Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity

Abstract

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.

Allogeneic CAR Invariant Natural Killer T Cells Exert Potent Antitumor Effects through Host CD8 T-Cell Cross-Priming

“…The potential contribution of the host immune system in the effect of CAR T cells has been shown in preclinical (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) and clinical (43)(44)(45) studies. Recent studies indicate that immunogenic cell death eliciting endogenous cells responses contribute to the effects of adoptively transferred immune effector cells, including TCR-transgenic T cells (46,47), NK cells (46).…”

A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas

“…Several recent studies of solid extracranial cancers have shown that strategic timing of chemotherapy and immunotherapy can achieve synergies that are significantly greater than either individual approach 3 – 8 . In addition to reducing tumor mass, thereby reverting T cell exclusion and promoting T cell infiltration 9 , chemotherapy can also generate pro-inflammatory T cell and myeloid cytokine expression 10 . Alkylating agents such as Temozolomide (TMZ), the primary chemotherapeutic agent for glioblastoma (GBM), methylates the O 6 position of guanine residues thereby inducing mispairing with thymine during replication inducing cascading cycles of thymine excision and reinsertion, DNA strand breaks, and activation of the DNA damage response leading to cytotoxicity.…”

Novel Redirected T–Cell Immunotherapies for Advanced Prostate Cancer

“…It has recently been shown that conditioning chemotherapy, commonly referred to as "lymphodepletion", plays a critical role in modulating the TME for CAR T cell effect. In particular, cyclophosphamide administration increased intra-tumoral PSCA-targeted CAR T cell accumulation and expansion in vivo (38). Gene ontology enrichment analysis identified T cell migration and IFN-γ production as key processes enhanced by cyclophosphamide pre-treatment.…”