Chimeric antigen receptor T cell therapy and tumor-associated myeloid cell reprogramming for combined immunotherapy of glioblastoma

GBM remains uniformly lethal, with a median survival of little more than a year from diagnosis. While immunotherapies have revolutionized the SOC for many cancers, patients with GBM have not greatly benefitted from those developments so far. CAR T cell therapy has proven remarkably effective in treating hematological malignancies. However, for solid tumors, especially GBM, CAR T cell therapy remains inefficient mainly due to pronounced tumor immunosuppression and heterogeneous expression of tumor-specific antigens, leading to adaptive resistance and antigen escape. The iTME of GBM plays an essential role in the tumor’s response to immunotherapies. MG and tumor-infiltrating MdCs are among the most prevalent immune cell types in the GBM iTME. In response to the blockade of the CD47-SIRPA tumor-immune checkpoint axis, these GBM-associated MG and MdCs, collectively termed GAMs, regain their phagocytic effector function against GBM cells. In this work, I present the development of a novel CAR T cell to target GBM via the tumor-specific EGFRvIII and reprogram the GBM immunosuppressive iTME through paracrine secretion of a SIRPG-related protein, termed SGRP, which blocks CD47, eliciting phagocytosis. As a proof of concept, I show the therapeutic potential of an anti-EGFRvIII-SGRP CAR T cell in orthotopic GBM and anti-CD19-SGRP CAR T cell in peripheral lymphoma mouse xenograft models. Here, I describe the following significant findings: (1) anti-EGFRvIII-SGRP CAR T cells eradicate EGFRvIII-mosaic GBM, resulting in the long-term survival of GBM mouse xenografts; (2) the combination of conventional anti-EGFRvIII CAR T cells with anti-CD47 antibodies does not warrant comparable efficacy, highlighting the importance of sustained paracrine myeloid cell modulation; (3) anti-EGFRvIII-SGRP CAR T cell treatment induces myeloid-mediated tumor cell uptake in the brain and elicits a peripheral innate chemotactic cytokine response; (4) anti-CD19-SGRP CAR T cell treatment significantly prolongs survival of lymphoma mouse xenografts compared to conventional anti-CD19 CAR T cell therapy. This work provides evidence that tumor-targeting by CAR T cells and paracrine modulation of tumor-associated myeloid cells via a SIRPG-derived molecule is a compelling novel combinatorial therapeutic approach to mitigate the impact of GBM immunosuppression and heterogeneity, encouraging clinical translation in GBM and other myeloid-infiltrated cancers.