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WO2025152901A1 - Chimère virus oncolytique-lymphocyte t pour thérapie anticancéreuse et son utilisation - Google Patents

Chimère virus oncolytique-lymphocyte t pour thérapie anticancéreuse et son utilisation

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Publication number
WO2025152901A1
WO2025152901A1 PCT/CN2025/072088 CN2025072088W WO2025152901A1 WO 2025152901 A1 WO2025152901 A1 WO 2025152901A1 CN 2025072088 W CN2025072088 W CN 2025072088W WO 2025152901 A1 WO2025152901 A1 WO 2025152901A1
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eoa
cells
cell
tumor
oncolytic virus
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平渊
陈宇轩
陈小红
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Ruidax Gene Technology Co Ltd
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Ruidax Gene Technology Co Ltd
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    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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    • A61K35/761—Adenovirus
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    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/763—Herpes virus
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001154—Enzymes
    • A61K39/001162—Kinases, e.g. Raf or Src
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/001171—Gangliosides, e.g. GM2, GD2 or GD3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
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    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
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    • A—HUMAN NECESSITIES
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/852—Pancreas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/86—Lung
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K2039/876—Skin, melanoma
    • C—CHEMISTRY; METALLURGY
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    • C12N2510/00—Genetically modified cells

Definitions

  • the present invention relates to the field of biomedicine, and more specifically, to an oncolytic virus-T cell chimera for tumor treatment and application thereof.
  • Oncolytic virus therapy is an emerging cancer immunotherapy modality.
  • Oncolytic viruses can induce tumor-specific inflammatory responses and kill tumor cells without infecting cells in normal tissues by selectively replicating in tumor cells.
  • Talimogene laherparepvec T-VEC, Imlygic
  • HSV-1 herpes simplex virus type 1
  • T-VEC can lyse tumor cells and subsequently release potent danger signals (DAMPs and PAMPs), tumor-derived antigens, and express the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to promote antitumor immune responses.
  • DAMPs and PAMPs potent danger signals
  • GM-CSF cytokine granulocyte-macrophage colony-stimulating factor
  • OVs encoding specific biomacromolecules for PDL1 or combined therapy with PDL1 antibodies and OVs have been widely studied to alleviate the immunosuppressive tumor microenvironment (TME), which may also form tumor resistance to oncolytic virus therapy.
  • TEE immunosuppressive tumor microenvironment
  • ICIs immune checkpoint inhibitors
  • the combination of oncolytic virus therapy with checkpoint blockade immunotherapy is often limited, so new strategies are needed to target the delivery of OVs and ICIs to tumors to address these current problems.
  • OV-infected host cells have been shown to have lower proliferation capacity and gradually reduced survival ability, which may impair their killing function to target tumors.
  • biomaterial-based carriers either organic or inorganic, can be tailored to load OVs by chemical or physical means and release OVs in response to specific stimuli in the TME, most of them are hampered by clinical applicability, rapid clearance (by the endothelial reticular system), and nonspecific uptake by healthy tissues.
  • the present application provides a tumor-targeted OV delivery system, which can deliver a CRISPR-Cas9 genome editor by integrating genetically engineered OVs with T cells.
  • This Cas9 editor is controlled by sgRNA targeting the PDL1 gene to knock out PDL1 in tumor cells.
  • This strategy takes advantage of the tumor targeting of T cells and uses biofilms to protect OVs from systemic neutralization.
  • the present invention provides the following technical solutions:
  • the T cells include one or more of TCR-T cells, CAR-T cells, and tumor infiltrating lymphocytes (TILs) derived from human PDAC pancreatic cancer tumors.
  • TILs tumor infiltrating lymphocytes
  • the tumor-targeted oncolytic virus delivery system is obtained by attaching the oncolytic virus to T cells through the biophysical interaction between the T cell receptor TCR and pMHC-I, or the chimeric antigen receptor CAR and tumor cell surface antigens.
  • the oncolytic virus includes one or more of an oncolytic adenovirus and an oncolytic herpes virus HSV-1.
  • the specific preparation method of the oncolytic virus-T cell chimera comprises the following steps:
  • Step 2 M@eOA is anchored to OT-1CD8+T through biophysical interactions between TCR and MHC-I-OVA 257-264 ;
  • the specific preparation method of the oncolytic virus-T cell chimera comprises the following steps:
  • Step 1 eOA was encapsulated with the tumor cell membrane overexpressing specific tumor antigens (EphA2, PSCA, GD2) through liposome extrusion technology to form M@eOA;
  • the specific preparation method of the oncolytic virus-T cell chimera comprises the following steps:
  • Step 1 After eOA infects 293T cells overexpressing PSCA, the cells are treated with relaxin B, and the vesicles containing eOA in the supernatant are collected. Then, the nanovesicles MV@eOA containing eOA are obtained by liposome extrusion technology.
  • Step 2 MV@eOA is anchored on CAR-T cells through the biophysical interaction between CAR and tumor antigen PSCA;
  • the specific preparation method of the oncolytic virus-T cell chimera comprises the following steps:
  • Step 1 eOA is encapsulated with patient-derived autologous tumor cell membranes through liposome extrusion technology to form M@eOA;
  • M@eOA is anchored on TIL cells through the biophysical interaction between TCR and pMHC-I of autologous tumor.
  • the oncolytic adenovirus includes an engineered oncolytic adenovirus, wherein the engineered oncolytic adenovirus is obtained by cloning Cas9, sgRNA targeting a target gene, and EGFP into an oncolytic adenovirus.
  • the clone is obtained by cloning Cas9, sgRNA targeting the target gene, and EGFP into the shuttle plasmid of OA, and then transforming the shuttle plasmid into an oncolytic adenovirus.
  • the shuttle plasmid comprises pDC315-hTERT-E1A.
  • a second aspect of the present invention provides a pharmaceutical composition for treating cancer, wherein the pharmaceutical composition comprises the oncolytic virus-T cell chimera according to any one of claims 1-8.
  • the tumor comprises a primary or disseminated tumor that expresses the antigen.
  • a fourth aspect of the present invention provides the use of the above-mentioned oncolytic virus-T cell chimera in combination with an anti-CTLA4 antibody in the preparation of a cancer therapeutic drug.
  • oncolytic virus constructs encoding Cas9 editors can destroy the PDL1 gene of tumor cells and infiltrating immune cells, thereby downregulating their PDL1 expression levels, which greatly helps to alleviate the tumor immunosuppressive microenvironment and facilitate the killing effect of T cell therapy and oncolytic therapy on tumors. Therefore, oncolytic virus-T cell chimeras (ONCOTECH) represent an innovative therapeutic platform that is not only suitable for systemic targeted delivery of OVs, but also helps to reshape the TME.
  • T cells including TCR-T and CAR-T cells
  • OVs including oncolytic viruses such as oncolytic adenovirus OA and oncolytic herpes virus HSV-1, to combine viral therapy and cell therapy for a wide range of cancer treatment applications.
  • oncolytic viruses such as oncolytic adenovirus OA and oncolytic herpes virus HSV-1
  • Figure 1 shows tumor PDL1 analysis and construction of engineered oncolytic adenovirus (eOA).
  • eOA engineered oncolytic adenovirus
  • a Overall survival of melanoma, pancreatic cancer, or glioma patients with high or low levels of PDL1 analyzed by gene expression profiling interactive analysis (GEPIA). Source data were isolated from TCGA, and n is the number of patients included in the survival analysis. Survival analysis was performed using the log-rank (Mantel-cox) test.
  • GEPIA gene expression profiling interactive analysis
  • Source data were isolated from TCGA, and n is the number of patients included in the survival analysis. Survival analysis was performed using the log-rank (Mantel-cox) test.
  • b Representative images of pancreatic cancer patient tumor immunohistochemistry (brown) PDL1 used to establish patient-derived xenografts (PDX) on NSG mice.
  • PDX mouse models were treated with saline, intratumorally (it) injected with OA (1 ⁇ 10 10 VP), intravenously (iv) injected with CAR-T cells (1 ⁇ 10 7 cells), and OA (it) and CAR-T cells (iv) were co-treated.
  • Scale bar 100 ⁇ m.
  • N 5 biologically independent mice, and 3 IHC sections were randomly analyzed per tumor. 0 points (-, negative), 1 point (+, weak), 2 points (++, moderate), 3 points (+++, strong).
  • c Flow gating strategy (upper) and representative flow cytometry plots of PDL1 expression in EpCAM + tumor cells after indicated treatments (lower).
  • d PDL1 expression in B16OVA tumor-bearing mice after indicated treatments.
  • Figure 2 shows the scheme of genome editing of PDL1 by engineered oncolytic adenovirus (eOA) which effectively improves viral therapy and/or adoptive T cell therapy.
  • eOA engineered oncolytic adenovirus
  • k Venn diagram of heat map of DEGs in T cell-treated mice, M@eOA and TM@eOA (left). Quantitative analysis of the number of DEGs in tumors after different treatments (right). Data represent mean ⁇ sd. P values were determined by one-way ANOVA with Tukey post hoc analysis (b) and two-way ANOVA with Bonferroni post hoc analysis (h), and P values are indicated in the figures.
  • k Venn diagram of heat map of DEGs in T cell-treated mice, M@eOA and TM@eOA (left). Quantitative analysis of the number of DEGs in tumors after different treatments (right). Data represent mean ⁇ sd. P values were determined by one-way ANOVA with Tukey post hoc analysis (b) and two-way ANOVA with Bonferroni post hoc analysis (h), and P values are indicated in the figures.
  • k Genetic mutations at the PDLI locus and Western blot analysis of PDL1 in metastatic B16OVA tumor lung tissue after treatment.
  • I In vivo bioluminescence images of mice bearing lung metastatic B16OVA tumors.
  • m Survival curves of mice after indicated treatment in metastatic B16OVA model.
  • n Experimental design and timeline for treatment of metastatic 4T1OVA tumors.
  • o Genetic mutations at the PDLI locus in 4T1-OVA tumor tissue after treatment.
  • p Representative lung images of the 4T1-OVA spontaneous metastasis model. Scale bar, 5 mm.
  • q Representative H&E staining images of lung metastases. Scale bar, 2 mm.
  • Figure 12 shows the long-term immune effects of B16OVA tumor-bearing mice.
  • a Timeline of the antitumor effects of TM@eOA on NK cell or CD4 + T cell depletion in B16OVA tumor-bearing mice.
  • b c, Tumor volume (b) and survival curve (c).
  • N 5 biologically independent mice.
  • d Representative cell images and quantitative analysis of effector memory T cells (CD3 + CD8 + CD44 + CD62L - , Tem) and central memory T cells (CD3 + CD8 + CD44 + CD62L + , Tcm) in the spleen of healthy mice or tumor-bearing mice after the indicated treatment.
  • N 5 biologically independent mice.
  • Figure 13 shows biosafety analysis and other in vivo antitumor experiments.
  • a Comparison of the antitumor effects of TM@eOA (Figure 11c) and T(iv)+eOA(iv) ( Figure 1n) treatment in B16OVA tumor-bearing mice.
  • B16OVA tumors were subcutaneously inoculated on day -7 and treated with OT-1CD8 + T (intravenous injection).
  • c Serum inflammatory cytokine levels 7 days after treatment.
  • d Serum inflammatory cytokine levels 7 days after treatment.
  • h Representative cytometry images and quantitative analysis of cytokine production (IFN ⁇ and GZMB) by vector OT-1 CD8 + T cells in lung metastases.
  • IFN ⁇ and GZMB cytokine production
  • g Schematic diagram of CLSM multicolor 3D real-time imaging of PDAC patient-derived organoids (PDOs) by CAR-T-MV@eOA, combined with cytometry and ELISA analysis.
  • h 3D CLSM imaging of PDAC PDOs by CAR-T-MV@eOA. Dead organoid cells labeled by YOYO-3.
  • j k Quantification of PDO cell death, cytometry analysis of the percentage of Ad5-positive PDO cells (j), and the MFI of PDL1 expression in PDO cells (k).
  • I CAR-T cell counts after co-culture with PDO cells.
  • T cells equipped with oncolytic viruses showed similar characteristics to native T cells (unanchored oncolytic viruses) in terms of proliferation rate and cell migration ( Figure 3k and Figure 4o-q), and the CD69 mean fluorescence intensity MFI of native T cells, a marker of early T cell activation, was also comparable to that of the T-M@eOA group after stimulation with anti-CD3/CD28 magnetic beads ( Figure 3l).
  • TM@eOA mouse bone marrow-derived macrophages
  • T cells T cells
  • B16OVA-mCherry cells B16OVA-mCherry cells
  • T-M@eOA was stained T cells and eOA with DiR and Cy7, respectively, and then injected fluorescently labeled T-M@eOA intravenously into B16OVA tumor-bearing mice (Figure 7a).
  • Flow cytometry results showed that T-M@eOA could maintain its in vivo stability after systemic administration, and there was no obvious shedding of oncolytic virus on carrier T cells (Figure 8a).
  • In vivo fluorescence imaging showed that 24 hours after T-M@eOA injection, the Cy7 signal in the tumor area was the strongest, while the M@eOA or T+M@eOA group showed moderate fluorescence intensity.
  • T-M@eOA oncolytic viruses and T cells into the body in an integrated mode
  • T+M@eOA may synergistically improve the targeting ability of oncolytic viruses and increase the infiltration of carrier T cells.
  • M@eOA delivered by carrier T cells targets tumors.
  • In vivo delivery of T-M@eOA induced a 20.6% gene mutation frequency in the PDL1 genomic locus ( Figure 8e), which was confirmed by spectral flow cytometry and RNA-Seq, namely by reducing the expression of PDL1 in tumor cells and immune cells ( Figures 7e, f and Figures 8f, g).
  • the treatment promoted the secretion of anti-tumor effector molecules (including human TNF ⁇ , IL12p70, IL-2, IFN ⁇ and GZMB, Figures 15o, p), demonstrating its powerful therapeutic effect against A549 human lung metastatic tumors ( Figures 15q, r).
  • anti-tumor effector molecules including human TNF ⁇ , IL12p70, IL-2, IFN ⁇ and GZMB, Figures 15o, p
  • TILs tumor-infiltrating lymphocytes
  • MVs microcapsules
  • CB cytochalasin B
  • CAR-T-MV@eOA treatment strongly inhibited the growth of PDX tumors within 20 days and effectively prolonged the survival time of tumor-bearing mice, with a survival rate of 80% within 30 days after treatment (Figure 18j). No significant changes in body temperature were observed after treatment (Figure 19l).
  • HSC CD34 hematopoietic stem cells

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Abstract

L'invention concerne une chimère virus oncolytique-lymphocyte T (ONCOTECH) pour une thérapie anticancéreuse et son utilisation. Selon l'invention, des adénovirus oncolytiques (OA) sont modifiés de façon à être porteurs de la capacité d'édition génique d'un éditeur de génome Cas9, et les OA sont ancrés sur la surface d'un lymphocyte T au moyen d'un antigène spécifique des lymphocytes T présenté par une couche de membrane biologique ou de microcapsule, de manière à former un ONCOTECH. Lors de l'injection intraveineuse de l'ONCOTECH, le lymphocyte T facilite l'administration des OA dans une tumeur exprimant un antigène homologue, puis les OA libérés de manière compétitive par le lymphocyte T lysent les cellules tumorales et perturbent un gène de ligand de mort programmée 1 (PDL1) au moyen d'une édition génique médiée par Cas9. Cette modalité thérapeutique permet d'inverser la pharmacorésistance des tumeurs à l'oncolyse et aux lymphocytes T, d'améliorer la présentation d'antigène et d'activer des réponses de lymphocytes T spécifiques d'une tumeur endogène, et d'induire un effet de mémoire immunitaire durable, ce qui permet d'améliorer significativement l'effet thérapeutique dans un modèle de tumeur de souris qui simule une série d'indicateurs cliniques.
PCT/CN2025/072088 2024-01-20 2025-01-13 Chimère virus oncolytique-lymphocyte t pour thérapie anticancéreuse et son utilisation Pending WO2025152901A1 (fr)

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