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

Our plain-English summary of 5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer immunotherapy, by F. Cappuccini, E. Pollock, S. Stribbling, et al (Oncotarget, 2017).

The study

• Authors: F. Cappuccini, E. Pollock, S. Stribbling, A.V.S. Hill, I. Redchenko
• Journal: Oncotarget
• Published: 2017;8(29):47474-47489
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a preclinical laboratory study in mice testing vaccines against the tumour antigen 5T4, delivered by the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA), alone and with immune checkpoint antibodies. In C57BL/6 mice, a ChAdOx1 prime induced human 5T4 (h5T4)-specific T cell responses that were increased by an MVA boost, while homologous MVA-MVA vaccination produced no detectable 5T4-specific T cells; responses were attributed mainly to CD8+ T cells. End point 5T4 antibody titres were reported as significantly higher after the heterologous regime. Vaccinated mice were not protected against TRAMP-C1 tumours expressing mouse 5T4, which grew at the same rate as in naive controls or faster after h5T4Ii vaccination. Against B16 melanoma transfected to express h5T4, preventive vaccination before challenge gave complete protection in five of six mice; in the therapeutic schedule, in which priming was given on the same day the tumour cells were inoculated, the vaccine only modestly delayed tumour growth. Adding anti PD-1 antibody in that schedule significantly delayed growth and improved survival, with 80 percent surviving with anti PD-1 and 65 percent with all three antibodies. The authors concluded the platform has translational potential warranting further clinical development.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal (mouse) experimental study of viral-vectored vaccines, with tumour challenge and checkpoint-antibody combination experiments
• Who was studied: 6-week-old male C57BL/6 mice (purchased from Harlan, UK), with some immunogenicity work in BALB/c mice; experiments used at least 6 animals per group and were repeated at least twice; work done at the Jenner Institute, University of Oxford (article published 2017)
• Exposure: Intramuscular vaccination with ChAdOx1 and MVA viral vectors expressing human 5T4, human 5T4 fused to the invariant chain (h5T4Ii), or mouse 5T4; standard doses printed as 108 IU ChAdOx1 and 107 pfu MVA (superscripts lost in conversion: 10 to the 8th and 10 to the 7th), with one-log reduced doses in therapeutic experiments; monoclonal antibodies against PD-1, PD-L1 and LAG-3 at 50 micrograms per mouse intraperitoneally or intratumourally
• Main results:
  • ChAdOx1 priming induced detectable h5T4-specific T cell responses, which the MVA boost increased, whereas no h5T4-specific T cells were detected in the MVA-MVA group
  • End point 5T4-specific antibody titres were reported as significantly higher after the heterologous than the homologous regime
  • In the TRAMP-C1 model (mouse 5T4), vaccination gave no protection; tumours grew as fast as in naive mice or faster with h5T4Ii
  • Preventive h5T4 vaccination before B16.h5T4 challenge: complete tumour protection in five of six mice, one mouse developing a tumour on day 48
  • In the therapeutic experiments, priming vaccination was given on the same day as tumour cell inoculation
  • In that therapeutic schedule, ChAdOx1-MVA delayed tumour progression while MVA-MVA vaccinated mice grew tumours like naive mice
  • Vaccine plus anti PD-1 antibody suppressed tumour growth and prolonged survival significantly more than the vaccine alone in tumour-bearing mice
  • Survival after tumour challenge: 80% with vaccine plus anti PD-1 and 65% with vaccine plus the mixture of all three antibodies, both significant versus vaccine alone
  • Intratumoural anti PD-1 gave no overall survival advantage over intraperitoneal delivery (pooled data from two experiments)
• The authors' conclusion: The authors concluded that their preclinical data show translational potential for the ChAdOx1-MVA h5T4 vaccination platform combined with PD-1 blockade, and provide a foundation for further clinical development
• Limitations the authors state:
  • Even with combination treatment, tumour protection was not complete
  • The TRAMP-C1 model was found unsuitable for testing the human 5T4-targeting vaccine, so efficacy was tested in B16 cells transfected with human 5T4
  • The authors stated the reasons for the discrepancy between their invariant-chain results and earlier LCMV data are unclear
  • Further investigation is needed into cytotoxicity and functional avidity of CD8+ T cells after the different regimens

Topics

Medical terms in this study, explained in our Lexicon: Glycoprotein, Immunotherapy, Monoclonal Antibody, PD-L1, Overall Survival, Lung Cancer, Mesothelioma.

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