Sequence similarities

96. It is understood that as discussed herein the use of the terms homology and identity mean the same thing as similarity. Thus, for example, if the use of the word homology is used between two non-natural sequences it is understood that this is not necessarily indicating an evolutionary relationship between these two sequences, but rather is looking at the similarity or relatedness between their nucleic acid sequences. Many of the methods for determining homology between two evolutionarily related molecules are routinely applied to any two or more nucleic acids or proteins for the purpose of measuring sequence similarity regardless of whether they are evolutionarily related or not.

97. In general, it is understood that one way to define any known variants and derivatives or those that might arise, of the disclosed genes and proteins herein, is through defining the variants and derivatives in terms of homology to specific known sequences. This identity of particular sequences disclosed herein is also discussed elsewhere herein. In general, variants of genes and proteins herein disclosed typically have at least, about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent homology to the stated sequence or the native sequence. Those of skill in the art readily understand how to determine the homology of two proteins or nucleic acids, such as genes. For example, the homology can be calculated after aligning the two sequences so that the homology is at its highest level.

98. Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. MoL Biol. 48: 443 (1970), by the search for similarity' method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by inspection.

99. It is understood that any of the methods typically can be used and that in certain instances the results of these various methods may differ, but the skilled artisan understands if identity is found with at least one of these methods, the sequences would be said to have the stated identity, and be disclosed herein.

100. For example, as used herein, a sequence recited as having a particular percent homology to another sequence refers to sequences that have the recited homology as calculated by any one or more of the calculation methods described above. For example, a first sequence has 80 percent homology, as defined herein, to a second sequence if the first sequence is calculated to have 80 percent homology to the second sequence using the Zuker calculation method even if the first sequence does not have 80 percent homology to the second sequence as calculated by any of the other calculation methods. As another example, a first sequence has 80 percent homology, as defined herein, to a second sequence if the first sequence is calculated to have 80 percent homology to the second sequence using both the Zuker calculation method and the Pearson and Lipman calculation method even if the first sequence does not have 80 percent homology to the second sequence as calculated by the Smith and Waterman calculation method, the Needleman and Wunsch calculation method, the Jaeger calculation methods, or any of the other calculation methods. As yet another example, a first sequence has 80 percent homology, as defined herein, to a second sequence if the first sequence is calculated to have 80 percent homology to the second sequence using each of calculation methods (although, in practice, the different calculation methods will often result in different calculated homology percentages).

2. Peptides a) Protein and Peptide variants

101. As discussed herein there are numerous variants of the chimeric PD-1 peptides, chimeric PD-L1 peptides, and chimeric CTLA-4 peptides that are known and herein contemplated. In addition, to the known functional PD-1 strain variants there are derivatives of the chimeric PD-1 peptides, chimeric PD-L1 peptides, and chimeric CTLA-4 peptides which also function in the disclosed methods and compositions. Protein variants and derivatives are well understood to those of skill in the art and can involve amino acid sequence modifications. For example, amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional or deletional variants. Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Immunogenic fusion protein derivatives, such as those described in the examples, are made by fusing a polypeptide sufficiently large to confer immunogenicity to the target sequence by cross-linking in vitro or by recombinant cell culture transformed with DNA encoding the fusion. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about from 2 to 6 residues are deleted at any one site within the protein molecule. These variants ordinarily are prepared by site specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example Ml 3 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once; insertions usually will be on the order of about from 1 to 10 amino acid residues; and deletions will range about from 1 to 30 residues. Deletions or insertions preferably are made in adjacent pairs, i.e. a deletion of 2 residues or insertion of 2 residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. The mutations must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Tables 2 and 3 and are referred to as conservative substitutions.

TABLE 2:Amino Acid Abbreviations

Amino Acid Abbreviations

Alanine Ala A allosoleucine Alle

Arginine Arg R asparagine Asn N aspartic acid Asp D

Cysteine Cys C glutamic acid Glu E

Glutamine Gin Q

Glycine Gly G

Histidine His H

Isolelucine He I

Leucine Leu L

Lysine Lys K phenylalanine Phe F proline Pro P pyroglutamic acid pGlu

Serine Ser S

Threonine Thr T

Tyrosine Tyr Y

Tryptophan Trp W

Valine Vai V

TABLE 3:Amino Acid Substitutions

Original Residue Exemplary Conservative Substitutions, others are known in the art.

Ala Ser

Arg Lys; Gin

Asn Gin; His

Asp Glu

Cys Ser

Gin Asn, Lys

Glu Asp

Gly Pro

His Asn;Gln

He Leu; Vai

Leu He; Vai

Lys Arg; Gin

Met Leu; He

Phe Met; Leu; Tyr

Ser Thr

Th- Ser

Trp Tyr

Tyr Trp; Phe

Vai He; Leu

102. Substantial changes in function or immunological identity are made by selecting substitutions that are less conservative than those in Table 3, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties will be those in which (a) a hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g.. glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, (e) by increasing the number of sites for sulfation and/or glycosylation.

103. For example, the replacement of one amino acid residue with another that is biologically and/or chemically similar is known to those skilled in the art as a conservative substitution. For example, a conservative substitution would be replacing one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as, for example, Gly, Ala; Vai, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. Such conservatively substituted variations of each explicitly disclosed sequence are included within the mosaic polypeptides provided herein.

104. Substitutional or deletional mutagenesis can be employed to insert sites for N- glycosylation (Asn-X-Thr/Ser) or O-glycosylation (Ser or Thr). Deletions of cysteine or other labile residues also may be desirable. Deletions or substitutions of potential proteolysis sites, e.g. Arg, is accomplished for example by deleting one of the basic residues or substituting one by glutaminyl or histidyl residues.

105. Certain post-translational derivatizations are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and asparyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Other post- translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the o-amino groups of lysine, arginine, and histidine side chains (T.E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco pp 79-86 [1983]), acetylation of the N-terminal amine and, in some instances, amidation of the C-terminal carboxyl.

106. It is understood that one way to define the variants and derivatives of the disclosed proteins herein is through defining the variants and derivatives in terms of homology/identity to specific known sequences. Specifically disclosed are variants of these and other proteins herein disclosed which have at least, 70% or 75% or 80% or 85% or 90% or 95% identity to the stated sequence. Those of skill in the art readily understand how to determine the homology of two proteins. For example, the homology can be calculated after aligning the two sequences so that the homology is at its highest level.

107. Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. MoL Biol. 48: 443 (1970). by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by inspection.

108. The same types of homology can be obtained for nucleic acids by for example the algorithms disclosed in Zuker, M. Science 244:48-52, 1989, Jaeger et al. Proc. Natl. Acad. Sci. USA 86:7706-7710, 1989, Jaeger et al. Methods Enzymol. 183:281-306, 1989.

109. It is understood that the description of conservative mutations and homology can be combined together in any combination, such as embodiments that have at least 70% homology to a particular sequence wherein the variants are conservative mutations.

110. As this specification discusses various proteins and protein sequences it is understood that the nucleic acids that can encode those protein sequences are also disclosed. This would include all degenerate sequences related to a specific protein sequence, i.e. all nucleic acids having a sequence that encodes one particular protein sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed protein sequence. It is also understood that while no amino acid sequence indicates what particular DNA sequence encodes that protein within an organism, where particular variants of a disclosed protein are disclosed herein, the know n nucleic acid sequence that encodes that peptide or protein is also known and herein disclosed and described.

111. It is understood that there are numerous ammo acid and peptide analogs which can be incorporated into the disclosed compositions. For example, there are numerous D amino acids or amino acids which have a different functional substituent then the amino acids shown in Table 2 and Table 3. The opposite stereo isomers of naturally occurring peptides are disclosed, as well as the stereo isomers of peptide analogs. These amino acids can readily be incorporated into polypeptide chains by charging tRNA molecules with the amino acid of choice and engineering genetic constructs that utilize, for example, amber codons, to insert the analog amino acid into a peptide chain in a site specific way.

112. Molecules can be produced that resemble peptides, but which are not connected via a natural peptide linkage. For example, linkages for amino acids or amino acid analogs can include CH2NH-, -CH2S-, -CH2-CH2 -CH=CH- (cis and trans), -COCH2 -- CH(0H)CH2— , and --CHH2SO — (These and others can be found in Spatola, A. F. in Chemistry and Biochemistry of Amino Acids. Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol. 1, Issue 3, Peptide Backbone Modifications (general review); Morley, Trends Pharm Sci (1980) pp. 463-468; Hudson, D. et al., Int J Pept Prot Res 14: 177-185 (1979) (-CH2NH-, CH2CH2-); Spatola et al. Life Sci 38: 1243-1249 (1986) (-CH H2-S); Hann J. Chem. Soc Perkin Trans. I 307-314 (1982) (— CH— CH— , cis and trans); Almquist et al. J. Med. Chem. 23: 1392-1398 (1980) (— COCH2— ); Jennings-White et al. Tetrahedron Lett 23:2533 (1982) (— COCH2— ); Szelke et al. European Appln, EP 45665 CA (1982): 97:39405 (1982) (-CH(OH)CH₂-); Holladay et al. Tetrahedron. Lett 24:4401-4404 (1983) (-C(OH)CH₂-); and Hruby Lz/e cz 31 : 189-199 (1982) (-CH2-S-); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is -CH2NH— . It is understood that peptide analogs can have more than one atom between the bond atoms, such as b-alanine, g-aminobutyric acid, and the like.

113. Amino acid analogs and analogs and peptide analogs often have enhanced or desirable properties, such as. more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others.

3. Pharmaceutical carriers/Delivery of pharmaceutical products

114. As described above, the chimeric PD-1 peptides, chimeric PD-L1 peptides, and chimeric CTLA-4 peptides disclosed herein can also be administered in vivo in a pharmaceutically acceptable carrier. Thus, in one aspect, disclosed herein are pharmaceutical composition comprising any one or more of the chimeric PD-1 peptides as set forth in SEQ ID NO: 8, SEQ ID NO: 9. SEQ ID NO: 10. SEQ ID NO: 11, the chimeric PD-L1 peptides as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, the chimenc CTLA-4 peptide as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, and/or SEQ ID NO: 29. 115. By "pharmaceutically acceptable" is meant a matenal that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.

116. It is understood and herein contemplated that the disclosed PD-1 peptides comprising pharmaceutical compositions are particularly useful in the treatment of diseases or conditions where PD-1 mediated immune suppression occurs. Thus, in one aspect, the disclosed pharmaceutical composition comprising one or more of the PD-1 peptides disclosed herein can be combined with a disease-specific treatment or vaccine to further increase the efficacy of the PD-1 peptides. For example, a pharmaceutical composition comprising one or more of the PD-1 peptides can be combined with anti-HER2 antibodies or HER-2 B cell epitopes for use in treating, inhibiting, and/or preventing breast cancer. Accordingly, in one aspect, disclosed herein are pharmaceutical compositions comprising one or more of the chimeric PD-1 peptides, chimeric PD-L1 peptides, and chimeric CTLA-4 peptides disclosed herein (for example, SEQ ID NO: 8, SEQ ID NO: 9.SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, and/or SEQ ID NO: 29) further comprising one or more HER-2 B cell epitopes (for example SEQ ID NO: 37 or 39 or chimeric epitopes SEQ ID NO: 38 or 40) and/or anti -HER-2 antibodies. In one aspect, specifically disclosed herein are pharmaceutic compositions comprising MVF-PD1 (92-110) as set forth in SEQ ID NO: 11; a MVF-HER-2 (266-296) peptide (for example as set forth in SEQ ID NO: 38), and a MVF-HER-2 (597-626) peptide (for example as set forth in SEQ ID NO: 40).

117. The compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular inj ection. by intraperitoneal injection, transdermally, extracorporeally, topically or the like, including topical intranasal administration or administration by inhalant. As used herein, "topical intranasal administration" means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector. Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation. The exact amount of the compositions required will vary⁷ from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every' composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.

118. Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein.

119. The materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell ty pe via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al.. Bioconjugate Chem.. 2:447-451 , (1991); Bagshawe, K.D., Br. J. Cancer, 60:275-281 , (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother ., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al., Biochem. Pharmacol. 42:2062-2065. (1991)). Vehicles such as "stealth" and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research. 49:6214- 6220, (1989); and Litzinger and Huang, Biochimica et BiophysicaActa, 1104: 179-187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry' of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis has been reviewed (Brown and Greene. DNA and Cell Biology 10:6, 399-409 (1991)). a) Pharmaceutically Acceptable Carriers

120. The compositions, including antibodies, can be used therapeutically in combination with a pharmaceutically acceptable carrier.

121. Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.

122. Pharmaceutical carriers are known to those skilled in the art. These most ty pically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.

123. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.

124. The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or trans dermally.

125. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

126. Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

127. Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.

128. Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and and amines and substituted ethanolamines. b) Therapeutic Uses

129. Effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms of the disorder are effected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge. N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389. A typical daily dosage of the antibody used alone might range from about 1 pg/kg to up to 100 mg/kg of body weight or more per day, depending on the factors mentioned above.

130. The chimeric PD-1 peptides, chimeras, and antibodies disclosed herein that inhibit the interaction of PD-1 and PD-L1 can be administered prophy tactically to patients or subjects who are at risk for developing a cancer, autoimmune disease, of Alzheimer’s disease or therapeutically (i.e., after diagnosis of a disease or onset of symptoms) for treatment of a cancer, autoimmune disease, of Alzheimer’s disease.

131. Other molecules or antibodies that interact with PD-1 or PD-L1 to inhibit PD- 1/PD-L1 interactions (for example, Pembrolixumab and nivolumab) can be used in combination with the disclosed chimeric PD-1 peptides, chimeric PD-L1 peptides, and chimeric CTLA-4 peptides, anti-PD-1 antibodies, anti-PD-Ll antibodies, and/or anti-CTLA-4 antibodies to treat a cancer, autoimmune disease or Alzheimer’s disease in a subject.

4. Antibodies

(1) Antibodies Generally

132. The term “antibodies” is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact immunoglobulin molecules, also included in the term “antibodies” are fragments or polymers of those immunoglobulin molecules, and human or humanized versions of immunoglobulin molecules or fragments thereof, as long as they are chosen for their ability to interact with PD-1 such that PD-1 is inhibited from interacting with PD-L1. Antibodies that bind SEQ ID NO: 1, SEQ ID NO: 2. SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and/or SEQ ID NO: 25 involved in the interaction between PD-1, PD-L1, or CTLA- 4 and their ligand or receptor are also disclosed. The antibodies can be tested for their desired activity using the in vitro assays described herein, or by analogous methods, after which their in vivo therapeutic and/or prophylactic activities are tested according to known clinical testing methods. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2. One skilled in the art would recognize the comparable classes for mouse. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. 133. The term "monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules. The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired antagonistic activity.

134. The disclosed monoclonal antibodies can be made using any procedure which produces mono clonal antibodies. For example, disclosed monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature. 256:495 (1975). In a hybridoma method, a mouse or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.

135. The monoclonal antibodies may also be made by recombinant DNA methods. DNA encoding the disclosed monoclonal antibodies can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). Libraries of antibodies or active antibody fragments can also be generated and screened using phage display techniques, e.g., as described in U.S. Patent No. 5,804,440 to Burton et al. and U.S. Patent No. 6,096,441 to Barbas et al.

136. In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Examples of papain digestion are described in WO 94/29348 published Dec. 22, 1994 and U.S. Pat. No. 4,342,566. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a fragment that has two antigen combining sites and is still capable of cross-linking antigen.

137. As used herein, the term “antibody or fragments thereof’ encompasses chimeric antibodies and hybrid antibodies, with dual or multiple antigen or epitope specificities, and fragments, such as F(ab’)2, Fab’, Fab. Fv. sFv, and the like, including hybrid fragments. Thus, fragments of the antibodies that retain the ability to bind their specific antigens are provided. For example, fragments of antibodies which maintain PD-1, PD-L1, or CTLA-4 binding activity or bind SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16. SEQ ID NO: 21. SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and/or SEQ ID NO: 25 are included within the meaning of the term “antibody or fragment thereof.” Such antibodies and fragments can be made by techniques known in the art and can be screened for specificity' and activity according to the methods set forth in the Examples and in general methods for producing antibodies and screening antibodies for specificity and activity (See Harlow and Lane. Antibodies. A Laboratory Manual. Cold Spring Harbor Publications, New York, (1988)).

138. Also included within the meaning of “antibody or fragments thereof’ are conjugates of antibody fragments and antigen binding proteins (single chain antibodies).

139. The fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the antibody or antibody fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove/add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the antibody or antibody fragment must possess a bioactive property⁷, such as specific binding to its cognate antigen. Functional or active regions of the antibody or antibody fragment may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a skilled practitioner in the art and can include site-specific mutagenesis of the nucleic acid encoding the antibody or antibody fragment. (Zoller, M.J. Ciirr. Opin. Biotechnol. 3:348-354. 1992).

140. As used herein, the term “antibody” or “antibodies” can also refer to a human antibody and/or a humanized antibody. Many non-human antibodies (e g., those derived from mice, rats, or rabbits) are naturally antigenic in humans, and thus can give rise to undesirable immune responses when administered to humans. Therefore, the use of human or humanized antibodies in the methods serves to lessen the chance that an antibody administered to a human will evoke an undesirable immune response. (2) Human antibodies

141. The disclosed human antibodies can be prepared using any technique. The disclosed human antibodies can also be obtained from transgenic animals. For example, transgenic, mutant mice that are capable of producing a full repertoire of human antibodies, in response to immunization, have been described (see, e.g.. Jakobovits et al.. Proc. Natl. Acad. Sci. USA, 90:2551-255 (1993); Jakobovits et al.. Nature, 362:255-258 (1993); Bruggermann et al., Year in Immunol., 7:33 (1993)). Specifically, the homozygous deletion of the antibody heavy' chain joining region (J(77)) gene in these chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production, and the successful transfer of the human germ-line antibody gene array into such germ-line mutant mice results in the production of human antibodies upon antigen challenge. Antibodies having the desired activity are selected using Env-CD4-co-receptor complexes as described herein.

(3) Humanized antibodies

142. Antibody humanization techniques generally involve the use of recombinant DNA technology⁷ to manipulate the DNA sequence encoding one or more polypeptide chains of an antibody molecule. Accordingly, a humanized form of a non-human antibody (or a fragment thereof) is a chimeric antibody or antibody chain (or a fragment thereof, such as an sFv, Fv, Fab, Fab'. F(ab’)2, or other antigen-binding portion of an antibody) which contains a portion of an antigen binding site from a non-human (donor) antibody integrated into the framework of a human (recipient) antibody.

143. To generate a humanized antibody, residues from one or more complementarity determining regions (CDRs) of a recipient (human) antibody molecule are replaced by residues from one or more CDRs of a donor (non-human) antibody molecule that is known to have desired antigen binding characteristics (e g., a certain level of specificity and affinity for the target antigen). In some instances, Fv framework (FR) residues of the human antibody are replaced by corresponding non-human residues. Humanized antibodies may also contain residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. In practice, humanized antibodies are ty pically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. Humanized antibodies generally contain at least a portion of an antibody constant region (Fc), typically that of a human antibody. (4) Administration of antibodies

144. Administration of the antibodies can be done as disclosed herein. Nucleic acid approaches for antibody delivery' also exist. The broadly neutralizing anti-PDl antibodies, anti- PD-L1 antibodies, anti-CTLA-4 antibodies, and antibody fragments (including any antibody that binds to SEQ ID NO: 1, SEQ ID NO: 2. SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and/or SEQ ID NO: 25) can also be administered to patients or subjects as a nucleic acid preparation (e.g., DNA or RNA) that encodes the antibody or antibody fragment, such that the patient's or subject's own cells take up the nucleic acid and produce and secrete the encoded antibody or antibody fragment. The delivery of the nucleic acid can be by any means, as disclosed herein, for example.

C. Method of treating disease

145. It is understood and herein contemplated that the disclosed compositions, comprising chimeric PD-1 peptides, chimeric PD-L1 peptides, chimeric CTLA-4 peptides, anti- PD-1 antibodies, anti-PD-Ll antibodies, and/or anti-CTLA-4 antibodies can be used to treat any disease where immune suppression and prevention of programmed cell death is advantageous to the disease, such as Alzheimer’s disease, autoimmune diseases, or any disease where uncontrolled cellular proliferation occurs such as cancers.

146. A non-limiting list of different types of autoimmune disease that can be treated using the chimeric peptides or pharmaceutical compositions disclosed herein includes, but is not limited to, Psoriasis, Alopecia Areata, Primary' biliary cirrhosis, Autoimmune polyendocrine syndrome, Diabetes mellitus ty pe 1, autoimmune thyroiditis, Systemic Lupus Ery thematosus, Multiple sclerosis. Guillain-Barre syndrome, Grave’s disease, Sjogren’s syndrome, ulcerative colitis, Autoimmune hemolyhic anemia, Pernicious anemia, Psoriatic arthritis, rheumatoid arthritis, relapsing polychondritis, myasthenia gravis, Acute disseminated encephalomyelitis, and Granulomatosis with polyangiitis.

147. A non-limiting list of different types of cancers that can be treated using the immune checkpoint therapies disclosed herein includes, but is not limited to, lymphomas (Hodgkins and non-Hodgkins), leukemias, carcinomas, carcinomas of solid tissues, squamous cell carcinomas, adenocarcinomas, sarcomas, gliomas, high grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumors, myelomas, AIDS-related lymphomas or sarcomas, metastatic cancers, or cancers in general.

148. A representative but non-limiting list of cancers that the disclosed immune checkpoint therapies and chimeric peptides can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides. Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, kidney⁷ cancer, lung cancers such as small cell lung cancer and nonsmall cell lung cancer, neuroblastoma/ glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, lary nx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary⁷ cancer, pulmonary⁷ cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon and rectal cancers, prostatic cancer, ipilimumab-refractory melanoma, or pancreatic cancer.

149. Accordingly, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example, breast cancer (including, but not limited to triple negative breast cancer), colon cancer, and melanoma), Alzheimer’s disease, or an autoimmune disease in a subject comprising administering to the subject the immune checkpoint therapy of any preceding aspect. For example, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example, breast cancer (including, but not limited to triple negative breast cancer), colon cancer, and melanoma), Alzheimer’s disease, or an autoimmune disease comprising administering to a subject an immune checkpoint therapy comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor.

150. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease, wherein the first therapeutic peptide is a programmed cell death- 1 (PD- 1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. In one aspect, the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11. In some aspects, the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20. For example, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20.

151. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6). and a linker (such as, for example. SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24. and SEQ ID NO: 25. In one aspect, the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11. Also disclosed herein are methods wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27. SEQ ID NO: 28 or SEQ ID NO: 29. For example, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

152. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease, wherein the first therapeutic peptide is a programmed cell death ligand-1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13. SEQ ID NO: 14. SEQ ID NO: 15. and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25. In one aspect the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20. Also disclosed herein are methods wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29. For example, in one aspect disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

153. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab. tislelizumab. INCMGA00012. AMP- 224, AMP -514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C. and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

154. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope (such as, for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6), and a linker (such as, for example, SEQ ID NO: 7) joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012. AMP- 224, AMP -514, CT-011. MK-3475, and acrixolimab). an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

155. Also disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease, wherein the first therapeutic peptide is a cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope (such as. for example, a measles virus fusion protein peptide including, but not limited to SEQ ID NO: 6). and a linker (such as. for example. SEQ ID NO: 7) joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab. dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab).

156. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer’s disease, or an autoimmune disease of any preceding aspect, wherein the cancer is selected from the group of cancers consisting of lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin’s Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma, neuroblastoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer (including, but not limited to triple negative breast cancer), epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancer; testicular cancer; prostatic cancer, or pancreatic cancer.

157. In one aspect, it is understood that the disclosed compositions can be combined with other treatments for a given disease or condition. For example, in one aspect, disclosed herein are methods of treating a cancer comprising administering to a subject a chimeric PD-1 peptide, a chimeric PD-L1 peptide, chimeric CTLA-4 peptide, an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP- 224, AMP -514, CT-011. MK-3475, and acrixolimab). an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170), and/or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab); wherein the disease or condition is breast cancer, and wherein the method further comprises administering to the subject one or more HER-2 B cell epitopes (for example, one or more of the HER-2 peptides as set forth in SEQ ID NO: 37 or 39 or chimeric MVF-HER-2 peptides as set forth in SEQ ID NO: 38 or 40) and/or one or more anti-HER-2 antibodies. It is understood that where a HER-2 B cell epitope or anti- HER-2 antibody is administered to the subject, the administration can be as a separate concurrent administration, prior administration of the HER-2 B cell epitope or anti-HER-2 antibody, subsequent administration of the HER-2 B cell epitope or anti-HER-2 antibody, or a HER-2 B cell epitope or anti-HER-2 antibody that is a component in the same pharmaceutical formulation as the chimeric PD-1 peptides, chimeric PD-L1 peptides, chimeric CTLA-4 peptides. For example, a method of treating breast cancer can comprise administering to a subject a immune checkpoint therapy comprising one or more of the chimenc PD-1 peptides, chimeric PD-L1 peptides, chimeric CTLA-4 peptides, anti-PD-1 antibodies, anti-PD-Ll antibodies, and/or anti-CTLA-4 antibodies set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5; SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19; SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, and/or SEQ ID NO: 29: the method further comprising administering to the subject one or more HER-2 B cell epitopes HER-2(266-296) as set forth in SEQ ID NO: 37 and/or HER-2 (597-626) as set forth in SEQ ID NO: 39 and/or chimeric epitopes MVF-HER-2 (266-296) peptide (for example as set forth in SEQ ID NO: 328, and a MVF-HER-2 (597-626) peptide (for example as set forth in SEQ ID NO: 40). Accordingly, in one aspect, disclosed herein is a method of treating breast cancer comprising administering to a subject with a breast cancer a pharmaceutical composition comprising any combination of i) a MVF-PD1 (92-110) as set forth in SEQ ID NO: 11; a MVF- PD-L1 (130-147) as set forth in SEQ ID NO: 20, MVF-CTLA-4 (130-150) as set forth in SEQ ID NO: 29. an anti-PD-1 antibody (such as, for example, pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab. vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011 , MK-3475, and acrixolimab), an anti-PD-Ll antibody (such as, for example, atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibehmab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170). or an anti-CTLA-4 antibody (such as, for example, ipilimumab and tremelimumab) and ii) a MVF-HER-2 (266-296) peptide (for example as set forth in SEQ ID NO: 38), and a MVF-HER-2 (597-626) peptide (for example as set forth in SEQ ID NO: 40).

158. In one aspect, disclosed herein are methods of treating, reducing, inhibiting, decreasing, ameliorating, and/or preventing a cancer and/or metastasis, Alzheimer's disease, or an autoimmune disease of any preceding aspect, wherein the autoimmune disease is selected from the group consisting of Psoriasis, Alopecia Areata, Primary biliary cirrhosis, Autoimmune poly endocrine syndrome, Diabetes mellitus type 1, autoimmune thyroiditis, Systemic Lupus Erythematosus, Multiple sclerosis. Guillain-Barre syndrome, Grave’s disease, Sjogren’s syndrome, ulcerative colitis. Autoimmune hemolytic anemia. Pernicious anemia. Psoriatic arthritis, rheumatoid arthritis, relapsing polychondritis, myasthenia gravis, Acute disseminated encephalomyelitis, and Granulomatosis with polyangiitis.

D. Examples

159. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

1. Example 1: Selection, Design, and Modeling of Peptide Epitopes for PD-1

160. The selection of candidate B-cell epitopes expressed on the surface of PD-1 was accomplished by an in-house (PEPTIDE COMPANION™, 5x.com) computer-aided analysis using six correlates of antigenicity' reviewed by Kaumaya et al: (a) The profiles of chain flexibility and mobility of individual sequences were calculated according to Karplus and Schultz; ) Hydropathy profiles were generated over a seven residue span setting and then smoothed with a three-residue span using the scale of Kyte and Doolittle; (c) Hydrophilicity profiles over a six-residue window were generated using the program of Hopp and Woods; (d) Analysis of the exposure of an amino acid residue to water (1.4A probe) was carried out by the solvent exposure algorithm; (e) Protrusion indices were calculated by the method of Thornton et al. that predicts portions of proteins that are accessible and protrude into the solvent; (/) The probability that a five-residue sequence is antigenic was determined by the method of Welling et al , Sequences were given a score of 1 to 6 based on their respective index values and were ranked: the highest ranking sequences had the highest individual score for the analyses examined (6/6), and successive candidates had the next highest score (5/6). etc. The best scoring epitopes were further ranked by correlation with their secondary structural attributes; e.g., an amphiphilic a-helical sequence or a P-tum loop regions are preferred over a random coil fragments. Computer programs by Chou and Fasman and Novotny et al. were used to predict the secondary structure (a-helix. -strand/sheet. P-tum/loop, random coil) and a-helical amphiphilic moment. Finally, consideration was given to the individual amino acid sequence. Electrostatic ion pairs and helix dipole interaction in helical segment were also considered (e.g., hydrophobic/hydrophilic balance). The sequences receiving the highest scores are displayed in Table 4. Employing this method, four of the twelve highest scoring B-cell epitope sequences of human PD-1 were prioritized. Amino acid 32-50, 45-64, 73-90 and 92-110 were chosen for evaluation in combination with information from the crystal structure of PD-1 :PDL1 (20). The structures of human PD-1 (PDB 3RRQ) and human PD-L1 (PDB 3BIS, 3FN3, 4Z18, 5C3T) have been determined, but those in turn did not account for significant plasticity within the human PD-1 upon complex formation demonstrated only very recently by the structure of the fully human PD-1/PD-L1 complex. Although the above structures provided a complete description of the interaction, the flat surface of the protein-protein interface still complicates drug design efforts in the absence of structural information on the small-molecule inhibitors in complex with either PD-1 or PD-L1 to guide further rational drug development. The crystal structure demonstrates that the receptor-ligand interaction is mediated in its major part by residues of COCFG strands within both PD-1 and PDL1. The protein-protein contacts involve both hydrophobic interactions and polar interactions, and bury a total surface area of 1,970 A2. The interaction is constructed around a central hydrophobic core contributed by both partners and constituted by nonpolar residues in the front sheet of PD-1 (Val64, Ilel 26, Leul28, Alal32, Ilel 34) and those of the front sheet of PD-L1 (LIle54, LTyr56, LMetl l5, LAlal21, LTyrl23), including a characteristic alkyl-p interaction of the side chains of Ilel34 and LTyrl23. This hydrophobic region is open to the solvent on the would-be antigen-binding site, and is neighbored by a buried region of mixed polar/nonpolar interactions on the opposite side of the molecule. Both these regions are surrounded by a peripheral network of polar residues (safe on the CDR loop side) providing additional hydrogen bond-mediated interactions between the receptor and the ligand. The structure shows that hPD-1, comprising residues 16-127 of the mature polypeptide, consists of a two-layer sandwich with the topology of IgSF domains (i.e. twoP sheets (GFCC and ABED) stabilized by a disulfide bond (Cys34- Cysl03).

TABLE 4, human PD-1 predicted B-cell epitopes

2. Example 2: Synthesis, Purification, and Characterization of PD-1 peptides and MVF-PD-1 peptides

161. Peptide synthesis was performed using 9600 Milligen/Biosearch solid-phase peptide synthesizer (Millipore, Bedford, MA) using Fmoc/Aoc chemistry. Clear amide resin (0.50 mmol/gm) (Peptide International, Louisville, KY) and Fmoc protected amino acids (P3BioSystems, Louisville, KY) were used for synthesis of all of the peptides. In the case of the chimeric peptides, the B cell epitopes were colinearly synthesized with the promiscuous Th MVF (residues 288-302) epitope using regioselective side chain protections and a GPSL linker. Some of the B cell epitopes were acetylated using Acetylimidazole (Sigma- Aldrich St. Louis, MO) in DMF. The peptides were reacted overnight then washed with DMF before cleavage. Peptides were cleaved using reagent R (trifluoroacetic acid: TFA: Thiansole: EDT: Anisole, 90:5:3:2)(Sigma-Aldrich, St. Louis, MO) The crude peptides were purified by reverse-phase HPLC in a gradient system using a C-4 vydac column in water/acetonitrile (0. 1% trifluoroacetic acid) on a Waters system. At the end of purification, the pure fractions were then analyzed in analytical HPLC, and fractions of interest were pooled together and lyophilized in 10% acetic acid solution. The final purified peptides listed in Table 5 were then identified using mass spectrometry (Campus Chemical Instrumentation Center, The Ohio State University, Columbus, OH).

Table 5: Peptide Sequences of PD-1

3. Example 3: Identification of peptide epitopes for huPD-Ll

162. The selection of candidate B-cell epitopes expressed on the surface of PD-L1 was accomplished by an in-house (Peptide Companion™, 5x.com) computer-aided analysis using six correlates of antigenicity, described as follows: (a) The profiles of chain flexibility and mobility of individual sequences were calculated; (6) Hydropathy profiles were generated over a seven residue span setting and then smoothed with a three-residue span using the scale of Kyte and Doolittle; (c) Hydrophilicity profiles over a six-residue window were generated using the program of Hopp and Woods; ( ) Analysis of the exposure of an amino acid residue to water (1 4A probe) was carried out by the solvent exposure algorithm; (e) Protrusion indices were calculated that predicts portions of proteins that are accessible and protrude into the solvent; (f) The probability that a five-residue sequence is antigenic w as determined by the method of Welling et al. Sequences were given a score of 1 to 6 based on their respective index values and were ranked: the highest ranking sequences had the highest individual score for the analyses examined, and successive candidates had the next highest score, etc.

163. The best scoring epitopes were further ranked by correlation with their secondary' structural attributes; e.g. an amphiphilic a-helical sequence or a P-tum loop regions are preferred over a random coil fragments. Computer programs by Chou and Fasman and Novotny et al. were used to predict the secondary structure (a-helix, P-strand/sheet, P-tum/loop, random coil) and a-helical amphiphilic moment. Finally, consideration was given to the individual amino acid sequence. Electrostatic ion pairs and helix dipole interaction in helical segment w ere also considered (e.g., hydrophobic/hydrophilic balance).

164. Peptide epitope mapping using algorithms of immunogenicity /antigenicity was used to identify 4 epitopes of PD-L1 and the analysis of these epitopes was combined with crystal structures complex of human PD-l/human PD-L1 (hPD-l/hPD-Ll) as disclosed by Zak et al. in 2015 (PDB ID: 4ZQK) to engineer a chimeric B-cell vaccine based on the extracellular domain of PD-1. The selection was further enhanced by examining the 3-D structure of PD-1 (PDB ID code: 4Z18, 4ZQK, 3BIK). All the four epitopes were modelled using PyMOL 3-D modeling software DeLano WL (2002) The PyMOL User ’s Manual. The sequences receiving the highest scores are displayed in Table 6. Employing this method, four of the twelve highest scoring B-cell epitope sequences of human PD-L1, amino acid 36-53, 50-67. 95-112 and 130- 147 were chosen for evaluation in combination with information from the crystal structure of PD-LPDLl.

TABLE 6, human PD-L1 predicted B-cell epitopes

165. The structures of human PD-1 (PDB 3RRQ) and human PD-L1 (PDB 3BIS, 3FN3, 4Z18, 5C3T) have been determined, but those in turn did not account for significant plasticity within the human PD-1 upon complex formation demonstrated only very recently by the structure of the fully human PD-1/PD-L1 complex. Although the above structures provided a complete description of the interaction, the flat surface of the protein-protein interface still complicates drug design efforts in the absence of structural information on the small-molecule inhibitors in complex with either PD-1 or PD-L1 to guide further rational drug development. The crystal structure demonstrates that the receptor-ligand interaction is mediated in its major part by residues of COCFG strands within both PD-1 and PDL1. The protein-protein contacts involve both hydrophobic interactions and polar interactions, and bury a total surface area of 1,970 A2. The interaction is constructed around a central hydrophobic core contributed by both partners and constituted by nonpolar residues in the front sheet of PD-1 (Vai 64, He 126, Leul28, Alai 32, Ilel 34) and those of the front sheet of PD-L1 (LIle54, LTyr56, LMetl l5, LAlal21, LTyrl23), including a characteristic alkyl-p interaction of the side chains of Ilel 34 and LTyrl23. This hydrophobic region is open to the solvent on the would-be antigen-binding site, and is neighbored by a buried region of mixed polar/nonpolar interactions on the opposite side of the molecule. Both these regions are surrounded by a peripheral network of polar residues (safe on the CDR loop side) providing additional hydrogen bond-mediated interactions between the receptor and the ligand.

4. Example 4: Synthesis of peptide epitopes for huPD-Ll

166. Four novel peptide sequences that were identified to target human PD-L1 were then synthesized using a 9600 Milligen/Biosearch solid-phase peptide synthesizer (Millipore, Bedford, MA, USA) with Fmoc/t-Butyl chemistry' and PyBOP/6Cl-HOBT coupling reagents on CLEAR amide resin (Peptides International. Louisville, KY, USA). Some peptide samples were acetylated using 1 -Acetylimidazole (Sigma-Aldrich St. Lois, MO, USA) before cleavage. All peptides were synthesized as chimeric constructs with a promiscuous T helper epitope derived from the measles virus fusion protein (MVF, amino acids 288-302) using a four residue linker (GPSL). Peptides were cleaved from the resin using cleavage reagent R (TFA)/thioanisole/EDT/anisole (90/5/3/2), and crude peptides were purified by semi preparative (C-4 Vydac columns) reversed-phase-high performance liquid chromatography (RP-HPLC; Waters, Bedford, MA, USA). RP-HPLC fractions showing the same retention time were pooled together and lyophilized. All peptides showed purity' in excess of 95%. Samples were then characterized by MALDI (Matrix Assisted Laser Desorption Ionization mass spectroscopy at the CCIC (Campus Chemical Instrumentation Center. The Ohio State University, Columbus, OH, USA) and analyzed on an analytical RP-HPLC system (Waters, Bedford, MA, USA). All peptides had the correct molecular mass.

Table 7: Peptide Sequences of PD-L1

5. Example 5: Selection, Design, and Modeling of Peptide Epitopes for CTLA-4

167. The selection of candidate B-cell epitopes expressed on the surface of CTLA-4 was accomplished by an in-house (Peptide Companion™, 5x.com) computer-aided analysis using six correlates of antigenicity reviewed by Kaumaya et al: (a) The profiles of chain flexibility and mobility⁷ of individual sequences w ere calculated according to Karplus and Schultz; (b) Hydropathy profiles were generated over a seven residue span setting and then smoothed with a three-residue span using the scale of Kyte and Doolittle; (c) Hydrophilicity profiles over a six- residue window were generated using the program of Hopp and Woods; (d) Analysis of the exposure of an amino acid residue to w ater (1.4A probe) was carried out by the solvent exposure algorithm of Rose et al. (e) Protrusion indices were calculated by the method of Thornton et al. that predicts portions of proteins that are accessible and protrude into the solvent; (/) The probability that a five-residue sequence is antigenic w as determined by the method of Welling et al. ; Sequences were given a score of 1 to 6 based on their respective index values and were ranked: the highest ranking sequences had the highest individual score for the analyses examined (6/6), and successive candidates had the next highest score (5/6). etc. The best scoring epitopes were further ranked by correlation with their secondary structural attributes; e.g., an amphiphilic a-helical sequence or a P-tum loop regions are preferred over a random coil fragments. Computer programs by Chou and Fasman and Novotny et al. were used to predict the secondary structure (a-helix. -strand/sheet, P-tum/loop, random coil) and a-helical amphiphilic moment. Finally, consideration was given to the individual amino acid sequence. Electrostatic ion pairs and helix dipole interaction in helical segment were also considered (e.g., hydrophobic/hydrophilic balance). The sequences receiving the highest scores are displayed in Table 8. Employing this method, four of the twelve highest scoring B-cell epitope sequences of human CTLA-4 were prioritized. Amino acid 59-77; 75-92; 92-114 and 130-150 were chosen for evaluation in combination with information from the crystal structure of CTLA-4 :B7-l/B7-2. The structures of human CTLA-4, B7-1, and B7-2 have been determined, but those in turn did not account for significant plasticity within the human CTLA-4 upon complex formation demonstrated only very recently by the structure of the fully human CTLA-4:B7-l/B7-2.

Although the above structures provided a complete description of the interaction, the flat surface of the protein-protein interface still complicates drug design efforts in the absence of structural information on the small-molecule inhibitors in complex with CTLA-4 to guide further rational drug development.

6. Example 6: Synthesis, Purification, and Characterization of CTLA-4 peptides and MVF-CTLA-4 peptides

168. Peptide synthesis was performed using 9600 Milligen/Biosearch solid-phase peptide synthesizer (Millipore, Bedford, MA) using Fmoc/Roc chemistry. Clear amide resin (0.50 mmol/gm) (Peptide International, Louisville, KY) and Fmoc protected amino acids (P3BioSystems, Louisville, KY) were used for synthesis of all of the peptides. In the case of the chimeric peptides, the B cell epitopes were colinearly synthesized with the promiscuous Th MVF (residues 288-302) epitope using regioselective side chain protections and a GPSL linker. Some of the B cell epitopes were acetylated using Acetylimidazole (Sigma- Aldrich St. Louis, MO) in DMF. The peptides were reacted overnight then washed with DMF before cleavage. Peptides were cleaved using reagent R (trifluoroacetic acid: TFA: Thiansole: EDT: Anisole, 90:5:3:2)(Sigma-Aldrich, St. Louis, MO). The crude peptides were purified by reverse-phase HPLC in a gradient system using a C-4 vydac column in water/acetonitrile (0.1% trifluoroacetic acid) on a Waters system. At the end of purification, the pure fractions were then analyzed in analytical HPLC, and fractions of interest were pooled together and lyophilized in 10% acetic acid solution. The final purified peptides listed in Table 9 were then identified using mass spectrometry (Campus Chemical Instrumentation Center, The Ohio State University, Columbus, OH). Table 9: Peptide Sequences of CTLA-4

7. Immunogenicity, antibodies isotype distribution in immunized BALB/c mice

169. Female BALB/c mice (6-8 weeks old) were immunized with combinations of MVF-PD-1, MVF-PD-L1, and MVF-CTLA-4 peptide with three weeks intervals as indicated (Figure 1). Each mice was received 100 pl of total 100 pg peptide vaccine mixed with ISA 720 (v:v=l : 1). The mice were boosted twice with three weeks intervals. Blood was collected weekly to monitor the antibody titers after the immunization. Antibodies against each peptide epitope were measured (Figure 2).

170. Additionally, the isotype of responding antibodies was measured for each epitope (Figure 3). Mice receiving the combination of PD-1 and PD-L1 peptides showed anti-PD-1 antibodies that were 45% IgGl, 15% IgG2a, 9%, IgG2b, and 16% IgG3. Antibodies against Pd- L1 were revealed antibody isotype having 39% IgGl, 24% IgG2a, 16% IgG2b, and 10% IgG3. Measuring the isotype of the antibodies against PD-L1 and CTLA-4 when PD-L1 and CTLA-4 peptides were administered showed a more even distribution of anti-PD-Ll antibodies across all isotypes. In particular, the anti-PD-Ll antibodies were 25% IgGl, 33% IgG2a, and 32% IgG2b. Anti-CTLA-4 antibodies had an isotype distribution of 30% IgGl, 25% IgG2a, and 30% IgG2b. When PD-1 and CTLA-4 peptides were co-administered, the anti-PD-1 antibodies showed a slight increase in IgG2b isotype antibodies but was otherwise the same as the isotype profile when PD-1 and PD-L1 were co-administered. CTLA-4 also showed a similar pattern as in other co-administrations but had slightly less IgGl and more IgG2a. 8. Immunogenicity and survival in PD-1/PD-L1 immunized BALB/c mice following CT26 challenge.

171. Wanting to see the effect of the combination immunization to tumor challenge, we next investigated the effect of PD-1 and PD-L1 peptide immunizations in a CT26 colon cancer model. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-PD-1(92)+MVF-PD-L1(36) or MVF-PD-1(92)+MVF- PD-Ll(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with CT26 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti-mouse PD-1 antibody (clone 29F.1A12) plus anti-mouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge (Figure 4A). Tumor growths were observed and measured by calipers; Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2.

172. The immunogenicity of each peptide in BALB/c mice immunized with various peptide constructs. Sera were tittered against each individual peptide immunogen. Titers are defined as the highest dilution of sera with an absorbance value of 0.2 after subtracting the blank. As expected, antibodies titers increased against each peptide (Figure 4B). Next we looked at tumor growth was observed using a two-way ANOVA and show n in line curves (Figure 4C) or plots of tumor volume LWW at day 14 and day 16 for each of group using a oneway ANOVA analysis (Figure 4D). Between two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated, mAbs vs PBS p<0.05; MVF-PD-1(92)+MVF-PD-L1(36) vs PBS with p<0.05; MVF-PD- 1(92)+MVF-PD-L1(13O) vs PBS with p<0.01. Figure 4E show s survival curves comparison.

9. Immunogenicity and survival in PD-1/PD-L1 immunized BALB/c mice following D2F2 and 4T1 challenge.

173. To test the effect of PD-1 and PD-L1 peptide immunizations in D2F2 and 4T1 breast cancer models, BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old w ere immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-PD-1(92)+MVF-PD-L1(36) or MVF-PD-1(92)+MVF- PD-Ll(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted wi th D2F2 or 4T1 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti-mouse PD-1 antibody (clone 29F.1A12) plus anti-mouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge (Figure 5A). Tumor growths were observed and measured by calipers; Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2.

174. Next we looked at tumor growth was observed using a two-way ANOVA and shown in line curves for D2F2 (Figure 5B) and 4T1 (Figure 5D) or plots of tumor volume LWW at day 14 and day 16 for each of group using a one-way ANOVA analysis for D2F2 (Figure 5C) and 4T1 (Figure 5E). Betw een two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated, mAbs vs PBS p<0.05; MVF-PD-1(92)+MVF-PD-L1(36) vs PBS with p<0.05; MVF-PD-1(92)+MVF-PD-L1(13O) vs PBS with p<0.01. In both breast cancer models, the PD-1/PD-L1 combination peptide vaccines showed significant reduction in tumor volume comparable to dual administration of anti-PD-1 and anti-PD-Ll antibodies. Figure 5F shows the percent survival in combination immunized mice following D2F2 and 4T1 challenge. Similar to the tumor volume results, the PD-1/PD-L1 combination peptide vaccines showed significant increased survival comparable to dual administration of anti-PD-1 and anti-PD-Ll antibodies in both breast cancer models.

10. Immunogenicity and survival in PD-l/CTLA-4 immunized BALB/c mice following CT26, D2F2 and 4T1 challenge.

175. Expanding our study to peptide combination immunizations other than PD-l/PD- L1 peptide combinations, we investigated the effect of PD-l/CTLA-4 peptide combination immunizations in colon (CT26) and breast cancer (D2F2 and 4T1) tumor models. Figure 6A shows the immunization and challenge protocol. As with earlier studies. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three w eeks apart. Mice were immunized with combination peptide vaccines, MVF-PD- l(92)+MVF-CTLA-4(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with CT26, D2F2, or 4T1 tumor cells 10⁵ per mouse. Control mice w ere treated twice weekly with PBS as negative control or with anti -mouse PD-1 antibody (clone 29F.1A12) plus anti -mouse CTLA-4 antibody (clone 9H10) as positive control starting 2 days after tumor challenge (Figure 6A). Tumor growths were observed and measured by calipers; Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. 176. Tumor growth was observed using a two-way ANOVA and shown in line curves for CT26 (Figure 6B), D2F2 (Figure 6D), and 4T1 (Figure 6F) or plots of tumor volume LWW at day 14 and day 16 for each of group using a one-way ANOVA analysis for CT26, (Figure 6C), D2F2 (Figure 6E) and 4T1 (Figure 6F). Between two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated. mAbs vs PBS p<0.05; MVF-PD-1(92)+ MVF-CTLA-4(130) vs PBS with p<0.01. In the CT26 colon cancer model and both breast cancer models, the PD-l/CTLA-4 combination peptide vaccines showed significant reduction in tumor volume comparable to dual administration of anti-PD-1 and anti-CTLA-4 antibodies. Figure 7 shows the percent survival in combination immunized mice following CT26, D2F2, and 4T1 challenge. Here, the PD-l/CTL-4 combination peptide vaccines showed significant increased survival comparable to dual administration of anti-PD-1 and anti-CTLA-4 antibodies in the CT26 challenge, but impressively showed survival surpassing antibody immunization in both breast cancer models.

11. Immunogenicity and survival in PD-L1/CTLA-4 immunized BALB/c mice following D2F2 and 4T1 challenge.

177. To see if the improvements observed with PD-1 and CTLA-4 combination therapy was limited to those peptides found on T cells or would be observed using other peptide combinations BALB/c mice vaccination and tumor engraftment. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-CTLA- 4(130)+MVF-PD-Ll(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with 4T1 or D2F2 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti-mouse CTLA-4 antibody (clone 9H10) plus antimouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge. Tumor growths were observed and measured by calipers. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2.

178. Tumor grow th was observed using a two-way ANOVA and show n in line curves for D2F2 (Figure 8B) and 4T1 (FigureD) or plots of tumor volume LWW at day 14 and day 16 for each of group using a one-way ANOVA analysis for D2F2 (Figure 8C) and 4T1 (Figure 8D). Between two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated, mAbs vs PBS p<0.05; MVF-PD- Ll(130)+MVF-CTLA-4(130). In the CT26 colon cancer model and both breast cancer models, the PD-L1/CTLA-4 combination peptide vaccines showed significant reduction in tumor volume comparable to dual administration of anti-PD-Ll and anti-CTLA-4 antibodies. Figure 8F shows the percent survival in combination immunized mice following D2F2 and 4T1 challenge. Here, the PD-L1/CTL-4 combination peptide vaccines showed significant increased survival comparable to dual administration of anti-PD-Ll and anti-CTLA-4 antibodies in the both breast cancer models.

12. Immunogenicity and survival in PD-L1/CTLA-4 immunized BALB/c mice following CT26 challenge

179. We next investigated the effect of PD-L 1 and CTL-4 peptide immunizations in CT26 colon cancer models. Figures 9A and 10A show the scheme of BALB/c mice vaccination and tumor engraftment. BALB/c mice (10 mice per group, one or two mice lost in some group due to non-immunization related reason) of 6-8 weeks old were immunized with MVF-peptide immunogens emulsified in ISA 720 with 3 times and three weeks apart. Mice were immunized with combination peptide vaccines, MVF-CTLA-4(59)+MVF-PD-Ll(36); MVF-CTLA- 4(59)+MVF-PD-L 1 ( 130); MVF-CTLA-4(130)+MVF-PD-Ll (36); MVF-CTLA-4( 130)+MVF- PD-Ll(130) prior to tumor challenge. Blood was collected as indicated and sera tested for antibody titers by ELISA. 2 weeks after the third immunization (3Y), the mice were engrafted with CT26 tumor cells 10⁵ per mouse. Control mice were treated twice weekly with PBS as negative control or with anti-mouse CTLA-4 antibody (clone 9H10) plus anti-mouse PD-L1 antibody (clone 10F.9G2) as positive control starting 2 days after tumor challenge. Tumor grow ths were observed and measured by calipers. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2. The immunogenicity of each peptide in BALB/c mice immunized with various peptide constructs (Figure 9B). Tumor growth was observed using a two-way ANOVA and shown in line curves for CT26 (Figures 9C and 10B) or plots of tumor volume LWW at day 14 and day 16 for each of group using a one-way ANOVA analysis for CT26 (Figure 9D or 10C). Between two groups comparison indicated, each of the treatment group vs PBS group with significant smaller tumor volume, p value as indicated. mAbs vs PBS p<0.05; MVF-PD-Ll(130)+MVF-CTLA-4(130). Figure 9E and 10D show' survival curves using the CT26 colon cancer model. Here w e observed that the combination peptide immunization performed as well as the combination of anti-PD-Ll and anti-CTLA-4 antibodies.. 13. Immunogenicity, antibodies isotype distribution in PD-1/PD-L1 immunized and anti-PD-l/anti-PD-Ll antibody immunized BALB/c mice following CT26 challenge.

180. Next we wanted to know the effect of combination PD-1 and PD-L1 peptide vaccines followed by treatment with anti-PD-Ll monoclonal antibody (10F.9G2) in CT26 tumor model. BALB/c mice were vaccinated with single peptide vaccine before challenging with CT26 tumor cells, each group indicated as following: MVF-PD-1 (92); MVF-PD-L1 (36); and MVF-PD-L1 (130)(Figure 11A). Mice were immunized at 3 weeks interval. 0.1 mg each peptide cancer vaccine were used per mouse and boosted with the designed doses for even’ 3 weeks intervals. Blood was collected weekly for monitoring antibody titers. After 2 weeks of the third time immunization (3Y), mice were challenged with 1X10⁵ per mouse CT26 tumor cells. After tumor challenge, the positive control group, we treat the mice with anti-mouse PD-L1 antibody (clone 10F.9G2) twice a week for at least up to three weeks, and the negative control group was treated with PBS. At the same time, all the immunized mice group were treated with anti-mouse PD-L1 antibody (clone 10F.9G2) twice a week for at least up to three weeks. Tumor volume was calculated as: Tumor volume (LWW) =(Length X Width X Width)/2.

181. As with other combination therapies, we observed that the immunogenicity for each petide increased with each immunization (Figure 1 IB). Tumor growth was measured using a two-way ANOVA and shown in line curves (Figure 1 1C) or one way ANOVA and displayed as plots (Figure 1 ID) at days 14 and 16 post challenge. All test groups showed significant reduction in tumor volume relative to untreated controls. We also measured survival following CT26 tumor challenge. Here, the combination of either MVF+PD-1 peptide and anti-PD-Ll antibody or MVF+PD-L1 peptide and anti-PD-Ll antibody showed increased survival relative to peptide or antibody alone..

14. Materials and Methods a) Animals: Rabbits and BALB/c mice

182. All experiments were performed in accordance with the U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals and approved by the Ohio State University Institutional Animals Care and Use Committee and detailed in the approved protocol. New Zealand white female rabbits and BALB/c female mice were purchased from Charles River Laboratories (Wilmington. MA, USA). All animal care and use was in accordance with ULAR (University Laboratory Animal Resources) institutional guidelines. b) Animal immunization

183. For each peptide, vaccine antibodies were raised using female New Zealand white rabbits (>2 Kg/8-10 weeks of age) purchased from Charles River Laboratories (Wilmington, MA, USA). Rabbits were immunized with Img each of two chimeric peptides chosen between chimeric MVF linked PD-1 peptides, chimeric MVF linked PD-L1 peptides, and chimeric MVF linked CTLA-4 peptides and boosted twice at three weeks and at six weeks. BALB/c mice w ere immunized with 100 pg MVF linked peptides. The four chimeric peptide based candidate vaccines were used to immunize all animals. BALB/c female mice (5-6 weeks old) were immunized with chimeric peptide immunogens 3 times at 3 week intervals referred to as primary immunization (1Y), first boost (2Y) and second boost (3Y). The mice sera were collected every week after secondary and tertiary immunization (2Y, 2Y+1, 2Y+2, 3Y, 3Y+1 and 3Y+2), and stored at -20° C for future use. (Figure 1) c) Cell lines

184. CT26 wild type (CT26 WT) and 4T1 tumor cell lines were purchased from ATCC (Manassas, VA, USA). Mouse mammary carcinoma cell line D2F2 wild type was kindly provided by Professor Wei-Zen Wei (Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA). D2F2 is sy ngeneic to BALB/c mice murine mammary tumor cells. CT26 WT and 4T1 cell lines were maintained in DMEM/RPMI- 1640 basic medium. D2F2 cell line was maintained in DMED with 10% NCTC-109 medium (Invitrogen, Waltham, MA, USA) and IX MEM Non-Essential Amino Acids Solution (ThermoFisher, Rockford, IL, USA). All cell culture media were supplied with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 pg/ml streptomycin. d) Enzyme-linked immunosorbent assay (ELISA)

185. Immunogenicity was evaluated by ELISA as per our laboratory standard protocols. Briefly, 96-well plates were coated with 100 pl of peptide as antigen at 2 pg/ml in PBS overnight at 4° C. Nonspecific binding sites were blocked for 1 h with 200 pl PBS (Research Products International. Mt Prospect. IL, USA. CAS No. 7647-145) 1% BSA (Bovine serum albumin, Thermo Fisher Scientific, Waltham, WA, USA, BP9703-100), and plates were washed with washing buffer (PBS diluted 0.05% Tween 1% horse serum). Vaccine antibodies in blocking buffer (PBS 1% BSA) were added to antigen-coated plate in duplicate wells, serially diluted 1 :2 in blocking buffer, and incubated for 2 h at room temperature. After washing the plate, the secondary antibody 100 pl of 1 :500 goat anti-mouse IgG conjugated to horseradish peroxidase (Invitrogen, Waltham, MA, USA, REF:31430) were added to each well and incubated for 1 h. After w ashing, the antibody w as detected using substrate solution (50 pl of 0. 15% H2O2 in 24 mM citric acid and 5 mM sodium phosphate buffer (pH 5.2) with 0.5 mg/ml 2, 2’-aminobis (3-ethylbenzthiazole-6-sulfonic acid, ABTS, Sigma, St. Louis, MO, USA) as the chromophore. Color development proceeded for 10 min, and the reaction was stopped with25 pl of 1% SDS (sodium dodecyl sulfate. Thermo Scientific. Waltham, WA, USA, Prod#28312). Absorbance was read at 415 nm using an ELISA Microplate reader (Molecular Devices, SPECTRAmax PLUS384, San Jose, CA, USA). e) Recombinant protein activity assay

186. For the detection of antibody reactivity with human CTLA-4 recombinant protein (CTLA-4, CT4-H5229, HIS tag, ACROBiosy stems. Newark, DE, USA) Ipg recombinant protein in 100 pl of PBS or the concentration as indicated in the figures was used to coat wells overnight at 4 °C. After the overnight incubation, nonspecific binding sites were blocked for 1 h with 200 pl PBS 1% BSA, and plates were washed with washing buffer (PBS diluted 0.05% Tween l%horse serum). Vaccine antibodies in blocking buffer were added to antigen-coated plate in duplicate wells, serially diluted 1:2 in blocking buffer, and incubated for 2 h at room temperature. After washing the plate, 100 pl of 1 :500 goat anti-mouse IgG conjugated to horseradish peroxidase (Invitrogen, Waltham, MA, USA, REF:31430) w ere added to each w ell and incubated for 1 h. The plate received a final w ash and 50 pl prepared substrate solution was added to each well (BIO-RAD, Hercules, CA. USA, Cat. #1721064). The reaction was stopped with 25 pl 5% SDS stopping buffer. Absorbance at 415nm was determined using a plate reader. f) Antibody isotyping assay

187. The assay was carried out by following the manufacturer’s instructions (BIORAD, Mouse Typer isotyping kit, Cat.#172-2055) and lab protocol. Briefly, mouse antibody isotypes (i.e. IgA, IgM. IgGl, lgG2a, lgG2b, and lgG3) were determined using the Mouse Typer isotyping Kit (BIO-RAD, Hercules, CA, USA, Cat. #172-2055). Briefly, wells of a 96-w-ell assay plate (COSTAR, Washington, D.C., USA, REF#2797) were coated with 100 pl of 2 pg/ml peptide antigen in ddH2O, and incubated at 4°C overnight. The plate was washed with washing buffer (0.05% tween-20 and 1% horse sera in PBS). The plate was blocked with 1% BSA in PBS at room temperature for 1 h. 100 pl of diluted sera was added to each well. Dilutions of each sera samples w ere determined by the ELISA titers absorbance of 0.4 or higher after subtracting the background. After washing the wells, 100 pl ready to use rabbit anti -mouse subclasses antibodies were added to each well respectively and incubated at room temperature for 2 h. The w ells w ere washed again, 100 pl (1/3000 dilution of goat anti-rabbit conjugated to HRP antibody (BIO-RAD, Hercules, CA, USA, Cat. #172-1019)) was added to each well and incubated for 1 h at room temperature in dark. The plate received a final wash and 50 pl prepared substrate solution was added to each well (BIO-RAD. Hercules, CA. USA. Cat. #1721064). The reaction was stopped with 25 pl 5% SDS stopping buffer. Absorbance at 415nm was determined using a plate reader. g) Statistical Analysis.

188. Mice challenged with tumor cells were monitored at least twice per week and tumor sizes were measured by calipers. Formula: Volume (LWW) = (Length X Width X Width)/2 was used to calculate tumor volumes. All values are showed as means ± standard deviation. Data statistical analysis was performed by GraphPad Prism 8.1.2 (GraphPad Software, Inc. San Diego, CA. USA) and the indicated statistical analysis. One-way analysis of variance (one-way ANOVA) and followed by the Tukey’s multiple comparisons test were used to compare data in multiple groups or data between groups in multiple groups. And the two-way ANOVA was used to analysis the whole curves comparison. The Log-rank (Mantel- Cox) test was use to compare the survival curves. P value or adjusted p value less than 0.05 was accepted as statistically significant different.

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F. Sequences

SEQ ID NO: 1 human PD1 residues 1-128

PPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQD

CRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKLQIKESLRAERVTERRAEVP

TAHPSPSP

SEQ ID NO: 2 PD1 (32-50)

VLNWYRMSPSNQTDKLAAF

SEQ ID NO: 3 PD1 (45-64)

KLAAFPEDRSQPGQDCRFR

SEQ ID NO: 4 PD1 (73-90)

DFHMSVVRARRNDSGTYL

SEQ ID NO: 5 PD1 (92-110)

GAISLAPKAQIKESLRAEL

SEQ ID NO: 6 Measles virus fusion protein (MVF)

KLLSLIKGVIVHRLEGVE

SEQ ID NO: 7 Linker

GPSL

SEQ ID NO: 8 MVF-PD1 (32-50)

KLLSLIKGVIVHRLEGVEGPSLVLNWYRMSPSNQTDKLAAF

SEQ ID NO: 9 MVF-PD1 (45-64)

KLLSLIKGVIVHRLEGVEGPSLKLAAFPEDRSQPGQDCRFR

SEQ ID NO: 10 MVF-PD1 (73-90)

KLLSLIKGVIVHRLEGVEGPSLDFHMSVVRARRNDSGTYL

SEQ ID NO: 11 MVF-PD1 (92-110)

KLLSLIKGVIVHRLEGVEGPSLGAISLAPKAQIKESLRAEL

SEQ ID NO: 12 human PD-L1 residues 1-273 AFTVTVPKDLYVVEYGSNMT1ECKFPVEKQLDLAALIVYWEMEDKNI1QFVHGEEDLK

VQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAP

YNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFN

VTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVA

LTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET

SEQ ID NO: 13 PD-L1 (36-53)

LIVYWEMEDKNIIQFVHG

SEQ ID NO: 14 PD-L1 (50-67)

FVHGEEDLKVQHS SYRQR

SEQ ID NO: 15 PD-L1 (95-112)

YRCMISYGGADYKRITVK

SEQ ID NO: 16 PD-L1 (130-147)

VTSEHELTCQAEGYPKAE

SEQ ID NO: 17 MVF- PD-L1 (36-53)

KLLSLIKGVIVHRLEGVEGPSLLIVYWEMEDKNIIQFVHG

SEQ ID NO: 18 MVF- PD-L1 (50-67)

KLLSLIKGVIVHRLEGVEGPSLFVHGEEDLKVQHS SYRQR

SEQ ID NO: 19 MVF- PD-L1 (95-112)

KLLSLIKGVIVHRLEGVEGPSLYRCMISYGGADYKRITVK

SEQ ID NO: 20 MVF- PD-L1 (130-147)

KLLSLIKGVIVHRLEGVEGPSLVTSEHELTCQAEGYPKAE

SEQ ID NO: 21 human CTLA residues 1-223

MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEY

ASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGL

RAMDTGLY1CKVEEMYPPPYYLGIGNGTQIYVIDPEPCPDSDFELWILAAVSSGEFFYSFL

LTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

SEQ ID NO: 22 CTLA-4 (59-77)

EYASPGKATEVRVTVLRQA

SEQ ID NO: 23 CTLA-4 (75-92)

RQADSQVTEVCAATYMMG

SEQ ID NO: 24 CTLA-4 (92-114)

GNELTFLDDSICTGTSSGNQVNFHMSVVRARRNDSGTYL

SEQ ID NO: 25 CTLA-4 (130-150)

KVELMYPPPYYLGIGNGTQIY

SEQ ID NO: 26 MVF-CTLA-4 (59-77)

KLLSLIKGVIVHRLEGVEGPSLEYASPGKATEVRVTVLRQA SEQ ID NO: 27 MVF-CTLA-4 (75-92)

KLLSLIKGVIVHRLEGVEGPSLRQADSQVTEVCAATYMMG

SEQ ID NO: 28 MVF-CTLA-4 (92-114)

KLLSLIKGVIVHRLEGVEGPSLGNELTFLDDSICTGTSSGNQVNFHMSVVRARRNDSGTY L

SEQ ID NO: 29 MVF-CTLA-4 (130-150)

KLLSLIKGVIVHRLEGVEGPSLKVELMYPPPYYLGIGNGTQIY

SEQ ID NO: 30 TT

NSVDDALINSTIYSYFPSV

SEQ ID NO: 31 TT1

PGINGKAIHLVNNQSSE

SEQ ID NO: 32 P2

QYIKANSKFIGITEL

SEQ ID NO: 33 P30

FNNFTVSFWLRVPKVS ASHLE

SEQ ID NO: 34 MVF (natural)

LSEIKGVIVHRLEGV

SEQ ID NO: 35 HBV

FFLLTRILTIPQSLN

SEQ ID NO: 36 CSP

TCGVGVRVRSRVNAANKKPE

SEQ ID NO: 37 HER-2 (266-296)

LHCPALVTYNTDTFESMPNPEGRYTFGASCV

SEQ ID NO: 38 MVF HER-2(266-296)

KLLSLIKGVIVHRLEGVEGPSLLHCPALVTYNTDTFESMPNPEGRYTFGASCV

SEQ ID NO: 39 HER-2 (597-626)

VARCPSGVKPDLSYMPIWKFPDEEGACQPL

SEQ ID NO: 40 MVF HER-2 (597-626)

KLLSLIKGVIVHRLEGVEGPSLVARCPSGVKPDLSYMPIWKFPDEEGACQPL

Claims

V. CLAIMS What is claimed is:

1. An immune checkpoint therapy comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor.

2. The immune checkpoint therapy of claim 1, wherein the immune checkpoint therapy comprises a first therapeutic peptide and a second therapeutic peptide.

3. The immune checkpoint therapy of claim 2, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand-1 (PD-L1) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

4. The immune checkpoint therapy of claim 3, wherein the Th epitope comprises a measles virus fusion protein peptide.

5. The immune checkpoint therapy of claim 4, wherein the Th epitope comprises SEQ ID NO: 6.

6. The immune checkpoint therapy of any of claims 3-5, wherein the linker comprises SEQ ID NO: 7.

7. The immune checkpoint therapy of any of claims 3-6, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

8. The immune checkpoint therapy of any of claims 3-7, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

9. The immune checkpoint therapy of claim 8, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20.

10. The immune checkpoint therapy of claim 2, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

11. The immune checkpoint therapy of claim 10, wherein the Th epitope comprises a measles virus fusion protein peptide.

12. The immune checkpoint therapy of claim 11 , wherein the Th epitope comprises SEQ ID NO: 6.

13. The immune checkpoint therapy of any of claims 10-12, wherein the linker comprises SEQ ID NO: 7.

14. The immune checkpoint therapy of any of claims 10-13, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8. SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

15. The immune checkpoint therapy of any of claims 10-14, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

16. The immune checkpoint therapy of claim 15, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

17. The immune checkpoint therapy of claim 2, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyle-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

18. The immune checkpoint therapy of claim 17, wherein the Th epitope comprises a measles virus fusion protein peptide.

19. The immune checkpoint therapy of claim 18, wherein the Th epitope comprises SEQ ID NO: 6.

20. The immune checkpoint therapy of any of claims 17-19, wherein the linker comprises SEQ ID NO: 7.

21. The immune checkpoint therapy of any of claims 17-20, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

22. The immune checkpoint therapy of any of claims 17-21, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

23. The immune checkpoint therapy of claim 22, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

24. The immune checkpoint therapy of claim 1, wherein the therapy comprises a first therapeutic peptide and an immune checkpoint inhibitor.

25. The immune checkpoint therapy of claim 24, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of wherein the immune

checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

26. The immune checkpoint therapy of claim 25, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab. nivolumab. cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab.

27. The immune checkpoint therapy of claim 25, wherein the checkpoint inhibitor is an anti- PD-L1 antibody selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-986189, KN035, cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170.

28. The immune checkpoint therapy of claim 25, wherein the checkpoint inhibitor is an anti- CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

29. The immune checkpoint therapy of claim 24, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti- CTLA-4 antibody.

30. The immune checkpoint therapy of claim 29, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab.

31. The immune checkpoint therapy of claim 29, wherein the checkpoint inhibitor is an anti- PD-Ll antibody selected from the group consisting of atezolizumab, avelumab, durvalumab. BMS-986189, KN035. Cosibelimab, AUNP12, BMS-936559, MPDL3280A. MSB0010718C, and CA-170.

32. The immune checkpoint therapy of claim 29, wherein the checkpoint inhibitor is an anti- CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

33. The immune checkpoint therapy of claim 24, wherein the first therapeutic peptide is a a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

34. The immune checkpoint therapy of claim 33, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab. nivolumab. cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab.

35. The immune checkpoint therapy of claim 33, wherein the checkpoint inhibitor is an anti- PD-Ll antibody selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-986189, KN035, Cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170.

36. The immune checkpoint therapy of claim 33, wherein the checkpoint inhibitor is an anti- CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

37. A method of treating a cancer. Alzheimer’s disease, or autoimmune disease in a subject comprising administering to the subject the immune checkpoint therapy of any of claims 1-36.

38. A method of treating a cancer, Alzheimer's disease, or an autoimmune disease in a subject comprising administering to a subject an immune checkpoint therapy comprising i) a first therapeutic peptide and ii) a second therapeutic peptide or an immune checkpoint inhibitor.

39. The method of claim 38, wherein the immune checkpoint therapy comprises a first therapeutic peptide and a second therapeutic peptide.

40. The method of claim 39, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2. SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) chimeric peptide comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

41. The method of claim 40, wherein the Th epitope comprises a measles virus fusion protein peptide.

42. The method of claim 41, wherein the Th epitope comprises SEQ ID NO: 6.

43. The method of claims 40-42. wherein the linker comprises SEQ ID NO: 7.

44. The method of claims 40-43, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

45. The method of claims 40-44, wherein the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

46. The method of claim 45, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the PD-L1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20.

47. The method of claim 39, wherein the first therapeutic peptide is a programmed cell death-1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 B cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24. and SEQ ID NO: 25.

48. The method of claim 47, wherein the Th epitope comprises a measles virus fusion protein peptide.

49. The method of claim 48. wherein the Th epitope comprises SEQ ID NO: 6.

50. The method of any of claims 47-49, wherein the linker comprises SEQ ID NO: 7.

51. The method of any of claims 47-50, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or SEQ ID NO: 11.

52. The method of any of claims 47-51, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

53. The method of claim 52, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

54. The method of claim 39, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the second therapeutic peptide is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25.

55. The method of claim 54, wherein the Th epitope comprises a measles virus fusion protein peptide.

56. The method of claim 55. wherein the Th epitope comprises SEQ ID NO: 6.

57. The method of claim 54-56, wherein the linker comprises SEQ ID NO: 7.

58. The method of claim 54-57, wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 or SEQ ID NO: 20.

59. The method of claim 54-58, wherein the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

60. The method of claim 59. wherein the PD-1 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 20 and the CTLA-4 peptide comprises the amino acid sequence as set forth in SEQ ID NO: 29.

61. The method of claim 38. wherein the immune checkpoint therapy comprises a first therapeutic peptide and an immune checkpoint inhibitor

62. The method of claim 61, wherein the first therapeutic peptide is a programmed cell death- 1 (PD-1) chimeric peptide comprising one or more PD-1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-1 B cell epitope to the Th epitope, wherein the one or more PD-1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

63. The method of claim 62, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acnxolimab.

64. The method of claim 62, wherein the checkpoint inhibitor is an anti-PD-Ll antibody selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-986189. KN035, cosibehmab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170.

65. The method of claim 62, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

66. The method of claim 61, wherein the first therapeutic peptide is a programmed cell death ligand- 1 (PD-L1) comprising one or more PD-L1 B cell epitopes, a T helper (Th) epitope, and a linker joining the PD-L1 B cell epitope to the Th epitope, wherein the one or more PD-L1 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

67. The method of claim 66. wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab.

68. The method of claim 66. wherein the checkpoint inhibitor is an anti-PD-Ll antibody selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-986189, KN035, Cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170.

69. The method of claim 66. wherein the checkpoint inhibitor is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

70. The method of claim 61, wherein the first therapeutic peptide is a a cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) chimeric peptide comprising one or more CTLA-4 cell epitopes, a T helper (Th) epitope, and a linker joining the CTLA-4 B cell epitope to the Th epitope, wherein the one or more CTLA-4 B cell epitopes consist of a sequence selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, and SEQ ID NO: 25; and wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, or anti-CTLA-4 antibody.

71. The method of claim 70, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab. nivolumab, cemiplimab, dostarlimab, retifanlimab, tonpalimab, vopratelimab, spartalizumab, camrehzumab, sintilimab, tislelizumab, INCMGA00012, AMP-224, AMP-514, CT-011, MK-3475, and acrixolimab.

72. The method of claim 70, wherein the checkpoint inhibitor is an anti-PD-Ll antibody selected from the group consisting of atezolizumab, avelumab, durvalumab, BMS-986189, KN035, Cosibelimab, AUNP12, BMS-936559, MPDL3280A, MSB0010718C, and CA-170.

73. The method of claim 70, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab.

74. The method of any of claims 37-73, wherein the cancer is selected from the group of cancers consisting of lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin’s Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma, neuroblastoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, colon cancer, cervical cancer, cervical carcinoma, breast cancer, epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancer; testicular cancer; prostatic cancer, or pancreatic cancer.

75. The method of claim 74. wherein the cancer is breast cancer.

76. The method of claim 75, wherein the method further comprises administering to the subject one or more one or more HER-2 B cell epitopes.

77. The method of claim 76, wherein the HER-2 B cell epitopes comprises one or more of the sequences as set forth in SEQ ID NO: 37 or 39.

78. The method of claim 76. wherein the HER-2 B cell epitopes comprises one or more synthetic HER-2 B cell epitopes as set forth in SEQ ID NO: 38 or 40.

79. The method of any of claims 76-78, wherein the HER-2 B cell epitopes are administered in the same composition with the PD-1 epitopes.

80. The method of claim 74, wherein the cancer is colon cancer.

81. The method of claim 74. wherein the cancer is melanoma.

82. The method of any of claims 37-73, wherein the autoimmune disease is selected from the group consisting of Psoriasis, Alopecia Areata, Primary biliary cirrhosis, Autoimmune poly endocrine syndrome, Diabetes mellitus type 1, autoimmune thyroiditis, Systemic Lupus Erythematosus, Multiple sclerosis, Guillain-Barre syndrome, Grave’s disease, Sjogren’s syndrome, ulcerative colitis, Autoimmune hemolytic anemia, Pernicious anemia, Psoriatic arthritis, rheumatoid arthritis, relapsing polychondritis, myasthenia gravis, Acute disseminated encephalomyelitis, and Granulomatosis with polyangiitis.