title: Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells.
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.
authors: Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA. paulrobbins@mail.nih.gov
authors: Paul F
authors: PF
authors: Robbins
authors: Yong-Chen
authors: YC
authors: Lu
authors: Mona
authors: M
authors: El-Gamil
authors: Yong F
authors: YF
authors: Li
authors: Colin
authors: C
authors: Gross
authors: Jared
authors: J
authors: Gartner
authors: Jimmy C
authors: JC
authors: Lin
authors: Jamie K
authors: JK
authors: Teer
authors: Paul
authors: P
authors: Cliften
authors: Eric
authors: E
authors: Tycksen
authors: Yardena
authors: Y
authors: Samuels
authors: Steven A
authors: SA
authors: Rosenberg
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D018984:Epitopes, T-Lymphocyte; D059472:Exome; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens
references: Nature. 2007 Mar 8;446(7132):153-8
references: 17344846
references: Genes Dev. 2002 May 1;16(9):1066-76
references: 12000790
references: J Immunol Methods. 1987 Aug 24;102(1):127-41
references: 3305708
references: PLoS One. 2007 Aug 29;2(8):e796
references: 17726526
references: Nature. 1992 Nov 12;360(6400):171-4
references: 1436094
references: Immunity. 2000 Jan;12(1):107-17
references: 10661410
references: Science. 1991 Dec 13;254(5038):1643-7
references: 1840703
references: J Immunother Emphasis Tumor Immunol. 1994 Jul;16(1):13-23
references: 8081556
references: Immunity. 1995 Feb;2(2):167-75
references: 7895173
references: J Clin Oncol. 2008 Nov 10;26(32):5233-9
references: 18809613
references: Oncoimmunology. 2012 Jul 1;1(4):409-418
references: 22754759
references: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9
references: 8170938
references: Science. 2002 Oct 25;298(5594):850-4
references: 12242449
references: J Clin Oncol. 2005 Apr 1;23(10):2346-57
references: 15800326
references: J Cell Biol. 2008 May 5;181(3):421-9
references: 18443220
references: Nature. 2012 Feb 08;482(7385):400-4
references: 22318521
references: Genes Dev. 2011 Oct 15;25(20):2158-72
references: 22012619
references: J Immunother. 2005 Jan-Feb;28(1):53-62
references: 15614045
references: Hum Mol Genet. 2011 Feb 1;20(3):510-27
references: 21078624
references: Cancer Immun. 2013 Jul 15;13:15
references: 23882160
references: J Exp Med. 1996 Mar 1;183(3):1185-92
references: 8642260
references: EMBO J. 1986 May;5(5):943-9
references: 3522223
references: Nature. 2012 May 09;485(7399):502-6
references: 22622578
references: J Exp Med. 1999 Mar 1;189(5):757-66
references: 10049939
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18599-604
references: 20937868
references: Immunogenetics. 1999 Nov;50(3-4):213-9
references: 10602881
references: Science. 2010 Oct 8;330(6001):228-31
references: 20826764
references: Cancer Res. 2012 Mar 1;72(5):1081-91
references: 22237626
references: Clin Cancer Res. 2011 Jul 1;17(13):4550-7
references: 21498393
references: Science. 1994 Apr 29;264(5159):716-9
references: 7513441
references: J Immunol. 2006 Jan 15;176(2):1053-61
references: 16393993