Domain-swapped T cell receptors improve the safety of TCR gene therapy.
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.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Michael T
MT
Bethune
Program in Immunology, Stanford University School of Medicine, Stanford, United States.
Marvin H
MH
Gee
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Mario
M
Bunse
Department of Immunobiology, University of Arizona, Tucson, United States.|The BIO5 Institute, University of Arizona, Tucson, United States.
Mark S
MS
Lee
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
Eric H
EH
Gschweng
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Meghana S
MS
Pagadala
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
Jing
J
Zhou
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States.
Donghui
D
Cheng
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
James R
JR
Heath
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
Donald B
DB
Kohn
Department of Immunobiology, University of Arizona, Tucson, United States.|The BIO5 Institute, University of Arizona, Tucson, United States.
Michael S
MS
Kuhns
Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
Wolfgang
W
Uckert
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
David
0000-0001-8723-8190
D
Baltimore
D000818:Animals; D004195:Disease Models, Animal; D019672:Genes, T-Cell Receptor; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006086:Graft vs Host Disease; D051379:Mice; D000072417:Protein Domains; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism*; D011995:Recombination, Genetic
D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins
T cell; T cell receptor; autoimmunity; cancer immunotherapy; human biology; immunology; medicine; mouse; protein engineering; receptor biogenesis