5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer immunotherapy.

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

doi:10.18632/oncotarget.17666

Abstract

The tumour-associated antigen 5T4 is an attractive target for cancer immunotherapy. However to date, reported 5T4-specific cellular immune responses induced by various immunisation platforms have been largely weak or non-existent. In the present study, we have evaluated a heterologous prime boost regime based on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA) expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse cancer model. Vaccination-induced immune responses were strong, durable and attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA vaccinated mice were completely protected against subsequent B16 melanoma challenge, but in therapeutic settings this regime was only modestly effective in delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1 demonstrated that the combination of vaccine with anti PD-1 mAb could significantly delay tumour growth and increase overall survival of tumour-bearing mice. Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.

Highlights

5T4 is an oncofoetal glycoprotein that belongs to the family of shared tumour antigens
Immunogenicity of viral vectors encoding human 5T4 antigen (h5T4) in C57BL/6 mouse strain and efficacy of the 5T4-targeting vaccine in the TRAMP-C1 tumour challenge model. It has been shown in the past that cellular immune responses against h5T4 antigen following a homologous modified vaccinia virus Ankara (MVA) vaccination regime have been weak [18] or nonexistent [19] in mouse models
Results presented in this study describe the advantage of targeting the 5T4 tumour antigen through a heterologous ChAdOx1-MVA vaccination platform over homologous MVA regime in that it induces strong tumour protective CD8+ T cell responses in preclinical settings

Summary

Introduction

5T4 is an oncofoetal glycoprotein that belongs to the family of shared tumour antigens It was identified in 1990 by searching for shared surface molecules of human trophoblast and cancer cells, with the rationale that they may have a function in survival of the foetus as a semiallograft [1]. The first clinical testing of the 5T4-targeting vaccine started more than a decade ago, with the 5T4 protein expressed from the modified vaccinia Ankara virus (MVA). This vaccine was administered to late stage colorectal cancer patients as a homologous prime-boost vaccine known under the trade name of TroVax [6]. The TroVax safety profile was good and the vaccine was well tolerated, vaccine-specific cellular immune responses and clinical efficacy were modest, with a trend toward improved progression-free survival in those patients with the highest 5T4-specific antibody titres [9, 10]

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