Prostvac, Psa-Targeted Immunotherapy: New Evidence for Mechanism of Action

3080 Background: PROSTVAC is being tested for treatment of metastatic castration-resistant prostate cancer in the PROSPECT phase 3 trial. PROSTVAC immunotherapy comprises subcutaneous dosing in a heterologous prime-boost regimen with recombinant vaccinia virus (PROSTVAC-V) for priming plus recombinant fowlpox virus (PROSTVAC-F) for boosting doses. Both products encode transgenes for PSA as the target tumor antigen plus TRICOM (B7-1, ICAM-1 and LFA-3) to enhance immune activation. Data from clinical and nonclinical studies provide evidence for mechanism of action potentially leading to improved overall survival following PROSTVAC immunotherapy. Methods: Subjects from a randomized double-blind placebo controlled Phase 2 study (NCT00078585) received PROSTVAC or empty vector. IFN-γ ELISPOT was performed on archived samples meeting viability requirements. Immune responses in therapeutic prostate cancer mouse studies were evaluated by immunoassays. Results: Subjects demonstrated significant enhancement of PSA-specific T cell responses following PROSTVAC immunotherapy compared to control subjects. T cells against endogenous, non-PSA tumor antigens (antigen spread) were also elevated following PROSTVAC immunotherapy. Treatment with PROSTVAC-V/F in mice amplified the magnitude and quality of activated PSA-specific T cells following heterologous vs. homologous prime-boost dosing regimen. Tumor-infiltrating CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines and amplified cytotoxic T cell activity. In vivo CD4 and CD8 T cell depletion revealed that both subsets contributed to anti-tumor efficacy. PROSTVAC immunotherapy also resulted in reduced Treg suppressor cells among total tumor-infiltrating T cells. Conclusions: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA directly elicited by active immunotherapy and to endogenous tumor antigens via immune-mediated antigen spreading. These results from clinical and nonclinical studies are predicted to explain improved overall survival following PROSTVAC immunotherapy in a phase 2 trial in advance of evidence from the ongoing phase 3 PROSPECT trial. Clinical trial information: NCT00078585.