Vaccines as treatments for prostate cancer

Abstract

Prostate cancer is a leading cause of death in men worldwide. For over 30 years, growing interest has focused on the development of vaccines as treatments for prostate cancer, with the goal of using vaccines to activate immune cells capable of targeting prostate cancer to either eradicate recurrent disease or at least delay disease progression. This interest has been prompted by the prevalence and long natural history of the disease and by the fact that the prostate is an expendable organ. Thus, an immune response elicited by vaccination might not need to target the tumour uniquely but could theoretically target any prostate tissue. To date, different vaccine approaches and targets for prostate cancer have been evaluated in clinical trials. Overall, five approaches have been assessed in randomized phase III trials and sipuleucel-T was approved as a treatment for metastatic castration-resistant prostate cancer, being the only vaccine approved to date by the FDA as a treatment for cancer. Most vaccine approaches showed safety and some evidence of immunological activity but had poor clinical activity when used as monotherapies. However, increased activity has been observed when these vaccines were used in combination with other immune-modulating therapies. This evidence suggests that, in the future, prostate cancer vaccines might be used to activate and expand tumour-specific T cells as part of combination approaches with agents that target tumour-associated immune mechanisms of resistance.

Fig. 1. Antitumour vaccine approaches in prostate cancer.

The types of vaccine platforms that have been explored for the treatment of prostate cancer using antigen-specific or non-antigen-specific approaches are shown. Vaccines have been delivered intradermally and intramuscularly alone or in combination with dendritic cells. In principle, antigens are present in whole-cell vaccines, are delivered as proteins or peptides, or are encoded by genetic vectors that activate CD4⁺ and CD8⁺ T cells within local lymph nodes and spleen, which can then traffic to tumour sites and mediate killing of antigen-expressing tumour cells. APC, antigen-presenting cell; CTLA4, cytotoxic T lymphocyte antigen 4; MHC, major histocompatibility complex; TCR, T cell receptor.

Fig. 2. Mechanisms of antitumour vaccine resistance and potential combination approaches in prostate cancer.

Antitumour vaccination leads to the activation of T cells that can express T cell-checkpoint molecules, such as PD1 and cytotoxic T lymphocyte antigen 4 (CTLA4), which can inhibit the effector function of these cells. Tumour cells can also secrete immune-inhibitor molecules, such as TGFβ, or recruit inhibitory immune populations that decrease the efficacy of vaccine-activated T cells. These mechanisms of resistance indicate pathways that can be targeted as parts of combination therapies using antitumour vaccines. GZMB, granzyme B; IDO, indoleamine 2,3-dioxygenase; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PFN, perforin; TAM, tumour-associated macrophage; TCR, T cell receptor.