Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer

Research output: Research - peer-reviewArticle

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 fi rst 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.

LanguageEnglish (US)
Pages264-276
Number of pages13
JournalCancer Discovery
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2017

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Non-Small Cell Lung Carcinoma
Neoplasms
T-Lymphocytes
Mutation
Therapeutics
T-Cell Antigen Receptor
Clone Cells
Cell Culture Techniques
Peptides
Antibodies

ASJC Scopus subject areas

  • Oncology

Cite this

@article{47fd7e752a484f24b2974f943f3d5333,
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 fi rst 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.",
author = "Valsamo Anagnostou and Smith, {Kellie N.} and Forde, {Patrick M.} and Noushin Niknafs and Rohit Bhattacharya and James White and Theresa Zhang and Vilmos Adleff and Jillian Phallen and Neha Wali and Carolyn Hruban and Guthrie, {Violeta B.} and Kristen Rodgers and Jarushka Naidoo and Hyunseok Kang and William Sharfman and Christos Georgiades and Franco Verde and Peter Illei and Li, {Qing Kay} and Edward Gabrielson and Brock, {Malcolm V.} and Zahnow, {Cynthia A.} and Baylin, {Stephen B.} and Scharpf, {Robert B.} and Brahmer, {Julie R.} and Rachel Karchin and Pardoll, {Drew M.} and Velculescu, {Victor E.}",
year = "2017",
month = "3",
doi = "10.1158/2159-8290.CD-16-0828",
volume = "7",
pages = "264--276",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "3",

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TY - JOUR

T1 - Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer

AU - Anagnostou,Valsamo

AU - Smith,Kellie N.

AU - Forde,Patrick M.

AU - Niknafs,Noushin

AU - Bhattacharya,Rohit

AU - White,James

AU - Zhang,Theresa

AU - Adleff,Vilmos

AU - Phallen,Jillian

AU - Wali,Neha

AU - Hruban,Carolyn

AU - Guthrie,Violeta B.

AU - Rodgers,Kristen

AU - Naidoo,Jarushka

AU - Kang,Hyunseok

AU - Sharfman,William

AU - Georgiades,Christos

AU - Verde,Franco

AU - Illei,Peter

AU - Li,Qing Kay

AU - Gabrielson,Edward

AU - Brock,Malcolm V.

AU - Zahnow,Cynthia A.

AU - Baylin,Stephen B.

AU - Scharpf,Robert B.

AU - Brahmer,Julie R.

AU - Karchin,Rachel

AU - Pardoll,Drew M.

AU - Velculescu,Victor E.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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 fi rst 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.

AB - 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 fi rst 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.

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DO - 10.1158/2159-8290.CD-16-0828

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EP - 276

JO - Cancer Discovery

T2 - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

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