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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Main Authors: 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
Format: Article
Language:English
Published: BMJ Publishing Group 2019-04-01
Series:Journal for ImmunoTherapy of Cancer
Subjects:
Online Access:http://link.springer.com/article/10.1186/s40425-019-0576-2
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spelling 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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