Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

• Published in: Journal for immunotherapy of cancer Vol. 2; no. 1; p. 34
• Main Authors: Mandl, Stefanie J, Rountree, Ryan B, Dela Cruz, Tracy B, Foy, Susan P, Cote, Joseph J, Gordon, Evan J, Trent, Erica, Delcayre, Alain, Franzusoff, Alex
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.10.2014; BMJ Publishing Group LTD; BioMed Central
• Subjects: Analysis; Antigens; Care and treatment; Cytotoxicity; Drug therapy; FDA approval; Flow cytometry; Immune response; Immunotherapy; Interferon; Lymphocytes; Medical prognosis; Metastasis; Methods; Patient outcomes; Peptides; Prostate cancer; Tumors; Active immunotherapy; Immune correlates; Teff :Treg ratio; Heterologous prime-boost; Mechanism of action; Prostate cancer; PROSTVAC
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-014-0034-0

PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit. PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNγ) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry. The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated 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. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells. PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study.