Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition

Barzin Y Nabet; Mohammad S Esfahani; Everett J Moding; Emily G Hamilton; Jacob J Chabon; Hira Rizvi; Chloe B Steen; Aadel A Chaudhuri; Chih Long Liu; Angela B Hui; Diego Almanza; Henning Stehr; Linda Gojenola; Rene F Bonilla; Michael C Jin; Young-Jun Jeon; Diane Tseng; Cailian Liu; Taha Merghoub; Joel W Neal; Heather A Wakelee; Sukhmani K Padda; Kavitha J Ramchandran; Millie Das; Andrew J Plodkowski; Christopher Yoo; Emily L Chen; Ryan B Ko; Aaron M Newman; Matthew D Hellmann; Ash A Alizadeh; Maximilian Diehn

doi:10.1016/j.cell.2020.09.001

Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition

Cell. 2020 Oct 15;183(2):363-376.e13. doi: 10.1016/j.cell.2020.09.001. Epub 2020 Oct 1.

Authors

Barzin Y Nabet¹, Mohammad S Esfahani², Everett J Moding¹, Emily G Hamilton³, Jacob J Chabon⁴, Hira Rizvi⁵, Chloe B Steen⁶, Aadel A Chaudhuri⁷, Chih Long Liu⁸, Angela B Hui¹, Diego Almanza³, Henning Stehr⁹, Linda Gojenola⁹, Rene F Bonilla¹⁰, Michael C Jin², Young-Jun Jeon¹¹, Diane Tseng², Cailian Liu¹², Taha Merghoub¹³, Joel W Neal⁸, Heather A Wakelee⁸, Sukhmani K Padda⁸, Kavitha J Ramchandran⁸, Millie Das¹⁴, Andrew J Plodkowski¹⁵, Christopher Yoo¹⁰, Emily L Chen¹⁰, Ryan B Ko¹⁰, Aaron M Newman¹⁶, Matthew D Hellmann¹⁷, Ash A Alizadeh¹⁸, Maximilian Diehn¹⁹

Affiliations

¹ Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
² Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
³ Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Program in Cancer Biology, Stanford University, Stanford, CA, USA.
⁴ Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁵ Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁷ Department of Radiation Oncology, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁹ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁰ Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
¹¹ Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
¹² Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹³ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy at MSK, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁴ Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁵ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
¹⁷ Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy at MSK, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: hellmanm@mskcc.org.
¹⁸ Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: arasha@stanford.edu.
¹⁹ Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Electronic address: diehn@stanford.edu.

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.

Keywords: circulating tumor DNA; immune checkpoint inhibition; immunotherapy; liquid biopsy; non-small cell lung cancer; response classification.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antineoplastic Agents, Immunological / pharmacology
B7-H1 Antigen / immunology
B7-H1 Antigen / metabolism
Biomarkers, Pharmacological / blood*
Biomarkers, Tumor / genetics
CD8-Positive T-Lymphocytes / pathology
Carcinoma, Non-Small-Cell Lung / pathology
Circulating Tumor DNA / analysis*
Circulating Tumor DNA / genetics
Female
Humans
Immune Checkpoint Inhibitors / immunology
Immune Checkpoint Inhibitors / metabolism
Immune Checkpoint Inhibitors / therapeutic use*
Immunotherapy / methods
Lung Neoplasms / pathology
Male
Middle Aged
Programmed Cell Death 1 Receptor / metabolism

Substances

Antineoplastic Agents, Immunological
B7-H1 Antigen
Biomarkers, Pharmacological
Biomarkers, Tumor
Circulating Tumor DNA
Immune Checkpoint Inhibitors
PDCD1 protein, human
Programmed Cell Death 1 Receptor

Abstract

Publication types

MeSH terms

Substances

Grants and funding