Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research

Abstract

A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival-with substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well.

Figure 1

Current immunotherapy approaches for prostate cancer (adapted from Drake (55), which provides further details). A) Sipuleucel-T: This immunotherapy is made individually for each patient. Cells obtained by leukapheresis are sent to a central facility for processing and manufacture. Monocytes are prepared from the apheresis product and subsequently cultured with a proprietary protein cassette that couples the vaccine target (prostatic acid phosphatase; PAP) to GM-CSF. This process produces an active cellular immunotherapy product, which is then shipped to the administering physician’s office for i.v. infusion. This process is repeated 3 times over a 4- to 6-week period. B) PROSTVAC-VF: This agent includes plasmid DNA encoding 3 costimulatory molecules, as well as prostate-specific antigen (PSA) as a vaccine target. Plasmid DNA is incorporated into either vaccinia or fowlpox viruses using a packing cell line. Patients are treated with a vaccinia prime followed by a series of fowlpox-based boosts, all given intradermally. C) Anti-CTLA-4: This approach is based on the finding that interactions between B7 molecules on antigen-presenting cells and CTLA-4 on tumor-specific T cells is inhibitory. Thus, CTLA-4 engagement negatively regulates the proliferation and function of such T cells. Under certain conditions, blocking CTLA-4 using a monoclonal antibody (ipilimumab, BMS, or tremilimumab [Pfizer]) restores T-cell function.

Figure 1

Current immunotherapy approaches for prostate cancer (adapted from Drake (55), which provides further details). A) Sipuleucel-T: This immunotherapy is made individually for each patient. Cells obtained by leukapheresis are sent to a central facility for processing and manufacture. Monocytes are prepared from the apheresis product and subsequently cultured with a proprietary protein cassette that couples the vaccine target (prostatic acid phosphatase; PAP) to GM-CSF. This process produces an active cellular immunotherapy product, which is then shipped to the administering physician’s office for i.v. infusion. This process is repeated 3 times over a 4- to 6-week period. B) PROSTVAC-VF: This agent includes plasmid DNA encoding 3 costimulatory molecules, as well as prostate-specific antigen (PSA) as a vaccine target. Plasmid DNA is incorporated into either vaccinia or fowlpox viruses using a packing cell line. Patients are treated with a vaccinia prime followed by a series of fowlpox-based boosts, all given intradermally. C) Anti-CTLA-4: This approach is based on the finding that interactions between B7 molecules on antigen-presenting cells and CTLA-4 on tumor-specific T cells is inhibitory. Thus, CTLA-4 engagement negatively regulates the proliferation and function of such T cells. Under certain conditions, blocking CTLA-4 using a monoclonal antibody (ipilimumab, BMS, or tremilimumab [Pfizer]) restores T-cell function.

Figure 1

Current immunotherapy approaches for prostate cancer (adapted from Drake (55), which provides further details). A) Sipuleucel-T: This immunotherapy is made individually for each patient. Cells obtained by leukapheresis are sent to a central facility for processing and manufacture. Monocytes are prepared from the apheresis product and subsequently cultured with a proprietary protein cassette that couples the vaccine target (prostatic acid phosphatase; PAP) to GM-CSF. This process produces an active cellular immunotherapy product, which is then shipped to the administering physician’s office for i.v. infusion. This process is repeated 3 times over a 4- to 6-week period. B) PROSTVAC-VF: This agent includes plasmid DNA encoding 3 costimulatory molecules, as well as prostate-specific antigen (PSA) as a vaccine target. Plasmid DNA is incorporated into either vaccinia or fowlpox viruses using a packing cell line. Patients are treated with a vaccinia prime followed by a series of fowlpox-based boosts, all given intradermally. C) Anti-CTLA-4: This approach is based on the finding that interactions between B7 molecules on antigen-presenting cells and CTLA-4 on tumor-specific T cells is inhibitory. Thus, CTLA-4 engagement negatively regulates the proliferation and function of such T cells. Under certain conditions, blocking CTLA-4 using a monoclonal antibody (ipilimumab, BMS, or tremilimumab [Pfizer]) restores T-cell function.

Figure 2

If therapeutic vaccines can eventually lead to prolonged slowing of tumor growth rate due to continuous immune pressure from an ongoing, dynamic antitumor immune response, then even if tumor growth slows at an identical rate in 2 different patients, a patient given vaccine earlier in the disease course (A) might have a much improved outcome compared to a patient given vaccine later in the disease course (B). Dashed line = disease trajectory if no therapy is given. † = death from cancer.

Figure 3

Overall survival curves for (A) sipuleucel-T (n = 127) (1), (B) sipuleucel-T (n = 516) (4), and (C) PSA-TRICOM (n = 125) (9). Note that there is no separation in overall survival curves (vaccine vs. control) until 6 to 12 months following initiation of trial, suggesting that patients who died within the first 6 to 12 months had no benefit from vaccine.

Figure 3

Overall survival curves for (A) sipuleucel-T (n = 127) (1), (B) sipuleucel-T (n = 516) (4), and (C) PSA-TRICOM (n = 125) (9). Note that there is no separation in overall survival curves (vaccine vs. control) until 6 to 12 months following initiation of trial, suggesting that patients who died within the first 6 to 12 months had no benefit from vaccine.