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Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients
- Source :
- Journal for Immunotherapy of Cancer, Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-12 (2019)
- Publication Year :
- 2018
-
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 Electronic supplementary material The online version of this article (10.1186/s40425-019-0576-2) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
CD4-Positive T-Lymphocytes
Male
Cancer Research
Receptors, Enterotoxin
Mice
0302 clinical medicine
Immunogenicity, Vaccine
Immunology and Allergy
Cytotoxic T cell
Vaccines, Synthetic
biology
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Combined Modality Therapy
3. Good health
medicine.anatomical_structure
GUCY2C
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Female
Immunotherapy
Antibody
Colorectal Neoplasms
Research Article
Guanylyl cyclase C
Colon
T cell
Immunology
Genetic Vectors
Dose-Response Relationship, Immunologic
lcsh:RC254-282
Cancer Vaccines
Adenoviridae
03 medical and health sciences
Immune system
Antigen
medicine
Immune Tolerance
Animals
Humans
Aged
Neoplasm Staging
Pharmacology
business.industry
Rectum
Cancer
medicine.disease
Antibodies, Neutralizing
Colorectal cancer
030104 developmental biology
biology.protein
Cancer vaccine
business
Vaccine
CD8
T-Lymphocytes, Cytotoxic
Subjects
Details
- ISSN :
- 20511426
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal for immunotherapy of cancer
- Accession number :
- edsair.doi.dedup.....97f7101db3d4b5594a6db1501b3a57cf