Novel Redirected T-Cell Immunotherapies for Advanced Prostate Cancer

Abstract

Immunotherapy has failed to achieve durable remissions in advanced prostate cancer patients. More potent T-cell-redirecting strategies may be needed to overcome the immunologically exclusive and suppressive tumor microenvironment. Clinical trials are underway, seeking to define the optimal target for T-cell redirection, such as PSMA, PSCA, or STEAP-1, as well as the optimal strategy, with CAR or bispecific antibodies. As results continue to emerge from these trials, understanding differential toxicity and efficacy of these therapies based on their targets and functional modifications will be key to advancing these promising therapies toward clinical practice. This review provides a unique depth and breadth of perspective regarding the diverse immunotherapy strategies currently under clinical investigation for men with advanced prostate cancer.

Figure 1.

Mechanisms of action of BiTE antibody (A, B) and CAR-T (C, D) therapies.

Figure 2.

Immunosuppressive barriers to CAR T-cell function in advanced (metastatic) prostate cancer. Recent studies, including those discussed in this review, suggest that both tumor- and T-cell–intrinsic factors could hamper the efficacy of CAR T cells in prostate cancer. Barriers include elaboration of immunosuppressive cytokines (e.g., TGFβ), increased expression of inhibitory ligands (e.g., PD-L1), apoptosis of CAR T cells, and metabolic stress operative in the TME. A formidable stromal barrier may result in CAR T-cell and bystander immune cell migration along the protumor extracellular matrix (ECM), instead of infiltration into the tumor bed. T cell–intrinsic defects, including replicative senescence, inhibitory receptor upregulation/exhaustion, and reduced early memory T-cell function, may also prevent CAR T cells from eliciting an effective antitumor response.