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

Valsamo Anagnostou, Patrick M. 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 N. Smith, Tricia R. Cottrell, Lamia Rhymee, Doreen N. Palsgrove, Christine L. Hann, Benjamin Levy, Josephine FelicianoChristos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V. Brock, James M. Isbell, Jennifer L. Sauter, Janis Taube, Robert B. Scharpf, Rachel Karchin, Drew M. Pardoll, Jamie E. Chaft, Matthew D. Hellmann, Julie R. 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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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