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.
| Language | English (US) |
|---|---|
| Pages | 264-276 |
| Number of pages | 13 |
| Journal | Cancer Discovery |
| Volume | 7 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2017 |
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ASJC Scopus subject areas
- Oncology
Cite this
Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. / Anagnostou, Valsamo; Smith, Kellie; Forde, Patrick; Niknafs, Noushin; Bhattacharya, Rohit; White, James; Zhang, Theresa; Adleff, Vilmos; Phallen, Jillian; Wali, Neha; Hruban, Carolyn; Guthrie, Violeta B.; Rodgers, Kristen; Naidoo, Jarushka; Kang, Hyunseok; Sharfman, William; Georgiades, Christos S; Verde, Franco; Illei, Peter B; Li, Qing Kay; Gabrielson, Edward; Brock, Malcolm V; Zahnow, Cynthia; Baylin, Stephen B; Scharpf, Robert B; Brahmer, Julie; Karchin, Rachel; Pardoll, Andrew Mark; Velculescu, Victor E.
In: Cancer Discovery, Vol. 7, No. 3, 01.03.2017, p. 264-276.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer
AU - Anagnostou, Valsamo
AU - Smith, Kellie
AU - Forde, Patrick
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 S
AU - Verde, Franco
AU - Illei, Peter B
AU - Li, Qing Kay
AU - Gabrielson, Edward
AU - Brock, Malcolm V
AU - Zahnow, Cynthia
AU - Baylin, Stephen B
AU - Scharpf, Robert B
AU - Brahmer, Julie
AU - Karchin, Rachel
AU - Pardoll, Andrew Mark
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.
UR - http://www.scopus.com/inward/record.url?scp=85014747024&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014747024&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-16-0828
DO - 10.1158/2159-8290.CD-16-0828
M3 - Article
VL - 7
SP - 264
EP - 276
JO - Cancer Discovery
T2 - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 3
ER -