title: Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor.
abstract: Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8(+)PD-1(+) T-cell subset, matching of TCRA-TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity. Cancer Immunol Res; 4(9); 734-43. ©2016 AACR.
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Anna
authors.initials: A
authors.lastname: Pasetto
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Drew C
authors.initials: DC
authors.lastname: Deniger
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland. Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Matus-Nicodemos
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington.
authors.forename: Bryan
authors.initials: B
authors.lastname: Howie
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Parkhurst
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jared
authors.initials: J
authors.lastname: Gartner
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Trebska-McGowan
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Crystal
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland. sar@mail.nih.gov.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060965:Clonal Evolution; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D011948:Receptors, Antigen, T-Cell