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WO2025166179A1 - Méthode d'amélioration de thérapies par cellules car-t - Google Patents

Méthode d'amélioration de thérapies par cellules car-t

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Publication number
WO2025166179A1
WO2025166179A1 PCT/US2025/014058 US2025014058W WO2025166179A1 WO 2025166179 A1 WO2025166179 A1 WO 2025166179A1 US 2025014058 W US2025014058 W US 2025014058W WO 2025166179 A1 WO2025166179 A1 WO 2025166179A1
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WO
WIPO (PCT)
Prior art keywords
car
emapalumab
cell therapy
administered
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014058
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English (en)
Inventor
Owen B. WILSON
Marcela V. Maus
Matthew John FRIGAULT
Kathleen Mary Ellen GALLAGHER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Swedish Orphan Biovitrum AB
General Hospital Corp
Original Assignee
Swedish Orphan Biovitrum AB
General Hospital Corp
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Publication date
Application filed by Swedish Orphan Biovitrum AB, General Hospital Corp filed Critical Swedish Orphan Biovitrum AB
Publication of WO2025166179A1 publication Critical patent/WO2025166179A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A61K40/4211—CD19 or B4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex

Definitions

  • the instant disclosure relates to methods of treating cancer, including methods of improving CAR-T cell therapies.
  • CAR-T cells are frequently used in the treatment of hematological malignancies such as non-Hodgkin lymphoma.
  • Non-Hodgkin lymphoma is a heterogeneous group of cancers originating in B lymphocytes, T lymphocytes or natural killer cells. In the United States, B cell lymphomas represent 80-85% of cases reported. Non-Hodgkin lymphoma is the most prevalent hematological malignancy and is the seventh leading site of new cancers among men and women and account for 4% of all new cancer cases and 3% of deaths related to cancer. Large B-cell lymphomas represent the most common sub-group of NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of large B-cell lymphoma, accounting for approximately 30% of NHL cases.
  • DLBCL Diffuse large B-cell lymphoma
  • PMBCL Primary mediastinal B-cell lymphoma
  • Follicular lymphoma FL
  • FL Follicular lymphoma
  • TFL Treatment options for relap sed/refractory PMBCL and TFL are similar to those in DLBCL. Given the low prevalence of these diseases, no large prospective randomized studies in these patient populations have been conducted. Patients with chemotherapy refractory disease have a similar or worse prognosis to those with refractory DLBCL.
  • IFNy plays two major roles in this context: (i) IFNy stimulates T-cell activity proliferation, especially in CAR-T cells containing a CD28 costimulatory domain, and (ii) IFNy drives macrophage activation and subsequent production of proinflammatory cytokines/chemokines. See, e.g., Bailey et. al., B Blood Cancer Discov. 2022 Mar 1; 3(2): 136-153.
  • CRS CRS
  • ICANS ICANS
  • CRS is defined as a constellation of symptoms which may include (but are not limited to) fever, chills, hypotension, hypoxia, and when extreme, macrophage activation syndrome.
  • Manifestations of ICANS vary and include confusion, obtundation, seizures, hallucinations, aphasia, ataxia, and more rarely, profound cerebral edema.
  • the future success and application of commercial product to a broader population of patients is limited by the development of these toxicities. Therefore, there remains an unmet need for methods of improving existing CAR-T cell therapies to decrease toxicities.
  • a method of improving a CAR-T cell therapy by decreasing a CAR-T cell associated toxicity in a subject receiving CAR-T cell therapy comprising administering to the subject an effective dose of emapalumab.
  • the toxicity is cytokine-release syndrome.
  • the toxicity is immune effector cell-associated neurotoxicity syndrome (ICANS).
  • the toxicity is prolonged cytopenia.
  • the emapalumab is administered at a dose of 0.1 to 10 mg/kg intravenously. In some embodiments, the emapalumab is administered at a dose of 1 to 10 mg/kg intravenously. In some embodiments, the emapalumab is administered at a dose of 3 mg/kg intravenously. In some embodiments, the dose is a one-time dose.
  • the CAR-T cell therapy has IFNy mediated toxicities.
  • the CAR-T cell therapy is axicabtagene ciloleucel.
  • the axicabtagene ciloleucel is administered at a target dose of 2 x 10 6 anti-CD19 CAR-T cells/kg, administered intravenously.
  • the axicabtagene ciloleucel is administered as a one-time dose.
  • the axicabtagene ciloleucel is administered concurrently, before or after emapalumab administration.
  • the axicabtagene ciloleucel is administered one day before emapalumab administration. In some embodiments, the axicabtagene ciloleucel is administered one to five days before emapalumab administration. In some embodiments, the axicabtagene ciloleucel is administered about 24 hours after emapalumab administration. [0012] In some embodiments, the emapalumab is administered about 1-5 days after the lymphodepleting regimen. In some embodiments, the CAR-T cell therapy is administered concurrently with or about one to five days after the emapalumab.
  • the subject is further administered at least one additional therapy.
  • the at least one additional therapy is a lymphodepleting regimen.
  • the lymphodepleting regimen is administered for 1, 2, 3, 4, 6, 7, or more days.
  • the lymphodepleting regimen comprises fludarabine and cyclophosphamide or bendamustine.
  • the lymphodepleting regimen comprises radiation
  • the lymphodepleting chemotherapy regimen is administered prior to the administration of the CAR-T cell therapy.
  • the method results in a prolongation of the duration of response to the CAR-T cell therapy of at least 10% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in an increase in the overall response rate to the CAR-T cell therapy of at least 10% as compared to the overall response rate to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 10% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • the method results in an increase in overall survival after administration of the CAR-T cell therapy of at least 10% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in at least 500 CAR-T cells per microliter blood of the subject.
  • the patient has a large B-cell lymphoma that is refractory to first-line chemoimmunotherapy. In some embodiments, the patient has a large B-cell lymphoma that relapses within 12 months of first-line chemoimmunotherapy. In some embodiments, the patient has a relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. In some embodiments, the patient has non-Hodgkin lymphoma. In some embodiments, the patient has diffuse large B-cell lymphoma. In some embodiments, the patient has primary mediastinal B-cell lymphoma. In some embodiments, the patient has diffuse large B-cell lymphoma arising from follicular lymphoma. In some embodiments, the patient has high grade B-cell lymphoma.
  • a method for treating cancer in a subject in need thereof comprising: (a) administering to the subject a lymphodepleting regimen; (b) administering to the subject emapalumab; and (c) administering to the subject a CAR-T cell therapy.
  • the emapalumab is administered at a dose of 0.1 to 10 mg/kg intravenously. In some embodiments, the emapalumab is administered at a dose of 1 to 10 mg/kg intravenously. In some embodiments, the emapalumab is administered at a dose of 3 mg/kg intravenously. In some embodiments, the dose is a one-time dose.
  • the CAR-T cell therapy has IFNy mediated toxicities.
  • the CAR-T cell therapy is axicabtagene ciloleucel.
  • the axicabtagene ciloleucel is administered at a target dose of 2 x 10 6 anti-CD19 CAR-T cells/kg, administered intravenously.
  • the axicabtagene ciloleucel is administered as a one-time dose.
  • the axicabtagene ciloleucel is administered concurrently, before or after emapalumab administration.
  • the axicabtagene ciloleucel is administered one day before emapalumab administration.
  • the axicabtagene ciloleucel is administered one to five days before emapalumab administration. In some embodiments, the emapalumab is administered about 1-5 days after the lymphodepleting regimen. In some embodiments, the CAR-T cell therapy is administered concurrently with or about one to five days after the emapalumab.
  • the subject is further administered at least one additional therapy.
  • the at least one additional therapy is a lymphodepleting regimen.
  • the lymphodepleting regimen is administered for 1, 2, 3, 4, 6, 7, or more days.
  • the lymphodepleting regimen comprises fludarabine and cyclophosphamide or bendamustine.
  • the lymphodepleting regimen comprises radiation
  • the lymphodepleting chemotherapy regimen is administered prior to the administration of the CAR-T cell therapy.
  • the method results in a prolongation of the duration of response to the CAR-T cell therapy of at least 10% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in an increase in the overall response rate to the CAR-T cell therapy of at least 10% as compared to the overall response rate to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 10% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, the method results in an increase in overall survival after administration of the CAR-T cell therapy of at least 10% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • the patient has a large B-cell lymphoma that is refractory to first-line chemoimmunotherapy. In some embodiments, the patient has a large B-cell lymphoma that relapses within 12 months of first-line chemoimmunotherapy. In some embodiments, the patient has a relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. In some embodiments, the patient has non-Hodgkin lymphoma. In some embodiments, the patient has diffuse large B-cell lymphoma. In some embodiments, the patient has primary mediastinal B-cell lymphoma. In some embodiments, the patient has diffuse large B-cell lymphoma arising from follicular lymphoma. In some embodiments, the patient has high grade B-cell lymphoma.
  • the method further comprises monitoring the levels of CAR-T cells in the blood of the subject, such as by in vitro measuring the level of CAR-T cells in a blood sample obtained from the subject.
  • the levels of CAR-T cells in the blood of the subject such as in a blood sample obtained from the subject, is measured every other day.
  • the levels of CAR-T cells in the blood of the subject such as in a blood sample obtained from the subject, is measured once every 5 days.
  • the levels of CAR-T cells in the blood of the subject, such as in a blood sample obtained from the subject is measured once a week.
  • FIG. 1 shows a schematic illustrating the design of a clinical trial to assess the impact of emapalumab on CAR-T related cytokine release syndrome in patients with non-Hodgkin’s lymphoma (NHL).
  • a method of decreasing a CAR-T cell associated toxicity in a subject receiving CAR-T cell therapy comprising administering to the subject an effective amount of emapalumab.
  • a method for treating cancer in a subject in need thereof comprising: (a) administering to the subject a lymphodepleting chemotherapy regimen; (b) administering to the subject emapalumab; and (c) administering to the subject a CAR-T cell therapy.
  • a method of improving a CAR-T cell therapy further comprises a step of monitoring the levels of CAR-T cells in the blood of the subject.
  • the level of CAR-T cells is typically measured in a blood sample obtained from the subject.
  • Methods for measuring the levels of CAR-T cells in the blood, such as in a blood sample, are well known in the art an include, for example, flow cytometry.
  • the levels of CAR-T cells may be monitored at any suitable interval.
  • the levels of CAR-T cells are measured daily.
  • the levels of CAR-T cells are measured every other day.
  • the levels of CAR-T cells are measured every 3 days.
  • the levels of CAR-T cells are measured every five days. In some embodiments, the levels of CAR-T cells are measured once a week. In some embodiments, the levels of CAR-T cells are measured every other week. In some embodiments, the levels of CAR-T cells are measured once a month. In some embodiments, the levels of CAR-T cells are measured on day 3, 7, 14, 21, and 28 after administration of the CAR-T cells. In some embodiments, the levels of CAR-T cells are measured on day 3 and 7 after administration of the CAR-T cells and then once a week.
  • CRS cytokine-release syndrome
  • immune cells e.g., B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes
  • inflammatory cytokines can include Tumor necrosis factor (TNF), IFNy, IL-ip, IL-2, IL-6, IL-8, and IL-10.
  • CRS Crexid fever
  • Symptoms of CRS are essentially those of an exaggerated inflammatory response and include fever, chills, skin rashes, myalgia, nausea, vomiting, diarrhea, hypoxia, tachycardia, hypotension, confusion, seizures, as well as kidney and liver function abnormalities.
  • the clinical manifestation can range from mild to life-threatening (Grade 1-4) and ultimately death (Grade 5). See, e.g., Shimabukuro-Vornhage et al., J Immunother Cancer. 2018; 6: 56.
  • Grading of CRS is also described further in the examples, e.g., in Table 2.
  • Low grade CRS is usually treated symptomatically, using, for example, antihistamines, antipyretics and fluids.
  • High grade CRS caused by agents that are administered repeatedly may require dose adjustments or treatment interruptions.
  • CAR-T cell therapies which are generally administered once and only reach their full dose after expansion in the blood.
  • High grade CRS after the administration of CAR-T cells has limited treatment options, which include IL-6 blockade, TNF inhibition, and steroids.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of 1, 2, 3 or 4 grades compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 1 grade compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 2 grades compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 3 grades compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 10% compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 20% compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 30% compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 40% compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in CRS of at least 50% compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • the toxicity being improved by the methods described herein is Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS).
  • ICANS is associated with disruption of the blood-brain barrier and increased cytokine levels in the cerebrospinal fluid.
  • white blood cell counts, proteins, IFNy, IL-6, IL- 10, and granzyme B may be increased in the CSF and/or IFNy, IL-10, granzyme B, granulocyte-macrophage colonystimulating factor (GM-CSF), MIP-la, IL-2, ferritin and TNF may be increased in the serum.
  • GM-CSF granulocyte-macrophage colonystimulating factor
  • MIP-la granulocyte-macrophage colonystimulating factor
  • IL-2 ferritin
  • ferritin and TNF may be increased in the serum. See, e.g., Sterner and Sterner, Fron. Immunol. 2022; 13: 879608.
  • ICANS Symptoms of ICANS include confusion, headache, attention deficits, word finding difficulties, focal neurological deficits, or encephalopathy but may be as severe as cerebral edema, transient coma, or seizures. ICANS is mostly treated symptomatically, using mainly steroids. Similar to CRS, ICANS is classified by grade (Grade 1 being the mildest and Grade 4 being the most severe, and Grade 5 being death). ICANS grading is also described further in the examples, e.g., in Table 3 and Table 4.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of 1, 2, or 3 grades compared to the CRS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 1 grade compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 2 grades compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 3 grades compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 10% compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 20% compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 30% compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 40% compared to the ICANS induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in ICANS of at least 50% compared to the ICANS induced by administration of the CAR-T cell in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine of at least 10% compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine of at least 20% compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine of at least 30% compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine of at least 40% compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in the release of at least one inflammatory cytokine of at least 50% compared to the levels of the cytokine after administration of the CAR-T cell therapy in the absence of emapalumab.
  • the inflammatory cytokine may be INFy, IL-ip, IL-2, IL-5, IL-6, IL-8, IL-10, IL-13, GM-CSF, granzyme B, MIP-la, ferritin or TNF.
  • the levels of the inflammatory cytokine may be determined using any suitable method known in the art or described herein (e.g., ELISA or RNA sequencing).
  • the levels of the inflammatory cytokine may be determined in any suitable sample from the patient, such as blood, serum, or CSF.
  • the toxicity being improved by the methods described herein is prolonged cytopenia.
  • Cytopenias are a group of conditions characterized by lower than normal blood cell counts. Examples of cytopenias include anemia (low red blood cell counts), leukopenia (low white blood cell counts), neutropenia (low neutrophil counts) and thrombocytopenia (low platelet counts).
  • Patients receiving CAR-T cell therapies are generally lymphodepleted prior to administration of the CAR-T cells. This lymphodepletion can cause cytopenia, however, prolonged or recurrent cytopenia may also occur after CAR-T cell therapy, sometimes more than 30 days after. The cause of these prolonged cytopenias is not fully understood, however, is has been suggested that cytokines play a role. See Sharma et al., Cancers (Basel). 2022 Mar; 14(6): 1501.
  • Cytopenia increases the risk of infection and bleeding in a patient. Treatment of prolonged cytopenias is largely symptomatic with use of transfusion products and supportive care with colony stimulating factor. Similar to CRS and ICANS, cytopenias are classified by grade (Grade 1 being the mildest and Grade 4 being the most severe). [0045] In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least one cytopenia of 1, 2, or 3 grades compared to the cytopenia induced by administration of the CAR-T cell in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least one cytopenia of at least 1 grade compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least one cytopenia of at least 2 grades compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least one cytopenia of at least 3 grades compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least one cytopenia of at least 4 grades compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • the at least one cytopenia may be anemia, leukopenia, neutropenia, or thrombocytopenia.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least cytopenia of at least 10% compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least cytopenia of at least 20% compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least cytopenia of at least 30% compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least cytopenia of at least 40% compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a reduction in at least cytopenia of at least 50% compared to the cytopenia induced by administration of the CAR-T cell therapy in the absence of emapalumab.
  • the at least one cytopenia may be anemia, leukopenia, neutropenia, or thrombocytopenia.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • the duration of response is generally defined as the interval from response initiation (when the treated subject first shows a complete or partial response to therapy) to the earlier of disease progression or death.
  • Disease relapse after CAR-T cell therapy in B-cell malignancies is generally measured as the recurrence of tumor cells after the subject has achieved a complete response.
  • the relapse can be categorized as the bone marrow relapse, the extramedullary relapse (e.g., in central nervous system), or a combined relapse according to anatomical. Relapse may further be categorized as antigen-positive or antigennegative based on the expression profile of initially targeted antigens of tumor cells.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 10% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 20% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 30% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 40% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 50% as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in a prolongation of the duration of response to the CAR-T cell therapy of at least 1, 2, 3, 4, or 5 years as compared to the duration of response to the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase of the number CAR-T cells in the blood of a subject compared to the number of CAR-T cells in the absence of emapalumab.
  • the number of CAR-T cells in the blood can be determined using any suitable method known in the art or described herein, including for example flow cytometry.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in at least 400 CAR-T cells per microliter in the blood of the subject. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in at least 450 CAR-T cells per microliter in the blood of the subject. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in at least 500 CAR-T cells per microliter in the blood of the subject.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in at least 550 CAR-T cells per microliter in the blood of the subject. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in at least 600 CAR-T cells per microliter in the blood of the subject.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab.
  • Overall response rate is generally defined as the proportion of patients in a treatment group who have a partial response (a reduction in tumor burden) or complete response (complete clearance of the tumor) to a therapy (not including stable disease).
  • Overall response rate is a measure of tumoricidal activity.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy of at least 10% as compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy of at least 20% as compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy of at least 30% as compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy of at least 40% as compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall response rate after administration of the CAR-T cell therapy of at least 50% as compared to the overall response rate after administration of the CAR-T cell therapy in the absence of emapalumab. Progression-Free Survival
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • Progression-free survival is generally defined as the time between randomization (or treatment) in a clinical trial to the earlier of disease progression or death.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 10% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 20% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 30% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 40% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 50% as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in progression-free survival after administration of the CAR-T cell therapy of at least 4, 5, 6, 7, 8, 9, 10, 11, or 12 months as compared to the progression-free survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • Overall survival is generally defined as the time between treatment and death irrespective of disease progression.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 10% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 20% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 30% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab. In some embodiments, a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 40% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 50% as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 4, 5, 6, 7, 8, 9, 10, 11, or 12 months as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein results in an increase in overall survival after administration of the CAR-T cell therapy of at least 1, 2, 3, 4 or 5 years as compared to the overall survival after administration of the CAR-T cell therapy in the absence of emapalumab.
  • CAR-T cells being improved using the methods described herein or being used in the methods of treatment described herein may be used for any approved indication (see, e.g., Table 1).
  • CAR-T cell therapies are being used for cancers, mainly hematological malignancies such as leukemias and lymphomas.
  • the cancer is a relapsed or refractory cancer.
  • a subject being treated in accordance with a method described herein has received prior treatment for their cancer.
  • the subject has a cancer that has relapsed after prior therapy.
  • the subject has a cancer that is refractory to first-line chemoimmunotherapy.
  • the subject relapses within 12 months of first-line chemoimmunotherapy.
  • the subject has relapsed or refractory disease after two or more lines of systemic therapy.
  • the subject is not eligible for hematopoietic stem cell transplantation.
  • a subject being treated in accordance with a method described herein has a B-cell leukemia or lymphoma.
  • the subject has a B-cell precursor acute lymphoblastic leukemia (ALL). In some embodiments, the subject has a B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
  • ALL B-cell precursor acute lymphoblastic leukemia
  • the subject has diffuse large B-cell lymphoma (DLBCL). In some embodiments, the subject has a high grade B-cell lymphoma. In some embodiments, the subject has DLBCL arising from follicular lymphoma. In some embodiments, the subject has primary mediastinal large B-cell lymphoma. [0067] In some embodiments, a subject being treated in accordance with a method described herein has a large B-cell lymphoma. In some embodiments, a subject being treated in accordance with a method described herein has a relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.
  • DLBCL diffuse large B-cell lymphoma
  • a subject has a high grade B-cell lymphoma. In some embodiments, the subject has DLBCL arising from follicular lymphoma. In some embodiments, the subject has primary mediastinal large B-cell lymphoma.
  • a subject being treated in accordance with a method described herein has a large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy .
  • a subject being treated in accordance with a method described herein has follicular lymphoma.
  • the subject has relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
  • a subject being treated in accordance with a method described herein has mantle cell lymphoma. In some embodiments, the subject has mantle cell lymphoma.
  • a subject being treated in accordance with a method described herein has multiple myeloma.
  • the subject has relapsed or refractory multiple myeloma.
  • the subject has relapsed or refractory multiple myeloma after four or more prior lines of therapy (e.g., therapy including an immunomodulatory agent, a proteasome inhibitor, and/or an anti-CD38 monoclonal antibody).
  • the subject has non-Hodgkin lymphoma.
  • the terms “patient” and “subject” are used interchangeably herein.
  • the patient is a human adult.
  • the patient is a human child.
  • Emapalumab is a fully human anti-IFNy monoclonal antibody that was FDA approved in 2018 for the treatment of adult and pediatric primary hemophagocytic lymphohistiocytosis (HLH).
  • HHL primary hemophagocytic lymphohistiocytosis
  • emapalumab is administered at a dose of about 1 to about 10 mg/kg. In some embodiments of the methods of improving a CAR-T cell therapy or the methods of treatment described herein, emapalumab is administered at a dose of about 1 mg/kg. In some embodiments of the methods of improving a CAR-T cell therapy or the methods of treatment described herein, emapalumab is administered at a dose of about 2 mg/kg. In some embodiments of the methods of improving a CAR-T cell therapy or the methods of treatment described herein, emapalumab is administered at a dose of about 3 mg/kg.
  • emapalumab is administered at a dose of about 3 mg/kg. In some embodiments of the methods of improving a CAR-T cell therapy or the methods of treatment described herein, emapalumab is administered at a dose of about 5 mg/kg. In some embodiments of the methods of improving a CAR-T cell therapy or the methods of treatment described herein, emapalumab is administered at a dose of about 6 mg/kg. In some embodiments, emapalumab is administered as a one-time dose of 1 mg/kg intravenously.
  • emapalumab is administered as a one-time dose of 2 mg/kg intravenously. In some embodiments, emapalumab is administered as a one-time dose of 3 mg/kg intravenously. In some embodiments, emapalumab is administered as a one-time dose of 4 mg/kg intravenously. In some embodiments, emapalumab is administered as a onetime dose of 5 mg/kg intravenously. In some embodiments, emapalumab is administered as a one-time dose of 6 mg/kg intravenously.
  • the emapalumab may be administered at any suitable time.
  • the emapalumab is administered concurrently (i.e. same day) with the administration of the CAR- T cell therapy, after the administration of the CAR-T therapy or before the administration CAR-T therapy.
  • the emapalumab may be administered at any suitable time prior to the administration of the CAR-T cell therapy. In some embodiments, emapalumab is administered 1-5 days before the CAR-T cell administration. In some embodiments, emapalumab is administered 1- 3 days before the CAR-T cell administration. In some embodiments, emapalumab is administered 1 or 2 days before the CAR-T cell administration. In some embodiments, emapalumab is administered the day before the CAR-T cell administration.
  • the emapalumab may be administered at any suitable time after to the administration of the CAR-T cell therapy. In some embodiments, emapalumab is administered 1-5 days after the CAR-T cell administration. In some embodiments, emapalumab is administered 1-3 days after the CAR-T cell administration. In some embodiments, emapalumab is administered 1 or 2 days after the CAR-T cell administration. In some embodiments, emapalumab is administered the day after the CAR-T cell administration.
  • a one-time dose of 1 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy. In some embodiments, a one-time dose of 2 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy. In some embodiments, a one-time dose of 3 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy. In some embodiments, a one-time dose of 4 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy.
  • a one-time dose of 5 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy. In some embodiments, a one-time dose of 6 mg/kg emapalumab is administered intravenously the day before the CAR-T cell therapy.
  • the methods described herein further comprise the administration of a lymphodepleting chemotherapy regimen.
  • the emapalumab may be administered at any suitable time between the administration of the lymphodepleting chemotherapy regimen and the administration of the CAR-T cell therapy.
  • the emapalumab is administered 1-3 days after the lymphodepleting chemotherapy regimen.
  • the emapalumab is administered about 2 days after the lymphodepleting chemotherapy regimen.
  • the emapalumab is administered on day 1, with the CAR-T cell therapy being administered on day 0.
  • the methods described herein may be used to improve existing CAR-T cell therapies and the methods of treatment described herein comprise the administration of CAR-T cell therapies.
  • CAR-T cells are autologous cells modified to express a chimeric antigen receptor (CAR).
  • a CAR comprises an antigen recognition domain (often an scFv), a hinge domain (often from CD8, CD28 or IgG), a transmembrane domain (often from CD4, CD8 or CD28), and a signaling domain (often CD3Q.
  • Second and third generation CARs further comprise one and two co-stimulatory domains (e.g., CD28, 4- IBB, 0X40, CD27 or ICOS), respectively.
  • the CAR-T cell Upon binding to the antigen on the tumor cell, the CAR-T cell becomes activated attacks the tumor cell.
  • Any approved CAR-T cell therapy may be improved by or used in a method described herein.
  • the CAR-T cell therapy is a CD- 19 targeting CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is a CD-20 targeting CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is a CD-22 targeting CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is a BCMA targeting CAR-T cell therapy.
  • the CAR-T cell therapy is axicabtagene ciloleucel. In some embodiments, the CAR-T cell therapy is tisagenlecleucel. In some embodiments, the CAR-T cell therapy is brexucabtagene autoleucal. In some embodiments, the CAR-T cell therapy is lisocabtagene maraleucel. In some embodiments, the CAR-T cell therapy is idecabtagene vicleucel. In some embodiments, the CAR-T cell therapy is ciltacabtagene autoleucel.
  • the CAR-T cell therapy being improved by or used in the methods described herein may be administered at the dosage indicated on the drug label.
  • the CAR-T cell therapy is axicabtagene ciloleucel administered at a dose of 2 * 10 6 CAR-positive viable T cells per kg body weight with a maximum of 2 * 10 8 CAR-positive viable T cells per kg body weight (e.g., for the treatment of relapsed or refractory large B-cell lymphoma or relapsed or refractory follicular lymphoma).
  • the CAR-T cell therapy is tisagenlecleucel administered at a dose of 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight intravenously (e.g., for the treatment of Pediatric and Young Adult B-cell ALL in patients of 50 kg or less).
  • the CAR-T cell therapy is tisagenlecleucel administered at a dose of 0.1 to 2.5 x 10 8 total CAR-positive viable T cells (non-weight based) intravenously for patients above 50 kg (e.g., for the treatment of B-cell ALL in patients of over 50 kg).
  • the CAR-T cell therapy is tisagenlecleucel administered at a dose of 0.6 to 6.0 x 10 8 CAR-positive viable T cells intravenously (e.g., for the treatment of Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma).
  • the CAR-T cell therapy is brexucabtagene autoleucal administered at a dose of 2 * 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 2 * 10 8 CAR-positive viable T cells (e.g., for the treatment of mantle cell lymphoma).
  • the CAR-T cell therapy is brexucabtagene autoleucal administered at a dose of 1 x 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 1 x 10 8 CAR-positive viable T cells (e.g., for the treatment of ALL).
  • the CAR-T cell therapy is lisocabtagene maraleucel administered at a dose of 90 to 110 x io 6 CAR-positive viable T cells (e.g., for the treatment of LBCL after one line of therapy). In some embodiments, the CAR-T cell therapy is lisocabtagene maraleucel administered at a dose of 50 to 110 x io 6 CAR-positive viable T cells (e.g., for the treatment of LBCL after two lines of treatment).
  • the CAR-T cell therapy is idecabtagene vicleucel 300 to 460 x 10 6 CAR-positive T cells (e.g., for the treatment of relapsed or refractory multiple myeloma).
  • the CAR-T cell therapy is ciltacabtagene autoleucel administered at a dose of 0.5-1.0x l0 6 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 x 108 CAR-positive viable T cells per single-dose infusion (e.g., for the treatment of relapsed or refractory multiple myeloma).
  • the CAR-T cell therapy being improved by or used in the methods described herein may be administered at a higher dosage indicated on the drug label.
  • Examples of the dosages indicated on drug labels of FDA-approved CAR-T cell therapies are:
  • Axicabtagene ciloleucel 2 * 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 2 * 108 CAR-positive viable T cells.
  • o MCL 2 * 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 2 * 10 8 CAR-positive viable T cells.
  • o ALL 1 * 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 1 x 10 8 CAR-positive viable T cells.
  • Lisocabtagene maraleucel o
  • LBCL after one line of therapy 90 to 110 x io 6 CAR-positive viable T cells.
  • o For LBCL after two or more lines of therapy: 50 to 110 x 10 6 CAR-positive viable T cells.
  • Idecabtagene vicleucel 300 to 460 x io 6 CAR-positive T cells.
  • Ciltacabtagene autoleucel 0.5-1 ,0x 10 6 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 x 10 8 CAR-positive viable T cells per single-dose infusion.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is up to 25% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is 25%-50% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is 50%- 75%% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is 75%-100% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that about 1-1.5 times the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that about 1.5-2 times the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that about 2-2.5 times the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that about 2.5-5 times the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is about 50% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is about 100% higher than the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is about twice the dosage indicated on the drug label.
  • the dose of the CAR-T cell therapy being improved by or used in the methods described herein is administered at a dose that is about three times the dosage indicated on the drug label.
  • the methods of improving a CAR-T cell therapy and the methods of treatment described herein may further comprise the administration of one or more additional therapies. These may be, for example, therapies that are usually administered prior to or after CAR-T cell therapy.
  • the subject may undergo a lymphodepleting chemotherapy regimen prior to administration of the CAR-T cell therapy.
  • Such chemotherapy regimens are usually administered to patients prior to adoptive T cell therapies (such as CAR- T cell therapies) to improve CAR-T cell expansion and persistence.
  • T cell therapies such as CAR- T cell therapies
  • lymphodepleting chemotherapy regimens comprise fludarabine and cyclophosphamide, but a person of skill in the art will appreciate that any suitable lymphodepleting regimen may be used.
  • a method of improving a CAR-T cell therapy or a method of treatment described herein further comprises administering to the subject a lymphodepleting chemotherapy regimen.
  • the lymphodepleting chemotherapy regimen comprises fludarabine (e.g., at a dose of about 30 mg/m 2 /day) and/or cyclophosphamide (e.g. at a dose of about 500 mg/m 2 /day).
  • the lymphodepleting chemotherapy is administered for three days.
  • the lymphodepleting chemotherapy may be administered at any suitable time prior to the administration of the emapalumab and/or the CAR-T cell therapy.
  • the lymphodepleting chemotherapy is administered 3-5 days before the CAR-T cell therapy (e.g., from day -5 to day -3, with the CAR-T cell therapy being administered on day 0).
  • the lymphodepleting chemotherapy regimen is administered about 1-3 days before the emapalumab.
  • the administration of the lymphodepleting chemotherapy regimen ends about 2 days before the emapalumab.
  • agents that may be used for bridging therapy include rituximab, gemcitabine, etoposide, steroids, cisplatin, cytarabine, ibrutinib, lenalidomide, oxaliplatin, brentuximab vedotin, acalabrutinib, dexamethasone, cyclophosphamide, daratumumab, carfilzomib, bortezomib, pomalidomide and any combination thereof. See, e.g., Bhaskar et al., E EJHaem. 2022 Jan; 3 (Suppl 1): 39-45.
  • Example 1 Phase 2 multi-site, open-label study evaluating the safety and efficacy of emapalumab in subjects with received 2L or 3L axicabtagene ciloleucel for large B cell lymphoma.
  • This example describes a study to assess the impact of emapalumab as preventative management of CAR-T related cytokine release syndrome in patients with non-Hodgkin’s lymphoma (NHL), as measured by the incidence and maximal grade, following axicabtagene ciloleucel in subjects receiving 2L and 3L axicabtagene ciloleucel.
  • NDL non-Hodgkin’s lymphoma
  • the primary objective of this study is to assess the impact of emapalumab as preventative management of CAR-T related cytokine release syndrome in patients with nonHodgkin’ s lymphoma (NHL).
  • Secondary objectives include:
  • Exploratory objectives include:
  • Inclusion criteria for the study include: Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy .
  • At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, 0X40 agonists, 4- IBB agonists, etc.).
  • leukapheresis e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, 0X40 agonists, 4- IBB agonists, etc.
  • Age 18 or older Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  • EOG Eastern Cooperative Oncology Group
  • Adequate renal, hepatic, pulmonary and cardiac function defined as: ANC >1000/pL Platelet count >50, OOO/pL Absolute lymphocyte count > 100/ pL o Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) > 30 mL/min o Serum ALT/AST ⁇ 2.5 per institutional ULN o Total bilirubin ⁇ 1.5 mg/dl, except in subjects with Gilbert’s syndrome o Cardiac ejection fraction > 40%, no clinically significant pericardial effusion, and no clinically significant ECG findings o Baseline oxygen saturation >92% on room air Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). 11. Ability to understand and the willingness to sign a written informed consent document.
  • CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage within 6 months of enrollment.
  • Subjects will receive a non-myeloablative lymphodepleting regimen consisting of cyclophosphamide and fludarabine in order to induce lymphocyte depletion and create an optimal environment for expansion of axicabtagene ciloleucel in vivo.
  • Subjects will initiate lymphodepleting chemotherapy with cyclophosphamide and fludarabine beginning on Day -5 through Day -3.
  • the 3-day lymphodepleting chemotherapy regimen may be administered in an outpatient setting.
  • the lymphodepleting chemotherapy dose in will be cyclophosphamide (500 mg/m 2 ) and fludarabine (30 mg/m 2 ) both given for 3 concurrent days with the target dose of 2 x 10 6 anti-CD19 CAR-T cells/kg.
  • Cyclophosphamide (500 mg/m 2 ) and fludarabine (30 mg/m 2 ) both given for 3 concurrent days has been studied and tolerated in subjects with B cell malignancies 37 .
  • Patient may receive their treatment as an outpatient assuming daily follow-up for the first 14 days following axicabtagene ciloleucel infusion.
  • subjects may be hospitalized to receive their axicabtagene ciloleucel infusion and be observed for CRS and neurologic toxicities in the hospital setting, if deemed appropriate by the investigator.
  • subjects should not be discharged from the hospital until all axicabtagene ciloleucel-related non-hematological toxicities resolve to ⁇ Grade 1 or return to baseline.
  • Subjects may be discharged with non-critical and clinically stable or improving toxicities (e.g., renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator.
  • Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, hypotension, hypoxia, or ongoing neurologic toxicities > Grade 1, or if deemed necessary by the investigator.
  • Axicabtagene ciloleucel will be administered at a target dose of 2 x 10 6 anti-CD19 CAR-T cells/kg. Subjects who receive doses between 1-2 x 10 6 anti-CD19 CAR-T cells/kg will be included in the mITT analysis set. For subjects weighing greater than 100 kg, a maximum flat dose of 2 x 10 8 anti-CD19 CAR-T cells will be administered.
  • Emapalumab will be dosed at 3 mg/kg as an intravenous infusion on day -1 of cell infusion with cell infusion being on day 0.
  • Emapalumab is an intravenous infusion that should be given over 1 hour in the inpatient setting.
  • Corticosteroid therapy at a pharmacologic dose > 5 mg/day of prednisone or equivalent doses of other corticosteroids
  • other immunosuppressive drugs must be avoided for 7 days prior to leukapheresis, and 5 days prior to axicabtagene ciloleucel administration.
  • the package insert for Emapalumab administration advises to give dexamethasone prior to administration, but no steroids will be administered prior to Emapalumab administration during this trial.
  • Steroid prophylaxis will be re-instituted per emapalumab product label in the event of any single grade 3 anaphylaxis or if greater than 1/3 of the first 6 patients experience any other G2 infusion related reaction.
  • Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after axicabtagene ciloleucel administration, unless used to manage axicabtagene ciloleucel related toxicities.
  • Other medications that might interfere with the evaluation of the axicabtagene ciloleucel in combination with the investigational product, such as non-steroidal anti-inflammatory agents should also be avoided for the same time period unless medically necessary.
  • lymphoma such as chemotherapy, immunotherapy, targeted agents, radiation, and high dose corticosteroid, other than defined/allowed in this protocol, and other investigational agents are prohibited, except as needed for treatment of disease progression after the axicabtagene ciloleucel infusion.
  • Prophylactic steroids, anakinra or tocilizumab should not be used while on study. Patients should not receive anti-cytokine or steroid intervention for grade 1 CRS and/or ICANS. Patients who are prematurely treated prior to grade 2 will be replaced on study to accrue the analysis cohort of 28 patients.
  • G-CSF may be given after day +5 if CRS has resolved with down trending inflammatory markers.
  • TPO mimetics are allowed following day +30 of infusion. No GM-CSF is allowed to be given on study unless approved by sponsor.
  • Emapalumab has been associated with an increased incidence of infections. All patients should be screened for TB by either a purified protein derivative (PPD) test result or IFNy release assay as part of their infectious disease screening. Prophylaxis for TB should be administered to patients who are at risk for TB or known to have a positive purified protein derivative (PPD) test result or positive IFNy release assay.
  • PPD purified protein derivative
  • IFNy release assay Prophylaxis for TB should be administered to patients who are at risk for TB or known to have a positive purified protein derivative (PPD) test result or positive IFNy release assay.
  • PPD purified protein derivative
  • emapalumab treatment first 30 days after CAR-T
  • patients should be monitored for TB, adenovirus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) every 2 weeks and as clinically indicated.
  • EBV Epstein-Barr virus
  • CMV cytomegalovirus
  • HSV prophylaxis (acyclovir, famvir, etc) for 12 months following CAR-T.
  • PCP Bactrim, mepron, pentamidine IV, etc
  • Infusion-related reactions including drug eruption, pyrexia, rash, erythema, and hyperhidrosis, were reported with emapalumab treatment in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion. In the pivotal trial, the most commonly reported adverse reactions (>10%) for emapalumab included infection (56%), hypertension (41%), infusion-related reactions (27%), pyrexia (24%), hypokalemia (15%), constipation (15%), rash (12%), abdominal pain (12%), CMV-infection (12%), diarrhea (12%), lymphocytosis (12%), cough (12%), irritability (12%), tachycardia (12%), and tachypnea (12%).
  • Safety data will be reviewed and discussed with an external Data and Safety Monitoring Board (DSMB) per the study-specific DSMB charter.
  • DSMB Data and Safety Monitoring Board
  • An adverse event is defined as any untoward medical occurrence in a clinical trial subject. The event does not necessarily have a relationship with study treatment.
  • the definition of adverse events includes worsening of a pre-existing medical condition. Worsening indicates that the pre-existing medical condition has increased in severity, frequency, and/or duration or has an association with a worse outcome. A pre- existing condition that has not worsened during the study or involves an intervention such as elective cosmetic surgery or a medical procedure while on study, is not considered an adverse event.
  • Interventions for pretreatment conditions such as elective cosmetic surgery
  • medical procedures that were planned before study participation are not considered adverse events.
  • Hospitalization for study treatment infusions or precautionary measures per institutional policy are not considered adverse events.
  • disease progression as assessed by measurement of malignant lesions on radiographs or other methods should not be reported as adverse events. Death due to disease progression in the absence of signs and symptoms should be reported as the primary tumor type (e.g., B-Cell Lymphoma).
  • An SAE is any AE occurring at any dose and regardless of causality that:
  • An important medical event is an event that may not result in death, be life-threatening, or require hospitalization, but may be considered serious when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent 1 of the outcomes listed above.
  • the investigator is responsible for reporting adverse events directly related to study related procedures following study consent. Following initiation of emapalumab and cellular therapy infusion, the investigator is responsible for ensuring that all adverse events observed by the investigator or reported by the subject that occur starting at infusion of emapalumab through 1 month after treatment with emapalumab, are monitored and reported regardless of disease progression.
  • HHL Hemophagocytic Lymphohistiocytosis
  • MAS Macrophage Activation Syndrome
  • TLS Tumor Lysis Syndrome
  • the screening period begins on the date the subject signs the IRB/IEC approved ICF and continues through confirmation of enrollment. Informed consent must be obtained before completion of any non-standard of care study specific procedures. Procedures that are part of standard of care are not considered study specific procedures and may be performed prior to obtaining consent and used to confirm eligibility. Confirmation of this data must occur within the time allowance as outlined below and in the SOA.
  • subjects After written informed consent has been obtained, subjects will be screened to confirm study eligibility and participation. Only subjects who meet the eligibility criteria listed in Section 3 and who commence leukapheresis will be enrolled in the study. If at any time prior to enrollment the subject fails to meet the eligibility criteria, the subject should be designated as a screen failure on the subject screening log with the reasons for failing screening. Information regarding demographics, reason for screening failure, failed eligibility criteria, and any SAEs.
  • ⁇ PET performed following the subjects last line of therapy and prior to signing the consent may be used for confirmation of eligibility.
  • PET CT should be performed as close to enrollment as possible. If a PET is not accessible due to insurance reasons, CT imaging is allowable after discussion with the study PI. • Labs o Chemistry panel. o CBC with differential. o P-HCG pregnancy test (serum or urine) on all women of child-bearing potential.
  • HBV HBsAg, HBcAb, HBV NAT
  • HCV IgG, HCVNAT
  • HIV screening HIV screening
  • adenovirus PCR
  • CMV PCR and IgG
  • EBV PCR and IgG
  • Tb screening for latent Tb.
  • Subjects who are unable to complete or meet the eligibility criteria during the 28-day screening period will be permitted to rescreen. Subjects will retain the same subject identification number assigned at the original screening. If rescreening occurs within 28 days of the signing of the original informed consent, only the procedure(s)/assessment(s) that did not originally meet the eligibility criteria needs to be repeated; all other initial screening procedures/assessments do not need to be repeated. If rescreening occurs, or leukapheresis is delayed, more than 28 days from the signing of the original informed consent, subjects must be reconsented and repeat all screening procedures/assessments.
  • leukapheresis Before leukapheresis commences, the following criteria must be met. If criteria are not met, leukapheresis must be delayed until the event resolves.
  • Corticosteroid therapy at a pharmacologic dose >5 mg/day of prednisone or equivalent doses of other corticosteroids
  • other immunosuppressive drugs must be avoided for 7 days prior to leukapheresis.
  • bridging therapy must be administered after enrollment and completed prior to initiating lymphodepleting chemotherapy per the specifications outlined in Section 5.1.1 for bridging therapy.
  • PET will be older than 28 days at the initiation of lymphodepleting chemotherapy or if the subject receives any anti-cancer therapy with therapeutic intent (e.g., radiation, supraphysiologic doses of steroids, chemotherapy) between the last PET and initiation of lymphodepleting chemotherapy, the PET must be repeated to establish a new baseline.
  • therapeutic intent e.g., radiation, supraphysiologic doses of steroids, chemotherapy
  • lymphodepleting chemotherapy Before lymphodepleting chemotherapy commences, the following criteria must be met. If these criteria are not met, then lymphodepleting chemotherapy must be delayed until these events resolve: No evidence or suspicion of uncontrolled infection.
  • a delay in lymphodepleting chemotherapy may be required: Temperature is > 38.0°C within 48 hours prior to lymphodepleting chemotherapy or during lymphodepletion. Unexplained fever requires panculture, respiratory viral panel, chest computed tomography (CT), and any additional symptom-directed workup to rule out occult infection. Primary PI or sponsor is required to approve initiation of lymphodepletion if this occurs.
  • Corticosteroid therapy at a pharmacologic dose > 5 mg/day of prednisone or equivalent doses of other corticosteroids
  • other immunosuppressive drugs should be avoided unless defined in the protocol.
  • axicabtagene ciloleucel infusion Before axicabtagene ciloleucel infusion commences, the following criteria must be met: No evidence or suspicion of uncontrolled infection. Should an event not meet these criteria immediately prior to receiving axicabtagene ciloleucel, the axicabtagene ciloleucel infusion must be delayed until the event resolves. If the axicabtagene ciloleucel infusion is delayed > 2 weeks, lymphodepleting chemotherapy must be repeated. If CAR-T treatment is delayed more than 7 days, a new emapalumab dose will be given the day before CAR-T treatment.
  • All subjects will receive emapalumab and axicabtagene ciloleucel infusion at a healthcare facility followed by daily monitoring at a healthcare facility for at least 7 days to monitor for signs and symptoms of CRS and neurologic toxi cities.
  • subjects may be hospitalized to receive their emapalumab and axicabtagene ciloleucel infusion and be observed for CRS and neurologic toxicities in the hospital setting.
  • subjects should not be discharged from the hospital until all axicabtagene ciloleucel related non-hematological toxicities return to ⁇ Grade 1 or return to baseline.
  • Subjects may be discharged with non-critical and clinically stable or improving toxicities (e.g., renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator.
  • Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, hypotension, hypoxia, or ongoing central neurologic toxicities > Grade 1, or if deemed necessary by the investigator.
  • Subjects should be instructed to remain within proximity of the clinical study site for at least 4 weeks following axicabtagene ciloleucel infusion. During this period, the following procedures will be completed at the time points outlined in the SOA: • Neurological assessment for subjects to include ICANS (ICE scores)
  • CRP, ferritin, and LDH may assist with the diagnosis and define the clinical course in regard to CRS/ICANS. It is, therefore, mandatory that CRP, ferritin, and LDH (if elevated at baseline) be monitored daily starting at Day 0 and for at least 7 days at a healthcare facility. In addition, lactate should be monitored as clinically indicated.
  • Subject will allow key sponsor contacts to continue to access medical records so that information related to subjects health condition and initial treatment response may be obtained.
  • the following procedures will be completed for subjects as outlined in the SO A:
  • PET for disease assessment If the PET is not approved by the patients insurer CT will be allowed
  • Targeted adverse/serious adverse event reporting o Including neurological, hematological, infections, autoimmune disorders, and secondary malignancies
  • Targeted concomitant medication documentation (for 24 months or until disease progression, whichever occurs first) o Including gammaglobulins, immunosuppressive drugs, anti-infectives, and vaccinations
  • sites will need to make 2 attempts by a combination of telephone and mail to contact the subject. Sites must document both attempts to contact the subject. If a subject does not respond within 1 month after the second contact the subject will be considered lost to followup and no additional contact will be required.
  • All subjects will be consented to the CIBMTR immune effector cell therapy registry at the same time as consent for this protocol and data will be reported on standard schedules immediately following infusion as required by FDA. Following Month 24 patients, protocol long-term follow-up will continue through the CIBMTR immune effector cell therapy registry as part of the FDA mandated 15-year follow-up period. Patients may be transitioned to the CIBMTR long term follow-up before Month 24 at time of disease progression, initiation of anti-cancer therapy, withdrawal of consent or at the investigators discretion.
  • CRS & ICANS will be assessed by ASTCT grading standards, including ICE scores, which can be found in Table 2-Table 4.
  • CPAP Continuous positive airway pressure
  • BiPAP Bilevel positive airway pressure f Fever is defined as temperature >38°C not attributable to any other cause.
  • CRS grading is driven by hypotension and/or hypoxia.
  • ⁇ CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring one vasopressor and hypoxia requiring low- flow nasal cannula is classified as having Grade 3 CRS. Organ toxi cities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
  • a Low-flow nasal cannula is defined as oxygen delivered at ⁇ 6 liters/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 liters/minute.
  • Subjects will be evaluated for disease response by the site investigator at times indicated in the SOA. Disease assessments will be evaluated per Lugano criteria. Flow cytometric, molecular or cytogenetic studies will not be used to determine response.
  • PET-CT scans of the neck, chest, abdomen and pelvis, along with the appropriate imaging of all other sites of disease are required. Subjects will undergo additional PET or CT tumor assessments after their axicabtagene ciloleucel infusion. While PET is preferred, CT assessment may be used in place of PET in the event of failure to obtain insurance coverage. Month 1, 6 and 12 should be assessed via PET, CT will be allowed if denied by patients insurance. The first of these post-treatment PET tumor assessments will occur 4 weeks after infusion; subsequent assessments will occur at regular intervals throughout the post-treatment and long-term follow-up portions of the study, as highlighted in the SOA.
  • ORR Objective response rate
  • DOR Duration of response
  • PFS Progression-free Survival
  • OS Overall survival

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Abstract

La présente divulgation concerne des méthodes de traitement du cancer, y compris des méthodes d'amélioration de thérapies par cellules CAR-T.
PCT/US2025/014058 2024-02-01 2025-01-31 Méthode d'amélioration de thérapies par cellules car-t Pending WO2025166179A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022238901A1 (fr) * 2021-05-11 2022-11-17 Janssen Biotech, Inc. Procédés de réduction au minimum de la neurotoxicité associée à une thérapie cellulaire t du récepteur de l'antigène chimère (car)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022238901A1 (fr) * 2021-05-11 2022-11-17 Janssen Biotech, Inc. Procédés de réduction au minimum de la neurotoxicité associée à une thérapie cellulaire t du récepteur de l'antigène chimère (car)

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Title
ANONYMOUS MATTHEW R. ET AL: "Emapalumab for the treatment of refractory cytokine release syndrome in pediatric patients - ScienceDirect", BLOOD ADVANCES, vol. 7, no. 18, 18 September 2023 (2023-09-18), pages 5603 - 5607, XP093271116, ISSN: 2473-9529, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S2473952923004366> DOI: 10.1182/bloodadvances.2023010712 *
BAILEY, B BLOOD CANCER DISCOV, vol. 3, no. 2, 1 March 2022 (2022-03-01), pages 136 - 153
BHASKAR ET AL., E EJHAEM, vol. 3, January 2022 (2022-01-01), pages 39 - 45
CHEN ET AL., CANCERS, vol. 15, no. 3, February 2023 (2023-02-01), pages 663
MCNERNEY KEVIN O. ET AL: "Potential Role of IFN[gamma] Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy", BLOOD CANCER DISCOVERY, vol. 3, no. 2, 1 March 2022 (2022-03-01), pages 90 - 94, XP093270676, ISSN: 2643-3230, Retrieved from the Internet <URL:https://aacrjournals.org/bloodcancerdiscov/article-pdf/3/2/90/3411838/90.pdf> DOI: 10.1158/2643-3230.BCD-21-0203 *
NCT06285825: "Study Details | A Pilot Study of Emapalumab for the Treatment of CAR T-Cell Therapy-Associated Prolonged Cytopenia | ClinicalTrials.gov", 22 February 2024 (2024-02-22), XP093271218, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT06285825> *
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STERNERSTERNER, FRON. IMMUNOL, vol. 13, 2022, pages 879608

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