Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Nadeem Riaz; Jonathan J. Havel; Vladimir Makarov; Alexis Desrichard; Walter J. Urba; Jennifer S. Sims; F. Stephen Hodi; Salvador Martín-Algarra; Rajarsi Mandal; William H. Sharfman; Shailender Bhatia; Wen Jen Hwu; Thomas F. Gajewski; Craig L. Slingluff; Diego Chowell; Sviatoslav M. Kendall; Han Chang; Rachna Shah; Fengshen Kuo; Luc G.T. Morris; John William Sidhom; Jonathan P. Schneck; Christine E. Horak; Nils Weinhold; Timothy A. Chan

doi:10.1016/j.cell.2017.09.028

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Nadeem Riaz, Jonathan J. Havel, Vladimir Makarov, Alexis Desrichard, Walter J. Urba, Jennifer S. Sims, F. Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H. Sharfman, Shailender Bhatia, Wen Jen Hwu, Thomas F. Gajewski, Craig L. Slingluff, Diego Chowell, Sviatoslav M. Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G.T. MorrisJohn William Sidhom, Jonathan P. Schneck, Christine E. Horak, Nils Weinhold, Timothy A. Chan

School of Medicine

Research output: Contribution to journal › Article › peer-review

518 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	934-949.e15
Journal	Cell
Volume	171
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2017.09.028
State	Published - Nov 2 2017

Keywords

T cell receptor repertoire
clonal evolution/clonal selection
immunotherapy
ipilimumab
melanoma
neoantigen load
nivolumab
tumor immune evasion
tumor microenvironment
tumor mutation load/tumor mutation burden

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2017.09.028

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Riaz, N., Havel, J. J., Makarov, V., Desrichard, A., Urba, W. J., Sims, J. S., Hodi, F. S., Martín-Algarra, S., Mandal, R., Sharfman, W. H., Bhatia, S., Hwu, W. J., Gajewski, T. F., Slingluff, C. L., Chowell, D., Kendall, S. M., Chang, H., Shah, R., Kuo, F., ... Chan, T. A. (2017). Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell, 171(4), 934-949.e15. https://doi.org/10.1016/j.cell.2017.09.028

Riaz, N, Havel, JJ, Makarov, V, Desrichard, A, Urba, WJ, Sims, JS, Hodi, FS, Martín-Algarra, S, Mandal, R, Sharfman, WH, Bhatia, S, Hwu, WJ, Gajewski, TF, Slingluff, CL, Chowell, D, Kendall, SM, Chang, H, Shah, R, Kuo, F, Morris, LGT, Sidhom, JW, Schneck, JP, Horak, CE, Weinhold, N & Chan, TA 2017, 'Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab', Cell, vol. 171, no. 4, pp. 934-949.e15. https://doi.org/10.1016/j.cell.2017.09.028

@article{c97946a4046a4197a542899443f7bff3,

title = "Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab",

abstract = "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.",

keywords = "T cell receptor repertoire, clonal evolution/clonal selection, immunotherapy, ipilimumab, melanoma, neoantigen load, nivolumab, tumor immune evasion, tumor microenvironment, tumor mutation load/tumor mutation burden",

author = "Nadeem Riaz and Havel, {Jonathan J.} and Vladimir Makarov and Alexis Desrichard and Urba, {Walter J.} and Sims, {Jennifer S.} and Hodi, {F. Stephen} and Salvador Mart{\'i}n-Algarra and Rajarsi Mandal and Sharfman, {William H.} and Shailender Bhatia and Hwu, {Wen Jen} and Gajewski, {Thomas F.} and Slingluff, {Craig L.} and Diego Chowell and Kendall, {Sviatoslav M.} and Han Chang and Rachna Shah and Fengshen Kuo and Morris, {Luc G.T.} and Sidhom, {John William} and Schneck, {Jonathan P.} and Horak, {Christine E.} and Nils Weinhold and Chan, {Timothy A.}",

note = "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: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = nov,

day = "2",

doi = "10.1016/j.cell.2017.09.028",

language = "English (US)",

volume = "171",

pages = "934--949.e15",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

}

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 -

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

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