Despite significant improvements in detection and treatment, advanced prostate cancer remains incurable when androgen receptor (AR)-targeted therapies fail. New treatment options are needed for these men. The treatment of blood cancers has been revolutionised by new immunotherapy approaches, such as genetically engineered chimeric-antigen receptor (CAR) T cells. Our team has developed 3rd generation CAR T cells that recognize Lewis Y (LeY ) glycolipid antigen, which is over-expressed in >50% of solid tumours, including prostate cancer. Here, we evaluated their potential for incurable prostate cancer. In vitro, 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. However, when combined with carboplatin chemotherapy (but not docetaxel or the anti-PD-1 antibody nivolumab) the combination of treatments reduced tumours to <1% of the starting tumour volume. Residual cancer cells were surrounded by infiltrating T cells, 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.