Augmenting the efficacy of prostate cancer-directed CAR T cell therapy by combining immune-editing, chemotherapy and androgen receptor blockade

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Prostate cancer (PC) is the second most common cancer in men worldwide. Whereas primary tumors can often be successfully managed, new therapeutic options are urgently needed for advanced, thus far incurable stages of the disease. In recent years, immunotherapy became a new cornerstone in the treatment of cancer, including monoclonal antibodies that target immune checkpoint receptors and chimeric antigen receptor (CAR) T cells that target tumor-associated antigens. We recently demonstrated that our prostate-specific membrane antigen (PSMA)-targeting CAR T cells were able to eradicate human PC in a xenografted mouse model after local application, and, after systemic application, to inhibit tumor growth when combined with docetaxel (DTX) chemotherapy. Our preliminary data show that DTX or enzalutamide treatment increased CCL2 and CCL22 expression in PC cells, and that CAR T cells co-expressing the chemokine receptors CCR2 and CCR4 showed enhanced migration towards CCL2 and CCL22, respectively. We thus hypothesize that equipping CAR T cells with chemokine receptors will improve both their migration to CCL2/CCL22 secreting tumor cells as well as their ability to kill PSMA-expressing tumor cells after DTX or enzalutamide treatment. The objectives of our project are (i) to characterize the anti-tumor efficacy of gene-edited CCR2/CCR4-expressing PSMA-targeting CAR T cells alone and in combination with DTX and/or enzalutamide in vitro, and (ii) to validate the antitumor efficacy of CCR2/CCR4-expressing CAR T cells in mice xenografted orthotopically with metastasizing human PC cells upon non-ablative DTX and/or enzalutamide therapy. We believe that the results will expand our knowledge of immuno-oncological features of PC and pave the way for clinical trials.