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EP-4736874-A1 - METHODS FOR PREDICTING AND IMPROVING THE EFFICACY OF CAR T-CELL THERAPY

EP4736874A1EP 4736874 A1EP4736874 A1EP 4736874A1EP-4736874-A1

Abstract

Disclosed is a treatment with a combination of inhibitors useful to improve the effectiveness of CAR T-cell therapies by inhibiting hypoxia, VEGF pathways and inflammation at the tumor microenvironment, thereby enhancing the response to CAR T-cell therapy in tumor patients. There is also disclosed a method for predicting the response to CAR T-cell therapy by determining T cell surface expression markers.

Inventors

  • MAGNANI, CHIARA FRANCESCA
  • PONZO, Marianna
  • GAIPA, Giuseppe
  • BIONDI, ANDREA

Assignees

  • Fondazione Matilde Tettamanti e Menotti de Marchi Onlus
  • Universität Zürich

Dates

Publication Date
20260506
Application Date
20241104

Claims (10)

  1. An HIF1α or VEGFR2 or IFN inhibitor, or a combination thereof, for use in the treatment of tumor by means of CAR T cells, wherein said inhibitors or combinations thereof enhance CAR T-cell activity by preventing T-cell exhaustion and by reducing the immunosuppressive effect of tumor microenvironment.
  2. A combination of inhibitors for use according to claim 1, which is selected from the group consisting of (i) HIF1α and VEGFR2 inhibitors and (ii) HIF1α and IFN inhibitors.
  3. An inhibitor or inhibitor combination for use according to claim 1, wherein said inhibitor is an antibody.
  4. The inhibitor or inhibitor combination for use according to claim 1, wherein said tumor is a hematologic tumor.
  5. The inhibitor or inhibitor combination for use according to claim 4, wherein said hematologic tumor is acute lymphoblastic leukemia.
  6. The inhibitor or inhibitor combination for use according to claim 1, wherein said inhibitor or inhibitor combination is administered immediately before, during or immediately after the administration of the CAR T cell therapy.
  7. The inhibitor or inhibitor combination for use according to claim 1, wherein said inhibitor or inhibitor combination is administered prior to, following or concomitantly with (i) lymphodepletion or (ii) surgery to remove a tumor or (iii) radiotherapy.
  8. The inhibitor or inhibitor combination for use according to claim 1, wherein said tumor expresses CD19 and said CAR T cells carry a CD19-specific CAR.
  9. A method of predicting the response to CAR T-cell therapy, which comprises determining, in a sample of T cells isolated from a subject undergoing CAR T-cell therapy, the expression of a cell surface marker selected from PD1, TIGIT, TIM3 and LAG3, or a combination thereof, wherein detection of said surface marker expression in the T cell sample is indicative of a poor response to the CAR T-cell therapy.
  10. The method of claim 8, wherein the determination of surface marker expression is carried out by means of marker-specific antibodies.

Description

The present invention relates to a combination of biologically active agents useful to improve the effectiveness of CAR T-cell therapies. More precisely, the invention provides a combination of inhibitors able to counteract hypoxia, VEGF pathways and inflammation at the tumor microenvironment with CAR T-cell treatment thereby enhancing the response to CAR T-cell therapy in tumor patients. Another aspect of the invention relates to a method for predicting the response to CAR T-cell therapy by determining T cell surface expression markers. Background of the Invention CAR T-cell therapy, targeting the CD19 antigen, has demonstrated promising efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Nevertheless, only a fraction of B-ALL patients treated with CAR T cells maintains a durable remission long term. In a considerable portion of treated patients, relapse occurs in the presence of CD 19-expressing tumors, mainly because of CAR T-cell dysfunction and immune suppression within the tumor microenvironment (TME). Indeed, CAR T cells do not act on cancer cells in isolation, but within the TME, which is known to affect T-cell activity. Therefore, a major interest is to identify factors within the TME that influence the activity and potency of anti-CD19 CAR T cells with the final aim to develop more efficacious combinatorial therapies. We hypothesized that the immunological niche of the TME reacts to CAR T cell-mediated inflammation by modulating the immune response through the activation of inhibitory pathways and molecules, leading to insufficient CAR T-cell activity. Current CAR T-cell approaches are often insufficient in overcoming the TME barriers, as we demonstrated that the TME contains immunosuppressive factors, including myeloid-derived suppressor cells (MDSCs), hypoxia, and signaling molecules such as TGF-β, VEGF, type 1 and type 2 IFNs, and HIF1α. These factors promote T-cell dysfunction and interfere with CAR T-cell activity over time. Prior attempts to improve CAR T-cell efficacy have not fully addressed the need to modulate these immunosuppressive factors within the TME. Therefore, a therapeutic solution is required to prevent or treat CAR T-cell dysfunction and T-cell exhaustion and to counteract the adverse effect of the TME. Moreover, there is a need for a biomarker that could predict poor response to CAR T-cell therapy and also stratify the patients potentially benefitting of combinatorial therapy. Description of the invention In one aspect, the invention provides methods and compositions for enhancing CAR T cells-mediated cancer therapy by modulation of the hypoxic and/or chronically inflamed tumor microenvironment. In particular, the invention provides a therapeutic approach that combines targeting and inhibition of hypoxia-inducible and chronically inflamed factors, particularly HIF1α, VEGF and IFNs, to counteract TME-driven immunosuppression and improve the effectiveness of CAR T-cell therapy. By inhibiting the hypoxic and/or chronically inflamed tumor microenvironment, targeting HIF1α, VEGF, and IFN, the invention aims to reduce, in patients treated with CAR T-cell therapy, the immunosuppressive effect of the TME that contribute to T-cell exhaustion and CAR T-cell dysfunction, thereby maintaining a sustained anti-tumor response. Accordingly, in a first embodiment the invention provides a HIF1α or VEGFR2 or IFN inhibitor, or a combination thereof, for use in the treatment of tumor by means of CAR T cells, wherein said inhibitors or combinations thereof enhance CAR T-cell activity by preventing T-cell exhaustion and by reducing the immunosuppressive effect of tumor microenvironment. Tumors that can be treated according to the invention include stomach adenocarcinoma, colorectal carcinoma, hepatocellular carcinoma, gallbladder cancer, non-small cell bronchial carcinoma, non-small cell lung cancer, metastatic and malignant melanoma, breast cancer, pancreatic neuroendocrine tumor, soft tissue sarcoma, preferably hematological tumors and more preferably acute lymphoblastic leukemia (ALL). The CAR T-cell therapy exploits cells that have been modified to express one or more engineered CAR molecules directed against a tumor antigen. Tumor antigens which can be targeted by CAR T-cells according to the invention include CD19, BAFFR, BCMA, BTLA, B7-H3, B7-H6, CAIX, CA9, CD20, CD22, CD72, CD30, CD33, CD38, CD44, CD44v6, CD70, CD123, CD33, CD117, ADGRE2, CLL-1, FLT3, SSTR2, CEA, CSPG4, EGFR, EGFR family including ErbB2 (HER2), EGFRvIII, EGP2, EGP40, ERBB3, ERBB4, ErbB3/4, EPCAM, EphA2, EpCAM, folate receptor-a, FAP, FBP, fetal AchR, GD2, CAIX, GD3, Glypican-2, Glypican-3 (GPC3), Her2, HLA-A1+MAGE1, HLA-A1+NY-ESO-1, IL-11Ralpha, IL-13Ralpha2, Lambda, Lewis-Y, Kappa, KDR, Melanoma-associated antigen (MAGE), MCSP, Mesothelin, Muc1, Muc16, NCAM, NKG2D Ligands, NY-ESO-1, Preferentially expressed antigen of melanoma (PRAME), PSC1, PSCA, PSMA, ROR1, SP17, Survivin, TAG72 TEMs