Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Journal for ImmunoTherapy of Cancer

Alex Franzusoff²  Alain Delcayre¹  Erica Trent²  Evan J Gordon²  Joseph J Cote²  Susan P Foy²  Tracy B dela Cruz²  Ryan B Rountree²  Stefanie J Mandl² 

[1] ExoThera LLC, 675 Olive Street, Menlo Park 94025, CA, USA;Bavarian Nordic, Inc, 2425 Garcia Ave, Mountain View 94043, CA, USA

关键词: Teff :Treg ratio;    Heterologous prime-boost;    Immune correlates;    Mechanism of action;    Prostate cancer;    Active immunotherapy;    PROSTVAC;   

Others  :  1139867
DOI  :  10.1186/s40425-014-0034-0

 received in 2014-04-28, accepted in 2014-08-21,  发布年份 2014

【 摘 要 】

Background

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.

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 (IFN?) 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.

【 授权许可】

   
2014 Mandl et al.; licensee BioMed Central Ltd.

【 图 表 】

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