Abstract
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
Original language | English (US) |
---|---|
Pages (from-to) | 1214-1225 |
Number of pages | 12 |
Journal | Cancer research |
Volume | 79 |
Issue number | 6 |
DOIs | |
State | Published - 2019 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer. / Anagnostou, Valsamo; Forde, Patrick M.; White, James R.; Niknafs, Noushin; Hruban, Carolyn; Naidoo, Jarushka; Marrone, Kristen; Ashok Sivakumar, I. K.; Bruhm, Daniel C.; Rosner, Samuel; Phallen, Jillian; Leal, Alessandro; Adleff, Vilmos; Smith, Kellie N.; Cottrell, Tricia R.; Rhymee, Lamia; Palsgrove, Doreen N.; Hann, Christine L.; Levy, Benjamin; Feliciano, Josephine; Georgiades, Christos; Verde, Franco; Illei, Peter; Li, Qing Kay; Gabrielson, Edward; Brock, Malcolm V.; Isbell, James M.; Sauter, Jennifer L.; Taube, Janis; Scharpf, Robert B.; Karchin, Rachel; Pardoll, Drew M.; Chaft, Jamie E.; Hellmann, Matthew D.; Brahmer, Julie R.; Velculescu, Victor E.
In: Cancer research, Vol. 79, No. 6, 2019, p. 1214-1225.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer
AU - Anagnostou, Valsamo
AU - Forde, Patrick M.
AU - White, James R.
AU - Niknafs, Noushin
AU - Hruban, Carolyn
AU - Naidoo, Jarushka
AU - Marrone, Kristen
AU - Ashok Sivakumar, I. K.
AU - Bruhm, Daniel C.
AU - Rosner, Samuel
AU - Phallen, Jillian
AU - Leal, Alessandro
AU - Adleff, Vilmos
AU - Smith, Kellie N.
AU - Cottrell, Tricia R.
AU - Rhymee, Lamia
AU - Palsgrove, Doreen N.
AU - Hann, Christine L.
AU - Levy, Benjamin
AU - Feliciano, Josephine
AU - Georgiades, Christos
AU - Verde, Franco
AU - Illei, Peter
AU - Li, Qing Kay
AU - Gabrielson, Edward
AU - Brock, Malcolm V.
AU - Isbell, James M.
AU - Sauter, Jennifer L.
AU - Taube, Janis
AU - Scharpf, Robert B.
AU - Karchin, Rachel
AU - Pardoll, Drew M.
AU - Chaft, Jamie E.
AU - Hellmann, Matthew D.
AU - Brahmer, Julie R.
AU - Velculescu, Victor E.
N1 - Funding Information: P.M. Forde reports receiving a commercial research grant from AstraZe-neca, BMS, Corvus, Kyowa, Merck, and Novartis, and is a consultant/ advisory board member of Abbvie, AstraZeneca, BMS, Boehringer, EMD Serono, Lilly, Merck, and Novartis. J.R. White is a consultant at Personal Genome Diagnostics and has ownership interest (including stock, patents, etc.) in Resphera Biosciences. J. Naidoo reports receiving a commercial research grant from AstraZeneca/MedImmune and Merck, is a consultant/ advisory board member of AstraZeneca/MedImmune, Bristol-Myers Squibb, Takeda, Genentech/Roche, and has provided expert testimony for Bristol-Myers Squibb and AstraZeneca/MedImmune. V. Adleff is a consultant/advisory board member of Personal Genome Diagnostics. C.L. Hann reports receiving other commercial research support from Bristol-Myers Squibb and is a consultant/advisory board member of Bristol-Myers Squibb and Genentech. B. Levy is a consultant/advisory board member of Genentech, AstraZeneca, Eli Lilly, Celgene, and Takeda. J. Feliciano is a consultant/advisory board member of AstraZeneca, Merck, Genentech, and Eli Lilly, and has provided expert testimony for legal review. P. Illei reports receiving other commercial research support from Bristol Myers-Squib and is a consultant/advisory board member of AstraZeneca, Bayer, Roche, and Abbvie. J.M. Isbell has ownership interest (including stock, patents, etc.) in LumaCyte, Inc. J.L. Sauter has ownership interest (including stock, patents, etc.) in Merck & Company, Inc. (New), Chemed Corporation, Pfizer, Thermo Fisher Scientific, Celgene, and Allergan PLC SHS. J. Taube reports receiving a commercial research grant from Bristol Myers Squibb and is a consultant/advisory board member of Bristol Myers Squibb, Astra Zeneca, Merck, and Amgen. D.M. Pardoll reports receiving a commercial research grant from Bristol Myers Squibb, Astra Zeneca, Compugen, Merck, has ownership interest (including stock, patents, etc.) in WindMil, Trieza Therapeutics, Potenza, Ervaxx, Dracen Pharmaceuticals, DNAtrix, Aduro Biotech, Five Prime, and Tizona, and is a consultant/advisory board member of Amgen, Bayer, Camden Partners, Jansesen, FLX Bio, Immunomics, and Rock Springs Capitol. J.E. Chaft is a consultant/advisory board member of AstraZeneca, Merck, BMS, and Genentech. M.D. Funding Information: This work was supported in part by U.S. NIH grants CA121113 (to V. Velculescu, V. Anagnostou), CA006973 (to D. Pardoll, V. Velculescu), CA180950 (to V. Velculescu), the Commonwealth Foundation (to V. Velculescu), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (to V. Anagnostou, P. Forde, J. Brahmer, D. Pardoll, V. Velculescu), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to V. Velculescu), the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (to V. Anagnostou), MacMillan Foundation (to V. Anagnostou), the V Foundation (to V. Anagnostou, V. Velculescu), the ICTR-ATIP UL1TR001079 (to V. Anagnostou), the Pardee Foundation (to V. Anagnostou), Swim Across America (to V. Anagnostou), the William R. Brody Faculty Scholarship (to R. Karchin), the SU2C-ACS Lung Cancer Dream Team (to P. Forde and E. Gabrielson), PRIME Oncology (to J. Naidoo), the MSK Cancer Center Support Grant/Core Grant (P30 CA008747), the SU2C DCS International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415; to V. Velculescu), the SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team, Translational Cancer Research Grant (SU2C-AACR-DT23-17 to J. Brahmer, V. Velculescu), the Allegheny Health Network – Johns Hopkins Research Fund (to V. Anagnostou, V. Velcu-lescu), the LUNGevity Foundation (to V. Anagnostou and P. Forde), the Mark Foundation (to A. Leal, V. Velculescu), and Bristol Meyers Squibb (to P. Forde). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This publication was made possible in part by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by Grant Number UL1TR001079 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH. We thank Dr. Suzanne Topalian and members of our laboratories for helpful discussions and critical review of the manuscript. Funding Information: Hellmann reports receiving a commercial research grant from BMS, is a consultant/advisory board member of Merck, BMS, AstraZeneca/MedIm-mune, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs, and has provided expert testimony for a patent that 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 PGDx. J.R. Brahmer reports receiving a commercial research grant from BMS and is a consultant/advisory board member of BMS, Merck, Genentech, Amgen, Janssen, Syndax, Celgene, and AstraZeneca. V.E. Velculescu has ownership interest (including stock, patents, etc.) in Ignyta and Personal Genome Diagnostics and is a consultant/advisory board member of Ignyta and Personal Genome Diagnostics. No potential conflicts of interest were disclosed by the other authors. Funding Information: This work was supported in part by U.S. NIH grants CA121113 (to V. Velculescu, V. Anagnostou), CA006973 (to D. Pardoll, V. Velculescu), CA180950 (to V. Velculescu), the Commonwealth Foundation (to V. Velculescu), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (to V. Anagnostou, P. Forde, J. Brahmer, D. Pardoll, V. Velculescu), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to V. Velculescu), the Eastern Cooperative Oncology Group- American College of Radiology Imaging Network (to V. Anagnostou), MacMillan Foundation (to V. Anagnostou), the V Foundation (to V. Anagnostou, V. Velculescu), the ICTR-ATIP UL1TR001079 (to V. Anagnostou), the Pardee Foundation (to V. Anagnostou), Swim Across America (to V. Anagnostou), the William R. Brody Faculty Scholarship (to R. Karchin), the SU2C-ACS Lung Cancer Dream Team (to P. Forde and E. Gabrielson), PRIME Oncology (to J. Naidoo), the MSK Cancer Center Support Grant/Core Grant (P30 CA008747), the SU2C DCS International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415; to V. Velculescu), the SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team, Translational Cancer Research Grant (SU2C-AACR-DT23-17 to J. Brahmer, V. Velculescu), the Allegheny Health Network – Johns Hopkins Research Fund (to V. Anagnostou, V. Velculescu), the LUNGevity Foundation (to V. Anagnostou and P. Forde), the Mark Foundation (to A. Leal, V. Velculescu), and Bristol Meyers Squibb (to P. Forde). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This publication was made possible in part by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by Grant Number UL1TR001079 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH. We thank Dr. Suzanne Topalian and members of our laboratories for helpful discussions and critical review of the manuscript.
PY - 2019
Y1 - 2019
N2 - Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
AB - Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N ¼ 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57–18.35; P ¼ 0.007 and HR 6.91; 95% CI, 1.37–34.97; P ¼ 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non–small cell lung cancer (N ¼ 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.
UR - http://www.scopus.com/inward/record.url?scp=85062974749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062974749&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1127
DO - 10.1158/0008-5472.CAN-18-1127
M3 - Article
C2 - 30541742
AN - SCOPUS:85062974749
VL - 79
SP - 1214
EP - 1225
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 6
ER -