Thursday, July 09, 2020 5:54:57 PM
Federica Cappuccini 1, Richard Bryant 2 3, Emily Pollock 1, Lucy Carter 1, Clare Verrill 2 4, Julianne Hollidge 2, Ian Poulton 1, Megan Baker 1, Celia Mitton 1, Andrea Baines 1, Armin Meier 5, Guenter Schmidt 5, Richard Harrop 6, Andrew Protheroe 7, Ruth MacPherson 8, Steven Kennish 9, Susan Morgan 10, Selena Vigano 11, Pedro J Romero 11, Thomas Evans 12, James Catto 13, Freddie Hamdy 2 3, Adrian V S Hill # 1, Irina Redchenko # 14
Affiliations
1Nuffield Department of Medicine, The Jenner Institute, Oxford University, Oxford, UK.
2Nuffield Department of Surgical Sciences, Oxford University, Oxford, UK.
3Department of Urology, Churchill Hospital, Oxford, UK.
4Oxford NIHR Biomedical Research Centre, Oxford University, Oxford, UK.
5Definiens AG, Munchen, Bayern, Germany.
6Oxford Biomedica Plc, Oxford, UK.
7Department of Oncology, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK.
8Department of Radiology, Churchill Hospital, Oxford, UK.
9Department of Radiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
10Department of Pathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
11Oncology, University Hospital of Lausanne, Lausanne, Switzerland.
12Vaccitech UK Limited, Oxford, UK.
13Academic Urology Unit, The University of Sheffield, Sheffield, UK.
14Nuffield Department of Medicine, The Jenner Institute, Oxford University, Oxford, UK irina.redchenko@ndm.ox.ac.uk.
#Contributed equally.
PMID: 32591433 PMCID: PMC7319775 DOI: 10.1136/jitc-2020-000928
Abstract
Background: Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity.
Methods: In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells.
Results: The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-? ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ.
Conclusions: An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab.
Trial registration: The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).
Read more at the following link
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319775/
Good luck and GOD bless,
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