Chimeric Antigen Receptor-Engineered T Cells for the Treatment of Metastatic Prostate Cancer
Abstract： Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors ofScience, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review focuses on different means of accomplishing maximal effectiveness of CAR T cell therapy for prostate cancer bone metastases while minimizing side effects and CAR T cell-associated toxicities. CAR T cell based therapies for prostate cancer have the potential to be a therapy model for other solid tumors.