Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients
Abstract 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 cli...
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doaj-bdce3f30665a4a5db1e1ac2e6e6cfd892020-11-25T01:49:00ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-04-017111210.1186/s40425-019-0576-2Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patientsAdam E. Snook0Trevor R. Baybutt1Bo Xiang2Tara S. Abraham3John C. Flickinger4Terry Hyslop5Tingting Zhan6Walter K. Kraft7Takami Sato8Scott A. Waldman9Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityDepartment of Medical Oncology, Thomas Jefferson UniversityDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityAbstract 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 1011 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/NCT01972737http://link.springer.com/article/10.1186/s40425-019-0576-2Colorectal cancerGUCY2CGuanylyl cyclase CVaccine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Adam E. Snook Trevor R. Baybutt Bo Xiang Tara S. Abraham John C. Flickinger Terry Hyslop Tingting Zhan Walter K. Kraft Takami Sato Scott A. Waldman |
spellingShingle |
Adam E. Snook Trevor R. Baybutt Bo Xiang Tara S. Abraham John C. Flickinger Terry Hyslop Tingting Zhan Walter K. Kraft Takami Sato Scott A. Waldman Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients Journal for ImmunoTherapy of Cancer Colorectal cancer GUCY2C Guanylyl cyclase C Vaccine |
author_facet |
Adam E. Snook Trevor R. Baybutt Bo Xiang Tara S. Abraham John C. Flickinger Terry Hyslop Tingting Zhan Walter K. Kraft Takami Sato Scott A. Waldman |
author_sort |
Adam E. Snook |
title |
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients |
title_short |
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients |
title_full |
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients |
title_fullStr |
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients |
title_full_unstemmed |
Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients |
title_sort |
split tolerance permits safe ad5-gucy2c-padre vaccine-induced t-cell responses in colon cancer patients |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2019-04-01 |
description |
Abstract 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 1011 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 |
topic |
Colorectal cancer GUCY2C Guanylyl cyclase C Vaccine |
url |
http://link.springer.com/article/10.1186/s40425-019-0576-2 |
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