Despite significant improvements in detection and treatment, advanced prostate cancer remains incurable, when androgen receptor (AR)-targeted therapies fail. To evaluate potential treatments to eradicate resistant tumours, we used pre-clinical patient-derived xenograft models (PDXs) of prostate cancer, performing many more drug combinations than would be possible in patients themselves. Here we report a combination that elicited a complete response and eradicated the tumour, included an immunotherapy with genetically engineered chimeric-antigen receptor (CAR) T cells. Previous reports on the efficacy of CAR T in solid tumours, such as prostate cancer, were disappointing and likely due to the suppressive tumour microenvironment (TME) acting as a barrier to CAR T cells: combining CAR T cells with agent/s to address the TME appears necessary.
Our team has developed CAR T cells that recognize Lewis Y (LeY) glycolipid antigen that is over-expressed in >50% of solid tumours, including prostate cancer. Using PDX-derived organoids, we showed LeY-CAR T cells induced morphological destruction and propidium iodine (PI) uptake (indicating secondary necrosis); killing was mediated by granule exocytosis mechanism as granzyme/ perforin inhibitors significantly reduced cell death.
In contrast, in vivo PDX treatment with LeY-CAR T cells alone did not inhibit tumour growth. Our systematic testing of combinations with LeY-CAR T, showed carboplatin chemotherapy reduced tumours to <1% of the starting tumour volume: but nivolumab did not. Residual cancer cells were surrounded by infiltrating T cells in the residual grafts, indicating trafficking and persistence of CAR T cells in the combination treatment group vs CAR T cells alone
LeY-CAR T cell therapy is in early phase clinical development for patients with solid tumours, and these studies provide essential preclinical evidence of LeY-CAR T cell efficacy, defining an optimal treatment strategy for clinical trial design.