한빛사 논문
Gloria B. Kim1†, Jens Fritsche2†, Sebastian Bunk2†, Andrea Mahr2, Felix Unverdorben2, Kevin Tosh1, Hong Kong1, Colby R. Maldini1, Chui Lau1, Sriram Srivatsa1, Shuguang Jiang1, Joshua Glover1, Derek Dopkin1, Carolyn X. Zhang1, Heiko Schuster2, Daniel J. Kowalewski2, Valentina Goldfinger2, Martina Ott2, David Fuhrmann2, Maike Baues2, Hans Boesmueller3, Christoph Schraeder2, Gisela Schimmack2, Colette Song2, Franziska Hoffgaard2, Michael Roemer2, Chih-Chiang Tsou4, Martin Hofmann2, Thomas Treiber2, Meike Hutt2, Leonie Alten2, Maike Jaworski2, Amir Alpert4, Sarah Missel2, Carsten Reinhardt2, Harpreet Singh2,4, Oliver Schoor2, Steffen Walter4, Claudia Wagner2, Dominik Maurer2‡, Toni Weinschenk2,4*‡, James L. Riley1*‡
1Department of Microbiology, Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. 2Immatics Biotechnologies GmbH, Paul-Ehrlich-Str. 15, 72076 Tuebingen, Germany. 3Institute of Pathology and Neuropathology, Eberhard Karls University, 72076 Tuebingen, Germany. 4Immatics US, 2201 W. Holcombe Blvd., Suite 205, Houston, TX 77030, USA.
*Corresponding author.
†These authors contributed equally to this work.
‡These authors contributed equally to this work.
Abstract
T cell receptor (TCR)–based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide–human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.
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