Immunotherapy with genetically engineered chimeric-antigen receptor (CAR) T cells is a profound advance in cancer therapy. CAR T cells exemplify a new generation of therapies that function through immune activation and have revolutionised outcomes for haematological malignancies. However, CAR T cells are less effective against solid cancers, as the immunosuppressive tumour microenvironment (TME) precludes T cell infiltration, activation and cytotoxicity following antigen recognition. It is becoming increasingly evident that CAR T cells are ineffective as a single therapy for solid tumours, and that combining CAR T cells with agents to pre-condition the TME are essential. These barriers must be overcome to confidently proceed to clinical trials for patients with endocrine-related cancers, such as prostate cancer.
Recent studies have revealed that low-dose chemotherapy can alter the TME to maximise CAR T cell trafficking and efficacy in preclinical models of prostate cancer. Mechanistically, carboplatin remodels the TME to overcome immune-suppression, resulting in early and persistent infiltration of activated CAR T cells into the tumour. Chemotherapy pre-conditioning induces a cascade of changes to the TME, including the induction of an inflammatory cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-orienting M1 macrophage differentiation, thereby enhancing T cell trafficking and retention in the tumour mass. Collectively, these data suggest that chemotherapy pre-conditioning may increase the efficacy of CAR T cell therapy for solid tumours, and could achieve durable tumour regression in men with prostate cancer who have exhausted all treatment options.