title: Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
abstract: Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance:Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance.Cancer Discov; 7(3); 264-76. ©2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Valsamo
authors.initials: V
authors.lastname: Anagnostou
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kellie N
authors.initials: KN
authors.lastname: Smith
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Forde
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Noushin
authors.initials: N
authors.lastname: Niknafs
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhattacharya
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: James
authors.initials: J
authors.lastname: White
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Vilmos
authors.initials: V
authors.lastname: Adleff
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Neha
authors.initials: N
authors.lastname: Wali
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hruban
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Violeta B
authors.initials: VB
authors.lastname: Guthrie
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kristen
authors.initials: K
authors.lastname: Rodgers
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jarushka
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hyunseok
authors.initials: H
authors.lastname: Kang
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Sharfman
authors.affiliation: Department of Radiology and Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Christos
authors.initials: C
authors.lastname: Georgiades
authors.affiliation: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Franco
authors.initials: F
authors.lastname: Verde
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Illei
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Qing Kay
authors.initials: QK
authors.lastname: Li
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Scharpf
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. velculescu@jhmi.edu.|The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab / Q000494:pharmacology / Q000627:therapeutic use; D053613:Janus Kinase 1 / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D000077594:Nivolumab; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2