Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

PEACE Consortium; TRACERx Renal Consortium; Lewis Au; Emine Hatipoglu; Marc Robert de Massy; Kevin Litchfield; Gordon Beattie; Andrew Rowan; Desiree Schnidrig; Rachael Thompson; Fiona Byrne; Stuart Horswell; Nicos Fotiadis; Steve Hazell; David Nicol; Scott T.C. Shepherd; Annika Fendler; Robert Mason; Lyra Del Rosario; Kim Edmonds; Karla Lingard; Sarah Sarker; Mary Mangwende; Eleanor Carlyle; Jan Attig; Kroopa Joshi; Imran Uddin; Pablo D. Becker; Mariana Werner Sunderland; Ayse Akarca; Ignazio Puccio; William W. Yang; Tom Lund; Kim Dhillon; Marcos Duran Vasquez; Peter Parker; David Moore; Crispin Hiley; Debra Josephs; Ashish Chandra; James Spicer; Sarah Rudman; Andrew Tutt; Ian Tomlinson; Ben Challacombe; Simon Chowdhury; Karen Harrison-Phipps; Peter Hill; Catherine Horsfield; Tim O'Brien; Jonathon Olsburgh; Alexander Polson

doi:10.1016/j.ccell.2021.10.001

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

PEACE Consortium, TRACERx Renal Consortium, Lewis Au, Emine Hatipoglu, Marc Robert de Massy, Kevin Litchfield, Gordon Beattie, Andrew Rowan, Desiree Schnidrig, Rachael Thompson, Fiona Byrne, Stuart Horswell, Nicos Fotiadis, Steve Hazell, David Nicol, Scott T.C. Shepherd, Annika Fendler, Robert Mason, Lyra Del Rosario, Kim EdmondsKarla Lingard, Sarah Sarker, Mary Mangwende, Eleanor Carlyle, Jan Attig, Kroopa Joshi, Imran Uddin, Pablo D. Becker, Mariana Werner Sunderland, Ayse Akarca, Ignazio Puccio, William W. Yang, Tom Lund, Kim Dhillon, Marcos Duran Vasquez, Peter Parker, David Moore, Crispin Hiley, Debra Josephs, Ashish Chandra, James Spicer, Sarah Rudman, Andrew Tutt, Ian Tomlinson, Ben Challacombe, Simon Chowdhury, Karen Harrison-Phipps, Peter Hill, Catherine Horsfield, Tim O'Brien, Jonathon Olsburgh, Alexander Polson

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

159 Citations (Scopus)

Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8⁺ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Original language	English
Pages (from-to)	1497-1518.e11
Journal	CANCER CELL
Volume	39
Issue number	11
DOIs	https://doi.org/10.1016/j.ccell.2021.10.001
Publication status	Published - 8 Nov 2021

Keywords

anti-PD-1
autopsy
clear cell renal cell carcinoma
human endogenous retrovirus
multiregion
nivolumab
T cell receptor
TCR clonal maintenance
TCR clonal replacement

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2021.10.001

Cite this

PEACE Consortium, TRACERx Renal Consortium, Au, L., Hatipoglu, E., Robert de Massy, M., Litchfield, K., Beattie, G., Rowan, A., Schnidrig, D., Thompson, R., Byrne, F., Horswell, S., Fotiadis, N., Hazell, S., Nicol, D., Shepherd, S. T. C., Fendler, A., Mason, R., Del Rosario, L., ... Polson, A. (2021). Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. CANCER CELL, 39(11), 1497-1518.e11. https://doi.org/10.1016/j.ccell.2021.10.001

@article{6b1f98342a364d53899164eb152b2f8b,

title = "Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma",

abstract = "ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.",

keywords = "anti-PD-1, autopsy, clear cell renal cell carcinoma, human endogenous retrovirus, multiregion, nivolumab, T cell receptor, TCR clonal maintenance, TCR clonal replacement",

author = "{PEACE Consortium} and {TRACERx Renal Consortium} and Lewis Au and Emine Hatipoglu and {Robert de Massy}, Marc and Kevin Litchfield and Gordon Beattie and Andrew Rowan and Desiree Schnidrig and Rachael Thompson and Fiona Byrne and Stuart Horswell and Nicos Fotiadis and Steve Hazell and David Nicol and Shepherd, {Scott T.C.} and Annika Fendler and Robert Mason and {Del Rosario}, Lyra and Kim Edmonds and Karla Lingard and Sarah Sarker and Mary Mangwende and Eleanor Carlyle and Jan Attig and Kroopa Joshi and Imran Uddin and Becker, {Pablo D.} and Sunderland, {Mariana Werner} and Ayse Akarca and Ignazio Puccio and Yang, {William W.} and Tom Lund and Kim Dhillon and Vasquez, {Marcos Duran} and Peter Parker and David Moore and Crispin Hiley and Debra Josephs and Ashish Chandra and James Spicer and Sarah Rudman and Andrew Tutt and Ian Tomlinson and Ben Challacombe and Simon Chowdhury and Karen Harrison-Phipps and Peter Hill and Catherine Horsfield and Tim O'Brien and Jonathon Olsburgh and Alexander Polson",

note = "Funding Information: We thank the ADAPTeR trial and the Skin and Renal Unit research teams at The Royal Marsden NHS Foundation Trust, including L.D.R., K.L., and M.M., as well as K.E., S.S., Karen O'Meara, Emma Austin, Charlotte Lewis, Fiona Williams, Hamid Ahmod, E.C., Tara Foley, Dilruba Kabir, J.K., A.M., Nahid Shaikh, Kema Peat, Sarah Vaughan, and Lucy Holt. We acknowledge the valuable support of the PEACE consortium. We acknowledge the support of Emma Nye, Bruna Almeida, and the Experimental Histopathology Team. We also thank Lavinia Spain, Irene Lobon, Daqi Deng, Katja De Paepe, Andy Georgiou, Carmella Beastall, Nagina Mangal, Joanna Lynch, Katey Enfield, and Dhruva Biswas for their input. We thank Montserrat Rojo de la Vega for editorial input. We thank Toni Choueiri, Catherine Wu, David Braun, A. Ari Hakimi, Timothy A. Chan, and Christina S. Leslie for permission to use their published data for the single-cell meta-analysis. Most importantly, we thank the patients and their families. Funding Information: We thank the ADAPTeR trial and the Skin and Renal Unit research teams at The Royal Marsden NHS Foundation Trust, including L.D.R. K.L. and M.M. as well as K.E. S.S. Karen O'Meara, Emma Austin, Charlotte Lewis, Fiona Williams, Hamid Ahmod, E.C. Tara Foley, Dilruba Kabir, J.K. A.M. Nahid Shaikh, Kema Peat, Sarah Vaughan, and Lucy Holt. We acknowledge the valuable support of the PEACE consortium. We acknowledge the support of Emma Nye, Bruna Almeida, and the Experimental Histopathology Team. We also thank Lavinia Spain, Irene Lobon, Daqi Deng, Katja De Paepe, Andy Georgiou, Carmella Beastall, Nagina Mangal, Joanna Lynch, Katey Enfield, and Dhruva Biswas for their input. We thank Montserrat Rojo de la Vega for editorial input. We thank Toni Choueiri, Catherine Wu, David Braun, A. Ari Hakimi, Timothy A. Chan, and Christina S. Leslie for permission to use their published data for the single-cell meta-analysis. Most importantly, we thank the patients and their families. The ADAPTeR study (CA209-129) is sponsored by the Royal Marsden NHS Foundation Trust, and partly funded by National Institute for Health Research (NIHR) Biomedical Research Center (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (ICR) (A80), and Cancer Research UK (CRUK) (17767). Bristol-Myers Squibb was the drug provider and provided research funds. TRACERx Renal is funded by NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (A109). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK) (FC001169, FC001988, FC001099), the UK Medical Research Council (FC001169, FC001988, FC001099), and the Wellcome Trust (FC001988, FC001169, FC001099). This research was also funded in part by the CRUK City of London Centre Award (C7893/A26233), CRUK UCL Award C416/A26233), Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265), and the National Institute for Health Research UCL Hospitals Biomedical Research Centre. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. J.L, C.S. S.T. and S.A.Q. conceptualized the study. J.L. S.T. L.P. and L.A. conducted the trial. S.T. S.A.Q. B.C. T.M. M.M. E.H. G.K. K.L. D.S. L.A. and R.T. developed the methodology. M.M. E.H. G.K. D.S. R.T. L.A. K.L. and G.B. performed the formal analysis. A.R. F.B. E.H. I.U. L.A. and M.M. performed the study investigation. S.T. J.L. C.S. S.A.Q. M.J-H. A.R. L.A. E.H. F.B. N.F. S.Hazell, D.N. J.I.L. K.J. I.U. P.D.B. M.S.W. A.A. I.P. W.Y. T.L. K.D. and M.D.V. obtained the resources. L.A. and R.M. performed data curation. All authors performed data contribution and interpretation. L.A. E.H. and M.M. wrote the original draft. L.A. S.T. E.H. and M.M. reviewed and edited the article. M.M. E.H. G.K. L.A. G.B. and R.T. performed study visualization. S.T. S.A.Q. B.C. T.M. J.L. and C.S. supervised the study. S.T. J.L. L.A. E.H. and S.A.Q. administered the project. J.L, C.S. S.T. and S.A.Q. acquired the funding. All authors read and approved the manuscript. L.A. is funded by the Royal Marsden Cancer Charity. E.H. and M.M. are funded by Cancer Research UK (CRUK). F.B. is funded by the Rosetrees Trust (M829). J.A. is a full-time employee of Hoffmann-La Roche AG (Basel, Switzerland). D.A.M has received consultancy fees from AstraZeneca, Thermo Fisher, and Eli Lilly. A.F. has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No. 892360. L.P. has received research funding from Pierre Fabre, and honoraria from Pfizer, Ipsen, Bristol-Myers Squibb, and EUSA Pharma. R.S. has received non-financial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology, and Roche; and advisory board fees for Bristol Myers Squibb; and personal fees from Roche for an advisory board related to a trial-research project; all related to breast cancer research projects. R.S. reports no conflict of interests related to this project. M.J.H. is a Cancer Research UK (CRUK) Clinician Scientist (RCCFEL\100099) and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Center. M.J.H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. G.K. is a scientific co-founder of and consulting for Enara Bio and a member of its scientific advisory board. G.K. receives core funding from the Francis Crick Institute (FC0010099). B.C. is supported by a CRUK Project Grant. J.L. has received research funding from Bristol-Myers Squibb, Merck, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo, and served as a consultant to Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Nektar, Novartis, Pierre Fabre, Pfizer, Roche Genentech, Secarna, and Vitaccess. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.S. is Royal Society Napier Research Professor (RP150154). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Center of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Center, Experimental Cancer Medicine Center and the Breast Cancer Research Foundation, USA (BCRF). His research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union's Seventh Framework Program (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation program (835297), and Chromavision from the European Union's Horizon 2020 research and innovation program (665233). S.A.Q. is a CRUK Senior Cancer Research Fellowship (C36463/A22246) and is funded by a CRUK Biotherapeutic Program Grant (C36463/A20764) and the Rosetrees and Stonygate Trusts (A1388) and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust (539288). S.T. is funded by Cancer Research UK (grant reference number C50947/A18176), the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010988), the UK Medical Research Council (FC0010988), and the Wellcome Trust (FC0010988), the National Institute for Health Research (NIHR) Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (grant reference number A2204), Ventana Medical Systems Inc (grant reference numbers 10467 and 10530), the National Institutes of Health (Bethesda, MD) and Melanoma Research Alliance. ST has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. S.T. has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = nov,

day = "8",

doi = "10.1016/j.ccell.2021.10.001",

language = "English",

volume = "39",

pages = "1497--1518.e11",

journal = "CANCER CELL",

issn = "1535-6108",

publisher = "Cell Press",

number = "11",

}

PEACE Consortium, TRACERx Renal Consortium, Au, L, Hatipoglu, E, Robert de Massy, M, Litchfield, K, Beattie, G, Rowan, A, Schnidrig, D, Thompson, R, Byrne, F, Horswell, S, Fotiadis, N, Hazell, S, Nicol, D, Shepherd, STC, Fendler, A, Mason, R, Del Rosario, L, Edmonds, K, Lingard, K, Sarker, S, Mangwende, M, Carlyle, E, Attig, J, Joshi, K, Uddin, I, Becker, PD, Sunderland, MW, Akarca, A, Puccio, I, Yang, WW, Lund, T, Dhillon, K, Vasquez, MD, Parker, P , Moore, D , Hiley, C , Josephs, D , Chandra, A , Spicer, J , Rudman, S , Tutt, A , Tomlinson, I , Challacombe, B , Chowdhury, S , Harrison-Phipps, K , Hill, P , Horsfield, C , O'Brien, T , Olsburgh, J & Polson, A 2021, 'Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma', CANCER CELL, vol. 39, no. 11, pp. 1497-1518.e11. https://doi.org/10.1016/j.ccell.2021.10.001

TY - JOUR

T1 - Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

AU - PEACE Consortium

AU - TRACERx Renal Consortium

AU - Au, Lewis

AU - Hatipoglu, Emine

AU - Robert de Massy, Marc

AU - Litchfield, Kevin

AU - Beattie, Gordon

AU - Rowan, Andrew

AU - Schnidrig, Desiree

AU - Thompson, Rachael

AU - Byrne, Fiona

AU - Horswell, Stuart

AU - Fotiadis, Nicos

AU - Hazell, Steve

AU - Nicol, David

AU - Shepherd, Scott T.C.

AU - Fendler, Annika

AU - Mason, Robert

AU - Del Rosario, Lyra

AU - Edmonds, Kim

AU - Lingard, Karla

AU - Sarker, Sarah

AU - Mangwende, Mary

AU - Carlyle, Eleanor

AU - Attig, Jan

AU - Joshi, Kroopa

AU - Uddin, Imran

AU - Becker, Pablo D.

AU - Sunderland, Mariana Werner

AU - Akarca, Ayse

AU - Puccio, Ignazio

AU - Yang, William W.

AU - Lund, Tom

AU - Dhillon, Kim

AU - Vasquez, Marcos Duran

AU - Parker, Peter

AU - Moore, David

AU - Hiley, Crispin

AU - Josephs, Debra

AU - Chandra, Ashish

AU - Spicer, James

AU - Rudman, Sarah

AU - Tutt, Andrew

AU - Tomlinson, Ian

AU - Challacombe, Ben

AU - Chowdhury, Simon

AU - Harrison-Phipps, Karen

AU - Hill, Peter

AU - Horsfield, Catherine

AU - O'Brien, Tim

AU - Olsburgh, Jonathon

AU - Polson, Alexander

N1 - Funding Information: We thank the ADAPTeR trial and the Skin and Renal Unit research teams at The Royal Marsden NHS Foundation Trust, including L.D.R., K.L., and M.M., as well as K.E., S.S., Karen O'Meara, Emma Austin, Charlotte Lewis, Fiona Williams, Hamid Ahmod, E.C., Tara Foley, Dilruba Kabir, J.K., A.M., Nahid Shaikh, Kema Peat, Sarah Vaughan, and Lucy Holt. We acknowledge the valuable support of the PEACE consortium. We acknowledge the support of Emma Nye, Bruna Almeida, and the Experimental Histopathology Team. We also thank Lavinia Spain, Irene Lobon, Daqi Deng, Katja De Paepe, Andy Georgiou, Carmella Beastall, Nagina Mangal, Joanna Lynch, Katey Enfield, and Dhruva Biswas for their input. We thank Montserrat Rojo de la Vega for editorial input. We thank Toni Choueiri, Catherine Wu, David Braun, A. Ari Hakimi, Timothy A. Chan, and Christina S. Leslie for permission to use their published data for the single-cell meta-analysis. Most importantly, we thank the patients and their families. Funding Information: We thank the ADAPTeR trial and the Skin and Renal Unit research teams at The Royal Marsden NHS Foundation Trust, including L.D.R. K.L. and M.M. as well as K.E. S.S. Karen O'Meara, Emma Austin, Charlotte Lewis, Fiona Williams, Hamid Ahmod, E.C. Tara Foley, Dilruba Kabir, J.K. A.M. Nahid Shaikh, Kema Peat, Sarah Vaughan, and Lucy Holt. We acknowledge the valuable support of the PEACE consortium. We acknowledge the support of Emma Nye, Bruna Almeida, and the Experimental Histopathology Team. We also thank Lavinia Spain, Irene Lobon, Daqi Deng, Katja De Paepe, Andy Georgiou, Carmella Beastall, Nagina Mangal, Joanna Lynch, Katey Enfield, and Dhruva Biswas for their input. We thank Montserrat Rojo de la Vega for editorial input. We thank Toni Choueiri, Catherine Wu, David Braun, A. Ari Hakimi, Timothy A. Chan, and Christina S. Leslie for permission to use their published data for the single-cell meta-analysis. Most importantly, we thank the patients and their families. The ADAPTeR study (CA209-129) is sponsored by the Royal Marsden NHS Foundation Trust, and partly funded by National Institute for Health Research (NIHR) Biomedical Research Center (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (ICR) (A80), and Cancer Research UK (CRUK) (17767). Bristol-Myers Squibb was the drug provider and provided research funds. TRACERx Renal is funded by NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (A109). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK) (FC001169, FC001988, FC001099), the UK Medical Research Council (FC001169, FC001988, FC001099), and the Wellcome Trust (FC001988, FC001169, FC001099). This research was also funded in part by the CRUK City of London Centre Award (C7893/A26233), CRUK UCL Award C416/A26233), Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265), and the National Institute for Health Research UCL Hospitals Biomedical Research Centre. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. J.L, C.S. S.T. and S.A.Q. conceptualized the study. J.L. S.T. L.P. and L.A. conducted the trial. S.T. S.A.Q. B.C. T.M. M.M. E.H. G.K. K.L. D.S. L.A. and R.T. developed the methodology. M.M. E.H. G.K. D.S. R.T. L.A. K.L. and G.B. performed the formal analysis. A.R. F.B. E.H. I.U. L.A. and M.M. performed the study investigation. S.T. J.L. C.S. S.A.Q. M.J-H. A.R. L.A. E.H. F.B. N.F. S.Hazell, D.N. J.I.L. K.J. I.U. P.D.B. M.S.W. A.A. I.P. W.Y. T.L. K.D. and M.D.V. obtained the resources. L.A. and R.M. performed data curation. All authors performed data contribution and interpretation. L.A. E.H. and M.M. wrote the original draft. L.A. S.T. E.H. and M.M. reviewed and edited the article. M.M. E.H. G.K. L.A. G.B. and R.T. performed study visualization. S.T. S.A.Q. B.C. T.M. J.L. and C.S. supervised the study. S.T. J.L. L.A. E.H. and S.A.Q. administered the project. J.L, C.S. S.T. and S.A.Q. acquired the funding. All authors read and approved the manuscript. L.A. is funded by the Royal Marsden Cancer Charity. E.H. and M.M. are funded by Cancer Research UK (CRUK). F.B. is funded by the Rosetrees Trust (M829). J.A. is a full-time employee of Hoffmann-La Roche AG (Basel, Switzerland). D.A.M has received consultancy fees from AstraZeneca, Thermo Fisher, and Eli Lilly. A.F. has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 892360. L.P. has received research funding from Pierre Fabre, and honoraria from Pfizer, Ipsen, Bristol-Myers Squibb, and EUSA Pharma. R.S. has received non-financial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology, and Roche; and advisory board fees for Bristol Myers Squibb; and personal fees from Roche for an advisory board related to a trial-research project; all related to breast cancer research projects. R.S. reports no conflict of interests related to this project. M.J.H. is a Cancer Research UK (CRUK) Clinician Scientist (RCCFEL\100099) and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Center. M.J.H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. G.K. is a scientific co-founder of and consulting for Enara Bio and a member of its scientific advisory board. G.K. receives core funding from the Francis Crick Institute (FC0010099). B.C. is supported by a CRUK Project Grant. J.L. has received research funding from Bristol-Myers Squibb, Merck, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo, and served as a consultant to Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Nektar, Novartis, Pierre Fabre, Pfizer, Roche Genentech, Secarna, and Vitaccess. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.S. is Royal Society Napier Research Professor (RP150154). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Center of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Center, Experimental Cancer Medicine Center and the Breast Cancer Research Foundation, USA (BCRF). His research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union's Seventh Framework Program (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation program (835297), and Chromavision from the European Union's Horizon 2020 research and innovation program (665233). S.A.Q. is a CRUK Senior Cancer Research Fellowship (C36463/A22246) and is funded by a CRUK Biotherapeutic Program Grant (C36463/A20764) and the Rosetrees and Stonygate Trusts (A1388) and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust (539288). S.T. is funded by Cancer Research UK (grant reference number C50947/A18176), the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010988), the UK Medical Research Council (FC0010988), and the Wellcome Trust (FC0010988), the National Institute for Health Research (NIHR) Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (grant reference number A2204), Ventana Medical Systems Inc (grant reference numbers 10467 and 10530), the National Institutes of Health (Bethesda, MD) and Melanoma Research Alliance. ST has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. S.T. has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. Publisher Copyright: © 2021 The Authors

PY - 2021/11/8

Y1 - 2021/11/8

N2 - ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

AB - ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

KW - anti-PD-1

KW - autopsy

KW - clear cell renal cell carcinoma

KW - human endogenous retrovirus

KW - multiregion

KW - nivolumab

KW - T cell receptor

KW - TCR clonal maintenance

KW - TCR clonal replacement

UR - http://www.scopus.com/inward/record.url?scp=85119606374&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.10.001

DO - 10.1016/j.ccell.2021.10.001

M3 - Article

C2 - 34715028

AN - SCOPUS:85119606374

SN - 1535-6108

VL - 39

SP - 1497-1518.e11

JO - CANCER CELL

JF - CANCER CELL

IS - 11

ER -

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this