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Cancer Discov. 2017 Mar;7(3):264-276. doi: 10.1158/2159-8290.CD-16-0828. Epub 2016 Dec 28.

Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Author information

1
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
4
Personal Genome Diagnostics, Baltimore, Maryland.
5
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Radiology and Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
8
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
9
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. velculescu@jhmi.edu.

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.

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PMID:
28031159
PMCID:
PMC5733805
DOI:
10.1158/2159-8290.CD-16-0828
[Indexed for MEDLINE]
Free PMC Article

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