Journal Article

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

Waldman, Scott A., Abraham, Tara S., Sato, Takami, Snook, Adam E., Zhan, Tingting, Baybutt, Trevor R., Xiang, Bo, Hyslop, Terry, Flickinger, John C., Kraft, Walter K.

2019

Overview

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

• Publisher: BioMed Central,BioMed Central Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenoviridae - genetics / Adenoviridae - immunology / Adenoviruses / Aged / Animals / Antibodies / Antibodies, Neutralizing - blood / Antibodies, Neutralizing - immunology / Antigens / Autoimmunity / Binding sites / Cancer / Cancer patients / Cancer therapies / Cancer vaccines / Cancer Vaccines - administration & dosage / Cancer Vaccines - adverse effects / Cancer Vaccines - immunology / Care and treatment / CD4-Positive T-Lymphocytes - immunology / Clinical trials / Clinical/Translational Cancer Immunotherapy / Colon - pathology / Colon - surgery / Colon cancer / Colorectal cancer / Colorectal Neoplasms - blood / Colorectal Neoplasms - immunology / Colorectal Neoplasms - pathology / Colorectal Neoplasms - therapy / Combined Modality Therapy - methods / Dose-Response Relationship, Immunologic / Experiments / Female / Genetic Vectors - genetics / Genetic Vectors - immunology / Guanylyl cyclase C / GUCY2C / Humans / Immune response / Immune Tolerance / Immunogenicity, Vaccine / Immunology / Immunotherapy / Immunotherapy - methods / Laboratories / Lymphocytes / Male / Medical research / Medicine / Medicine & Public Health / Metastasis / Mice / Middle Aged / Neoplasm Staging / Oncology / Patient outcomes / Receptors, Enterotoxin - genetics / Receptors, Enterotoxin - immunology / Rectum - pathology / Rectum - surgery / Research Article / T cells / T-Lymphocytes, Cytotoxic - immunology / Toxicity / Tumors / Vaccine / Vaccines / Vaccines, Synthetic - administration & dosage / Vaccines, Synthetic - adverse effects / Vaccines, Synthetic - immunology