Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination with PD-1 mAb in a mouse model of prostate cancer.

Federica Cappuccini,Adrian V S Hill,Irina Redchenko,Emily Pollock,Stephen Stribbling

doi:10.1007/s00262-016-1831-8

Abstract

Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime–boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), induced strong sustained antigen-specific CD8+ T-cell responses in C57BL/6 and BALB/c male mice. Unexpectedly, the high vaccine immunogenicity translated into relatively low protective efficacy in the murine transplantable and spontaneous models of prostate cancer. A combination of the vaccine with PD-1 blocking antibody significantly improved survival of the animals, with 80 % of mice remaining tumour-free. These results indicate that the ChAdOx1–MVA vaccination regime targeting STEAP1 combined with PD-1 therapy might have high therapeutic potential in the clinic.

Highlights

Prostate cancer (PCa) is the most common non-skin cancer in males and the second leading cause of cancer deaths, with an estimated 233,000 men diagnosed in 2014 and 29,480 deaths predicted in the USA [1]
In the first round of experiments, we set out to investigate whether immunological tolerance to STEAP1 can be broken by the ChAdOx1–modified vaccinia virus Ankara (MVA)-based vaccine regime and to assess the magnitude of induced responses
C57BL/6, BALB/c and transgenic TRAMP male mice were primed with ChAdOx1.STEAP1 vaccine followed by MVA

Summary

Introduction

Prostate cancer (PCa) is the most common non-skin cancer in males and the second leading cause of cancer deaths, with an estimated 233,000 men diagnosed in 2014 and 29,480 deaths predicted in the USA [1]. The development of alternative therapies, aiming at activating host anti-tumour immunity. The use of therapeutic vaccination in cancer presents many challenges, with tolerance to self-antigens and active immunosuppressive mechanisms mounted by tumours being two major factors hampering cancer vaccine efficacy. We have evaluated an alternative PCa-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), as a vaccine target in mouse models. STEAP1 is expressed only in the prostate among normal tissues and overexpressed in various cancer types including prostate, bladder, lung, ovarian cancer and Ewing sarcoma [4]. Its unique and restricted expression pattern and growing evidence of its role in PCa initiation and progression [5,6,7] make STEAP1 an excellent target for a PCa vaccine

Methods

Results

Conclusion