TY - JOUR
T1 - Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
AU - Riaz, Nadeem
AU - Havel, Jonathan J.
AU - Makarov, Vladimir
AU - Desrichard, Alexis
AU - Urba, Walter J.
AU - Sims, Jennifer S.
AU - Hodi, F. Stephen
AU - Martín-Algarra, Salvador
AU - Mandal, Rajarsi
AU - Sharfman, William H.
AU - Bhatia, Shailender
AU - Hwu, Wen Jen
AU - Gajewski, Thomas F.
AU - Slingluff, Craig L.
AU - Chowell, Diego
AU - Kendall, Sviatoslav M.
AU - Chang, Han
AU - Shah, Rachna
AU - Kuo, Fengshen
AU - Morris, Luc G.T.
AU - Sidhom, John William
AU - Schneck, Jonathan P.
AU - Horak, Christine E.
AU - Weinhold, Nils
AU - Chan, Timothy A.
N1 - Funding Information:
We first thank each patient and their families for participation in this study. This work was funded by Bristol-Myers Squibb , the Pershing Square Sohn Cancer Research Foundation (T.A.C.), the PaineWebber Chair (T.A.C.), Stand Up 2 Cancer (T.A.C.), the Memorial Sloan Kettering Cancer Center (core grant 5P30 CA008748-50 ), and the STARR Cancer Consortium (T.A.C.). S.B. reports grants from Abraxis , Amgen , Bionomics , Bristol-Myers Squibb , EMD Serono , Immune Design , Immunogen , Merck , NantKwest , and OncoSec , and personal fees from Genentech. T.A.C. is a co-founder of Gritstone Oncology and reports research grants from Bristol-Myers Squibb . H.C. and C.E.H. are full-time employees and stock shareholders of Bristol-Myers Squibb. T.F.G. reports grants from Bristol-Myers Squibb , Incyte , Merck , Ono , Genentech , and Seattle Genetics , personal fees from AbbVie, Aduro, Bayer, Jounce Therapeutics, Merck, and Genentech, and is a stock shareholder of Jounce Therapeutics. J.J.H. reports that spouse is a full-time employee of Regeneron Pharmaceuticals. F.S.H. reports grants from Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb, EMD Serono, Genentech, Merck, and Novartis. W.-J.H. reports grants from Bristol-Myers Squibb , GlaxoSmithKline , MedImmune , and Merck , and personal fees from Merck. F.K. and V.M. report grants from Bristol-Myers Squibb . S.M.-A. reports personal fees from Bristol-Myers Squibb and Merck. L.G.T.M. reports personal fees from Merck. N.R. reports grants from Bristol-Myers Squibb , and personal fees from MedImmune. J.P.S. reports grants and personal fees from, and is a stock shareholder of, NexImmune . W.H.S. reports grants from Bristol-Myers Squibb and Merck and personal fees from Bristol-Myers Squibb, Castle Biosciences, Merck, and Novartis. C.L.S. reports grants from Merck and Polynoma , personal fees from Immatics, and is a patent holder for the University of Virginia. W.J.U. reports grants and personal fees from Bristol-Myers Squibb and MedImmune and personal fees from Green Peptide and eTheRNA. Medical writing and editorial assistance provided by Amrita Dervan, MSc, and Jay Rathi, MA, of Spark Medica (US), funded by Bristol-Myers Squibb .
Funding Information:
We first thank each patient and their families for participation in this study. This work was funded by Bristol-Myers Squibb, the Pershing Square Sohn Cancer Research Foundation (T.A.C.), the PaineWebber Chair (T.A.C.), Stand Up 2 Cancer (T.A.C.), the Memorial Sloan Kettering Cancer Center (core grant 5P30 CA008748-50), and the STARR Cancer Consortium (T.A.C.). S.B. reports grants from Abraxis, Amgen, Bionomics, Bristol-Myers Squibb, EMD Serono, Immune Design, Immunogen, Merck, NantKwest, and OncoSec, and personal fees from Genentech. T.A.C. is a co-founder of Gritstone Oncology and reports research grants from Bristol-Myers Squibb. H.C. and C.E.H. are full-time employees and stock shareholders of Bristol-Myers Squibb. T.F.G. reports grants from Bristol-Myers Squibb, Incyte, Merck, Ono, Genentech, and Seattle Genetics, personal fees from AbbVie, Aduro, Bayer, Jounce Therapeutics, Merck, and Genentech, and is a stock shareholder of Jounce Therapeutics. J.J.H. reports that spouse is a full-time employee of Regeneron Pharmaceuticals. F.S.H. reports grants from Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb, EMD Serono, Genentech, Merck, and Novartis. W.-J.H. reports grants from Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, and Merck, and personal fees from Merck. F.K. and V.M. report grants from Bristol-Myers Squibb. S.M.-A. reports personal fees from Bristol-Myers Squibb and Merck. L.G.T.M. reports personal fees from Merck. N.R. reports grants from Bristol-Myers Squibb, and personal fees from MedImmune. J.P.S. reports grants and personal fees from, and is a stock shareholder of, NexImmune. W.H.S. reports grants from Bristol-Myers Squibb and Merck and personal fees from Bristol-Myers Squibb, Castle Biosciences, Merck, and Novartis. C.L.S. reports grants from Merck and Polynoma, personal fees from Immatics, and is a patent holder for the University of Virginia. W.J.U. reports grants and personal fees from Bristol-Myers Squibb and MedImmune and personal fees from Green Peptide and eTheRNA. Medical writing and editorial assistance provided by Amrita Dervan, MSc, and Jay Rathi, MA, of Spark Medica (US), funded by Bristol-Myers Squibb.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/11/2
Y1 - 2017/11/2
N2 - The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action. Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against mutant neoepitopes may be a critical mechanism of action of Nivolumab.
AB - The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action. Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against mutant neoepitopes may be a critical mechanism of action of Nivolumab.
KW - T cell receptor repertoire
KW - clonal evolution/clonal selection
KW - immunotherapy
KW - ipilimumab
KW - melanoma
KW - neoantigen load
KW - nivolumab
KW - tumor immune evasion
KW - tumor microenvironment
KW - tumor mutation load/tumor mutation burden
UR - http://www.scopus.com/inward/record.url?scp=85031295254&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031295254&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.09.028
DO - 10.1016/j.cell.2017.09.028
M3 - Article
C2 - 29033130
AN - SCOPUS:85031295254
SN - 0092-8674
VL - 171
SP - 934-949.e15
JO - Cell
JF - Cell
IS - 4
ER -