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Domain-swapped T cell receptors improve the safety of TCR gene therapy

Bethune, Michael T. and Gee, Marvin H. and Bunse, Mario and Lee, Mark S. and Gschweng, Eric H. and Pagadala, Meghana S. and Zhou, Jing and Cheng, Donghui and Heath, James R. and Kohn, Donald B. and Kuhns, Michael S. and Uckert, Wolfgang and Baltimore, David (2016) Domain-swapped T cell receptors improve the safety of TCR gene therapy. eLife, 5 . Art. No. e19095. ISSN 2050-084X. PMCID PMC5101000. https://resolver.caltech.edu/CaltechAUTHORS:20161104-095700365

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Abstract

T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.7554/eLife.19095DOIArticle
https://elifesciences.org/content/5/e19095PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101000/PubMed CentralArticle
ORCID:
AuthorORCID
Heath, James R.0000-0001-5356-4385
Baltimore, David0000-0001-8723-8190
Additional Information:© 2016, Bethune et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received June 24, 2016. Accepted October 11, 2016. Published November 08, 2016. We thank Eugene Barsov and Richard Morgan (NCI) for providing the MSGV vector, Alok Joglekar (Caltech) for providing the pCCLc vector, and Gavin Bendle (Univ. of Birmingham) for providing the pMX vector. We also thank Gavin Bendle and Lili Yang (UCLA) for troubleshooting discussions related to mouse and human T cell transduction, Mireille Toebes (NKI) for helpful discussions related to tetramer production, and Owen N. Witte (UCLA) for use of his cell sorter. Short-dated Proleukin was provided without charge by Prometheus Laboratories Inc (San Diego, CA) through an investigator-initiated trial program. Biotinylated H-2K^b/Ova_(257-264) monomers were provided by the NIH Tetramer Core Facility (Atlanta, GA). We gratefully acknowledge the staff of the Caltech animal facility for animal husbandry. This work was supported by the U.S.A. National Institutes of Health grant 5 P01CA132681-5 to DB and the Prostate Cancer Foundation Challenge Award 15CHAL02 to DB and MTB is the recipient of a Jane Coffin Childs Postdoctoral Fellowship. MSK is a Pew Scholar supported by the Pew Charitable Trusts. Funding: National Institutes of Health 5P01CA132681-5 David Baltimore Prostate Cancer Foundation 15CHAL02 Michael T Bethune David Baltimore Jane Coffin Childs Memorial Fund for Medical Research Michael T Bethune Pew Charitable Trusts Michael S Kuhns The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions MTB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article MHG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article MB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article MSL, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article EHG, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article MSP, Acquisition of data, Drafting or revising the article JZ, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article DC, Acquisition of data, Drafting or revising the article JRH, Analysis and interpretation of data, Drafting or revising the article DBK, Analysis and interpretation of data, Drafting or revising the article MSK, Conception and design, Analysis and interpretation of data, Drafting or revising the article WU, Conception and design, Analysis and interpretation of data, Drafting or revising the article DB, Conception and design, Analysis and interpretation of data, Drafting or revising the article Ethics: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal experiments conducted at Caltech were approved by the Institutional animal care and use committee (IACUC) of the California Institute of Technology (IACUC protocol 1611). Animal experiments conducted at UCLA adhered to UCLA Department of Laboratory Animal Medicine Standards (UCLA Animal Research Committee protocol #2008-167). Animal experiments conducted at MDC Berlin were conducted in accordance with institutional and national guidelines, and approved by a state animal ethics committee (Landesamt für Gesundheit und Soziales protocol 0233/11). Reviewing editor: Satyajit Rath, Reviewing editor, National Institute of Immunology, India. Competing interests: MTB, MHG and DB: Co-inventor on a patent application concerning the described technology (USPTO patent application 20150197771). The other author declares that no competing interests exist.
Funders:
Funding AgencyGrant Number
NIH5 P01CA132681-5
Prostate Cancer Foundation15CHAL02
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
Pew Charitable TrustUNSPECIFIED
PubMed Central ID:PMC5101000
Record Number:CaltechAUTHORS:20161104-095700365
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161104-095700365
Official Citation:Domain-swapped T cell receptors improve the safety of TCR gene therapy Michael T Bethune, Marvin H Gee, Mario Bunse, Mark S Lee, Eric H Gschweng, Meghana S Pagadala, Jing Zhou, Donghui Cheng, James R Heath, Donald B Kohn, Michael S Kuhns, Wolfgang Uckert, David Baltimore eLife 2016;5:e19095 DOI:10.7554/eLife.19095
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:71738
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Nov 2016 16:14
Last Modified:03 Oct 2019 16:10

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