Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer

Valsamo Anagnostou, Patrick Forde, James R. White, Noushin Niknafs, Carolyn Hruban, Jarushka Naidoo, Kristen Marrone, I. K. Ashok Sivakumar, Daniel C. Bruhm, Samuel Rosner, Jillian Phallen, Alessandro Leal, Vilmos Adleff, Kellie Smith, Tricia R. Cottrell, Lamia Rhymee, Doreen N. Palsgrove, Christine Hann, Benjamin Levy, Josephine FelicianoChristos S Georgiades, Franco Verde, Peter B Illei, Qing Kay Li, Edward Gabrielson, Malcolm V. Brock, James M. Isbell, Jennifer L. Sauter, Janis M Taube, Robert B Scharpf, Rachel Karchin, Andrew Mark Pardoll, Jamie E. Chaft, Matthew D. Hellmann, Julie Brahmer, Victor E Velculescu

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1214-1225
Number of pages12
JournalCancer Research
Volume79
Issue number6
DOIs
StatePublished - Jan 1 2019

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Non-Small Cell Lung Carcinoma
DNA
Neoplasms
Therapeutics
Confidence Intervals
T-Lymphocytes
Residual Neoplasm
Therapeutic Uses
T-Cell Antigen Receptor
Immunotherapy
Disease-Free Survival
Lung Neoplasms
Recurrence

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; 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; Cottrell, Tricia R.; Rhymee, Lamia; Palsgrove, Doreen N.; Hann, Christine; Levy, Benjamin; Feliciano, Josephine; Georgiades, Christos S; Verde, Franco; Illei, Peter B; Li, Qing Kay; Gabrielson, Edward; Brock, Malcolm V.; Isbell, James M.; Sauter, Jennifer L.; Taube, Janis M; Scharpf, Robert B; Karchin, Rachel; Pardoll, Andrew Mark; Chaft, Jamie E.; Hellmann, Matthew D.; Brahmer, Julie; Velculescu, Victor E.

In: Cancer Research, Vol. 79, No. 6, 01.01.2019, p. 1214-1225.

Research output: Contribution to journalArticle

Anagnostou, Valsamo ; Forde, Patrick ; 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 ; Cottrell, Tricia R. ; Rhymee, Lamia ; Palsgrove, Doreen N. ; Hann, Christine ; Levy, Benjamin ; Feliciano, Josephine ; Georgiades, Christos S ; Verde, Franco ; Illei, Peter B ; Li, Qing Kay ; Gabrielson, Edward ; Brock, Malcolm V. ; Isbell, James M. ; Sauter, Jennifer L. ; Taube, Janis M ; Scharpf, Robert B ; Karchin, Rachel ; Pardoll, Andrew Mark ; Chaft, Jamie E. ; Hellmann, Matthew D. ; Brahmer, Julie ; Velculescu, Victor E. / Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer. In: Cancer Research. 2019 ; Vol. 79, No. 6. pp. 1214-1225.
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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.",
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T1 - Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer

AU - Anagnostou, Valsamo

AU - Forde, Patrick

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

AU - Cottrell, Tricia R.

AU - Rhymee, Lamia

AU - Palsgrove, Doreen N.

AU - Hann, Christine

AU - Levy, Benjamin

AU - Feliciano, Josephine

AU - Georgiades, Christos S

AU - Verde, Franco

AU - Illei, Peter B

AU - Li, Qing Kay

AU - Gabrielson, Edward

AU - Brock, Malcolm V.

AU - Isbell, James M.

AU - Sauter, Jennifer L.

AU - Taube, Janis M

AU - Scharpf, Robert B

AU - Karchin, Rachel

AU - Pardoll, Andrew Mark

AU - Chaft, Jamie E.

AU - Hellmann, Matthew D.

AU - Brahmer, Julie

AU - Velculescu, Victor E

PY - 2019/1/1

Y1 - 2019/1/1

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.

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