Immune Checkpoint Inhibitors in Prostate Cancer

Abstract

Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.

Keywords: immune checkpoint inhibitors; prostate cancer.

Figure 1

Select mechanisms to target immune pathways in prostate cancer (A) Viral vector from a vaccine containing a sequence for antigen presentation such as prostate-specific antigen or other targets that may be enriched in prostate cancer. (B) Many mutations commonly found in prostate cancer cause DNA repair deficiency or replication defects and lead to more mutations. If these mutations result in changes to the amino acid sequence of a protein, they can serve as potential tumor-specific neoantigens. (C) Treatment with poly-ADP (ribose) polymerase inhibitors (PARPis) can cause DNA to leak into the cytoplasm and trigger the cGAS-STING pathway which can induce an immunostimulatory response. Figure created via Adobe Inc. (2021). Adobe Illustrator version 25.2.3. Retrieved from https://adobe.com/products/illustrator (accessed on 11 April 2021).

Figure 2

The immune microenvironment of prostate cancers. Myeloid-derived suppressor cells, increased adenosine concentrations, and immune checkpoints promote an immunologically cold phenotype. Monoclonal antibodies that target these proteins can help reduce immunosuppression. Cell-based such as sipuleucel-T and chimeric antigen receptor (CAR) T cell therapies can be engineered to target specific aspects of the tumor. Figure created via Adobe Inc. (2021). Adobe Illustrator version 25.2.3. Retrieved from https://adobe.com/products/illustrator (accessed on 11 April 2021).