Abstract
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
| Original language | English |
|---|---|
| Pages (from-to) | 363-376.e13 |
| Journal | Cell |
| Volume | 183 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 15 2020 |
Keywords
- circulating tumor DNA
- immune checkpoint inhibition
- immunotherapy
- liquid biopsy
- non-small cell lung cancer
- response classification
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Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. / Nabet, Barzin Y.; Esfahani, Mohammad S.; Moding, Everett J. et al.
In: Cell, Vol. 183, No. 2, 15.10.2020, p. 363-376.e13.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition
AU - Nabet, Barzin Y.
AU - Esfahani, Mohammad S.
AU - Moding, Everett J.
AU - Hamilton, Emily G.
AU - Chabon, Jacob J.
AU - Rizvi, Hira
AU - Steen, Chloe B.
AU - Chaudhuri, Aadel A.
AU - Liu, Chih Long
AU - Hui, Angela B.
AU - Almanza, Diego
AU - Stehr, Henning
AU - Gojenola, Linda
AU - Bonilla, Rene F.
AU - Jin, Michael C.
AU - Jeon, Young Jun
AU - Tseng, Diane
AU - Liu, Cailian
AU - Merghoub, Taha
AU - Neal, Joel W.
AU - Wakelee, Heather A.
AU - Padda, Sukhmani K.
AU - Ramchandran, Kavitha J.
AU - Das, Millie
AU - Plodkowski, Andrew J.
AU - Yoo, Christopher
AU - Chen, Emily L.
AU - Ko, Ryan B.
AU - Newman, Aaron M.
AU - Hellmann, Matthew D.
AU - Alizadeh, Ash A.
AU - Diehn, Maximilian
N1 - Funding Information: We thank the patients and families who participated in this study. This work was supported by the National Cancer Institute (B.Y.N. and M.S.E., R25CA180993 ; M.S.E., T32CA009302 ; M. Diehn and A.A.A., R01CA188298 ), the US National Institutes of Health Director’s New Innovator Award Program (M. Diehn, 1-DP2-CA186569 ), the Virginia and D.K. Ludwig Fund for Cancer Research (M. Diehn and A.A.A.), the Bakewell Foundation (to M. Das and A.A.A.), the SDW/DT and Shanahan Family Foundations (to A.A.A.), and the CRK Faculty Scholar Fund (M. Diehn). A.A.A. is a scholar of the Leukemia and Lymphoma Society . M.D.H. and this research were supported, in part, by the Damon Runyon Cancer Research Foundation (grant no. CI-98-18 ), the Memorial Sloan Kettering Cancer Center support grant/core grant no. P30 CA008748 , and a Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant (SU2C-AACR-DT17-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research , the scientific partner of SU2C. M.D.H. is a member of the Parker Institute for Cancer Immunotherapy . B.Y.N. is supported by the Postdoctoral Research Fellowship ( 134031-PF-19-164-01-TBG ) from the American Cancer Society . The schematic in Figure 1B was produced using Servier Medical Art ( https://smart.servier.com ) licensed under CC BY 3.0. Funding Information: We thank the patients and families who participated in this study. This work was supported by the National Cancer Institute (B.Y.N. and M.S.E. R25CA180993; M.S.E. T32CA009302; M. Diehn and A.A.A. R01CA188298), the US National Institutes of Health Director's New Innovator Award Program (M. Diehn, 1-DP2-CA186569), the Virginia and D.K. Ludwig Fund for Cancer Research (M. Diehn and A.A.A.), the Bakewell Foundation (to M. Das and A.A.A.), the SDW/DT and Shanahan Family Foundations (to A.A.A.), and the CRK Faculty Scholar Fund (M. Diehn). A.A.A. is a scholar of the Leukemia and Lymphoma Society. M.D.H. and this research were supported, in part, by the Damon Runyon Cancer Research Foundation (grant no. CI-98-18), the Memorial Sloan Kettering Cancer Center support grant/core grant no. P30 CA008748, and a Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant (SU2C-AACR-DT17-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. M.D.H. is a member of the Parker Institute for Cancer Immunotherapy. B.Y.N. is supported by the Postdoctoral Research Fellowship (134031-PF-19-164-01-TBG) from the American Cancer Society. The schematic in Figure 1B was produced using Servier Medical Art (https://smart.servier.com) licensed under CC BY 3.0. Conceptualization, B.Y.N. M.S.E. A.A.A. and M. Diehn; Methodology, B.Y.N. and M.S.E.; Software, B.Y.N. M.S.E. C.L.L. C.B.S. and A.M.N.; Investigation, B.Y.N. E.G.H. J.J.C. E.J.M. A.A.C. A.B.H. D.A. M.C.J. Y.J.-J. and D.T.; Resources, B.Y.N. H.R. C.L.L. C.L. T.M. H.S. L.G. R.F.B. J.W.N. H.A.W. S.K.P. K.J.R. M. Das, A.J.P. C.Y. E.L.C. R.B.K. and M.D.H.; Formal Analysis, B.Y.N. and M.S.E.; Writing ? Original Draft, B.Y.N. M.S.E. M.D.H. A.A.A. and M. Diehn; Writing ? Review & Editing, all authors. J.J.C. reports paid consultancy from Lexent Bio Inc. A.A.C. reports speaker honoraria and travel support from Roche Sequencing Solutions (RSS), Varian, and Foundation Medicine; a research grant from RSS; and has served as a paid consultant for Oscar Health. T.M. is a co-founder of Imvaq. J.W.N. reports research support from Genentech (GNE)/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Takeda Pharmaceuticals, Nektar Therapeutics, Adaptimmune, and GSK, and has served in a consulting or advisory role for AstraZeneca (AZ), GNE/Roche, Exelixis Inc. Jounce Therapeutics, Takeda Pharmaceuticals, and Eli Lilly. H.A.W. has received honoraria from Novartis and AZ and has participated on the advisory boards of Xcovery, Janssen, and Mirati. S.K.P. reports grant support from EpicentRx, Forty Seven, Bayer, and Boehringer Ingelheim and serves in a consulting or advisory role for AZ, AbbVie, G1 Therapeutics, and Pfizer. M. Das reports grant support from AbbVie, United Therapeutics, Varian, and Celgene and serves in a consulting role for AZ and Bristol-Myers Squibb (BMS). A.M.N. has patent filings related to expression deconvolution and cancer biomarkers and has served as a consultant for Roche, Merck, and CiberMed. M.D.H. reports paid consultancy from BMS, Merck, GNE, AZ/MedImmune, Nektar, Syndax, Janssen, Mirati Therapeutics, Shattuck Labs, and Blueprint Medicines; travel/honoraria from BMS and AZ; research funding from BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics. A.A.A. reports ownership interest in CiberMed and FortySeven, patent filings related to cancer biomarkers, and paid consultancy from GNE, Roche, Chugai, Gilead, and Celgene. M. Diehn reports research funding from Varian, ownership interest in CiberMed, patent filings related to cancer biomarkers, paid consultancy from Roche, AZ, and BioNTech, and travel/honoraria from Reflexion. M.Diehn, A.A.A. B.Y.N. and M.S.E. are co-inventors on a provisional patent application filed by Stanford University relating to this manuscript. Publisher Copyright: © 2020 Elsevier Inc.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
AB - Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
KW - circulating tumor DNA
KW - immune checkpoint inhibition
KW - immunotherapy
KW - liquid biopsy
KW - non-small cell lung cancer
KW - response classification
UR - http://www.scopus.com/inward/record.url?scp=85092497602&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.09.001
DO - 10.1016/j.cell.2020.09.001
M3 - Article
C2 - 33007267
AN - SCOPUS:85092497602
SN - 0092-8674
VL - 183
SP - 363-376.e13
JO - Cell
JF - Cell
IS - 2
ER -