Munich, Germany (UroToday.com) In today’s thematic session on systemic treatment for advanced prostate cancer, Dr. Peter Mulders discussed immunotherapy strategies. He began with a history of immunotherapy, which began with the discovery of the 1st cancer vaccine in 1890. He then reviewed the mechanism of immune therapy, where a degenerating tumor expresses immunogenic targets such as PAP, PSCA, MUC-1, and PSA. Immature dendritic cells phagocytose dying tumor cells and present their antigens to T-cells. Newly activated tumor-specific T-cells proliferate, and when fully activated, they seek and kill tumor cells.
Current and emerging immunotherapies for prostate cancer have included Prostvac, Sipuleucel-T, and Ipilimumab. Prostvac is a viral-based vaccine that expresses PSA and immunostimulatory molecules, and is boosted by fowlpox expressing the same. Sipuleucel is a form of active cellular immunotherapy that works through ex-vivo activation of immune cells by recombinant PAP-GMCSF. Cells are then reinfused and stimulate PAP-specific immune response in vivo. Ipilimumab is a monoclonal antibody that binds and blocks CTLA-4, which nonspecifically inhibits immunosuppression and thus augments ongoing immune responses.
The phase 3 trial of sipuleucel-T demonstrated a 4.1 month survival benefit and reduction in risk of death by 22.5%. As is the case in other immunotherapy trials, PFS was nonsignificant. Post-hoc analysis demonstrated improved survival among PA2024 and PAP responders. Survival was also improved among all baseline PSA groups (HR 0.51-0.84 for PSA <22 to >134, respectively). Histological study demonstrated increased T-cell infiltration at the tumor interface among patients who underwent radical prostatectomy.
The phase 2 RCT of Prostvac vs. empty vector demonstrated a significant PSA-specific immune response, as well as a measurable impact on anti-PSA ab and antigen cascade. There was an 8.5 month OS benefit and reduction in risk of death by 44% for patients receiving prostvac vs. controls. As was the case with Sipuleucel, there was no impact on PFS. The addition of Ipilimumab to Prostvac improved median OS from 26.3 months to 34.4 months. However, phase 3 study of Ipilimumab vs. placebo after radiotherapy in patients with mCRPC did not show a survival benefit in the monotherapy setting; it did, however, demonstrate identifiable anti-tumor activity including reductions in PSA and improved PFS.
Immunotherapy, when compared with conventional therapy, has several important differences. While conventional therapy targets the tumor or its microenvironment, vaccines have a systemic effect. Conventional therapy tends to have an immediate effect that similarly has a prompt loss of effect, while immunotherapy has a delayed and often prolonged effect. Vaccines elicit a memory response and are limited by the need for an adequate immune system, while conventional therapy is limited by its toxicity.
Dr. Mulders concluded that immunotherapy is the future of systemic treatment for prostate cancer. It should be used earlier in the treatment algorithm, preferably in the non-metastatic castration sensitive setting. Smart combinations of medications utilizing synergistic pathways are key to achieving optimal, durable outcomes.
Presented By:
P.F.A. Mulders, Nijmegen (NL)
Reported By:
Nikhil Waingankar, MD, at the 31st Annual EAU Congress - March 12 - 15, 2016 – Munich, Germany
Fox Chase Cancer Center