@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.}",
note = "Funding Information: This work was supported by U.S. NIH grants CA121113 (V.E. Velculescu), CA006973 (S.B. Baylin, D.M. Pardoll, and V.E. Velculescu), CA180950 (V.E. Velculescu), and DE019032 (H. Kang and V.E. Velculescu), the Commonwealth Foundation (V.E. Velculescu), The Bloomberg-Kimmel Institute for Cancer Immunotherapy (J.R. Brahmer, D.M. Pardoll, and V.E. Velculescu), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (S.B. Baylin and V.E. Velculescu), the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (V. Anagnostou), MacMillan Foundation (V. Anagnostou), the William R. Brody Faculty Scholarship (R. Karchin), the LUNGevity Foundation (P.M. Forde), the Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15; P.M. Forde and E. Gabrielson), the Stand Up To Cancer-Dutch Cancer Society International Trans lational Cancer Research Dream Team Grant (SU2C-AACRDT1415; V.E. Velculescu), and the NCI Experimental Therapeutics Clinical Trials Network (H. Kang). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2017",
month = mar,
doi = "10.1158/2159-8290.CD-16-0828",
language = "English (US)",
volume = "7",
pages = "264--276",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "3",
}