Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells
Paul F. Robbins,Yong-Chen Lu,Mona El-Gamil,Yong F. Li,Colin A. Gross,Jared J. Gartner,J. Lin,Jamie K. Teer,Jamie K. Teer,Paul F. Cliften,Eric Tycksen,Yardena Samuels,Yardena Samuels,Steven A. Rosenberg +13 more
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TLDR
A new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors and identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer.Abstract:
Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex-binding algorithm for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.read more
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References
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A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma
P. van der Bruggen,Catia Traversari,Patrick Chomez,Christophe Lurquin,E De Plaen,B Van den Eynde,Alexander Knuth,Thierry Boon +7 more
TL;DR: In this paper, a gene was identified that directed the expression of antigen MZ2-E on a human melanoma cell line, which belongs to a family of at least three genes.
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Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes
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TL;DR: The adoptive transfer of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen resulted in the persistent clonal repopulation of T cells in cancer patients, leading to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction.
Journal Article
Patterns of Somatic Mutation in Human Cancer Genomes
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Journal ArticleDOI
Patterns of somatic mutation in human cancer genomes
Christopher Greenman,Philip J. Stephens,Raffaella Smith,Gillian L. Dalgliesh,Christopher I. Hunter,Graham R. Bignell,Helen Davies,Jon W. Teague,Adam Butler,Claire Stevens,Sarah Edkins,Sarah O’Meara,Imre Vastrik,Esther Schmidt,Tim Avis,Syd Barthorpe,Gurpreet Bhamra,Gemma Buck,Bhudipa Choudhury,Jody Clements,Jennifer Cole,Ed Dicks,Simon A. Forbes,Kris Gray,Kelly Halliday,Rachel Harrison,Katy Hills,Jon Hinton,Andy Jenkinson,David T. Jones,Andy Menzies,Tatiana Mironenko,Janet Perry,Keiran Raine,Dave Richardson,Rebecca Shepherd,Alexandra Small,Calli Tofts,Jennifer Varian,Tony Webb,Sofie West,Sara Widaa,Andrew D. Yates,Daniel P. Cahill,David N. Louis,Peter Goldstraw,Andrew G. Nicholson,Francis Brasseur,Leendert H. J. Looijenga,Barbara L. Weber,Yoke Eng Chiew,Anna deFazio,Mel Greaves,Anthony R. Green,Peter J. Campbell,Ewan Birney,Douglas F. Easton,Georgia Chenevix-Trench,Min-Han Tan,Sok Kean Khoo,Bin Tean Teh,Siu Tsan Yuen,Suet Yi Leung,Richard Wooster,P. Andrew Futreal,Michael R. Stratton,Michael R. Stratton +66 more
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
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SYFPEITHI: database for MHC ligands and peptide motifs.
TL;DR: The first version of the major histocompatibility complex (MHC) databank SYFPEITHI: database for MHC ligands and peptide motifs, is now available to the general public.
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