Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Abstract

Background: PROSTVAC W , 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. Methods: 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. Results: 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. Conclusions: 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.

Immunotherapy in prostate cancer: current state and future perspectives

“…This utilizes viral vectors derived from fowl pox and the booster vaccination, which both code for the same tumor-associated antigens. 30 This strategy was evaluated in patients with localized PCa with PSA recurrence after radical treatment. 31 A positive trend with prolongation of PSA-free survival was observed in the patient cohort that received a single injection of PROSTVAC-V followed by multiple injections of PROSTVAC-F. 31 Meanwhile, a study by Hodge et al showed much greater T-cell activation when a triad of costimulatory molecules (TRICOM) – leukocyte function-associated antigen-3 (LFA-3), B7.1, and intercellular adhesion molecule-1(ICAM-1) – are used in conjunction with PSA.…”

Immunotherapy as a Precision Medicine Tool for the Treatment of Prostate Cancer

“…The scientific rationale behind this vaccine is that the vaccinia vector acts as a single dose immunogenic factor, eliciting a strong immune response both against PSA and the viral protein, leading to the destruction of PSA-positive tumor cells and subsequently to the release of a wider range of TAAs (antigen spreading) that stimulate additional pro-inflammatory signals and additional tumor-specific T cell immune responses [109,125,126]. Under the same rationale, the fowlpox vector, transduced to code for the same TAA (PSA), is used for subsequent booster vaccinations in order to bypass the problem of the vaccinia virus vector being neutralized by the host immune system, as the former (PROSTVAC-F) is able to penetrate APCs without www.videleaf.com invoking the production of high volumes of neutralizing antibodies [62,127,128].…”

Polyomavirus BK and prostate cancer: a complex interaction of potential clinical relevance

“…Undoubtedly, the characterization of humoral and cellular immune responses against portions of viral proteins that are relevant for oncogenic activities, such as the p53‐binding regions of polyomaviruses LTag, could unravel the ways BKPyV becomes one of the major protagonists in PCa immunoediting, controlling cancer immune surveillance, and strengthening tumor immune escape. Therefore, further investigation of the systemic adaptive immune response to BKPyV LTag could clarify its role as a key target of cancer immune surveillance, which might also lead to an LTag‐targeted therapy, as already set by using target proteins such as the prostate‐specific antigen or the prostatic acid phosphatase for antigen‐specific immunotherapy .…”