Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients

BACKGROUND: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8(+), but not CD4(+), T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. METHODS: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 10(11) viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. RESULTS: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8(+) cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4(+) T cells are eliminated by self-tolerance, while CD8(+) T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. CONCLUSIONS: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8(+), but not autoimmune CD4(+), T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0576-2) contains supplementary material, which is available to authorized users.