5T4 Oncofoetal Glycoprotein: An Old Target for a Novel Prostate Cancer Immunotherapy

Oncotarget. 2017 Jul 18;8(29):47474-47489. 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.

Keywords: 5T4 oncofoetal antigen; cancer; immune checkpoint blockade; immunogenicity; viral vectored vaccine.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Antineoplastic Agents, Immunological / pharmacology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology
  • Combined Modality Therapy
  • Disease Models, Animal
  • Genetic Vectors / genetics
  • Humans
  • Immunity, Cellular
  • Immunity, Humoral
  • Immunotherapy
  • Male
  • Melanoma, Experimental
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Transgenes / genetics
  • Transgenes / immunology
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • Cancer Vaccines
  • Membrane Glycoproteins
  • trophoblastic glycoprotein 5T4, human