Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial

Abstract

BackgroundProstate 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.MethodsIn 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.ResultsThe vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ 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.ConclusionsAn 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 registrationThe trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).

Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression

“…11 17 18 Combinations of heterologous modalities of immunization (ie, vaccinating with different vectors encoding the same immunogen) have shown enhanced immune responses to the target antigen. 19 The rationale behind this strategy is that by using different vectors as boosters, it is possible to bypass the immune response elicited against the primer and also strengthen the immune response against the target antigen. [19][20][21] In the current study, we develop a novel recombinant Adenovirus 5 (Ad5) vaccine expressing TEM1-TT fusion protein (TEM1 Ad5) and demonstrate that heterologous priming with TEM1 plasmid-DNA vaccine followed by TEM1 Ad5 vaccine significantly improved TEM1-specific immune responses and antitumor effects compared with either vector alone.…”

“…19 The rationale behind this strategy is that by using different vectors as boosters, it is possible to bypass the immune response elicited against the primer and also strengthen the immune response against the target antigen. [19][20][21] In the current study, we develop a novel recombinant Adenovirus 5 (Ad5) vaccine expressing TEM1-TT fusion protein (TEM1 Ad5) and demonstrate that heterologous priming with TEM1 plasmid-DNA vaccine followed by TEM1 Ad5 vaccine significantly improved TEM1-specific immune responses and antitumor effects compared with either vector alone. 20 22 In vivo, dual treatment with RT and heterologous TEM1 vaccination disrupted the functional vasculature of the irradiated tumor, increased the systemic adaptive immune response, and significantly inhibited the growth of irradiated and non-irradiated (abscopal) tumor as compared with monotherapy.…”

“… 11 17 18 Combinations of heterologous modalities of immunization (ie, vaccinating with different vectors encoding the same immunogen) have shown enhanced immune responses to the target antigen. 19 The rationale behind this strategy is that by using different vectors as boosters, it is possible to bypass the immune response elicited against the primer and also strengthen the immune response against the target antigen. 19–21 …”

“… 19 The rationale behind this strategy is that by using different vectors as boosters, it is possible to bypass the immune response elicited against the primer and also strengthen the immune response against the target antigen. 19–21 …”

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

“…One of the vaccines, ChAdOx1-MVA 5T4, is a combination of two replication-deficient viruses, chimpanzee adenovirus and modified vaccinia ankara, targeting an oncofetal self-antigen 5T4 (NCT03815942) [ 136 ]. The 5T4 protein is expressed in numerous malignancies but seldom in normal tissue [ 137 ].…”