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Cancer Res. 2019 Mar 15;79(6):1214-1225. doi: 10.1158/0008-5472.CAN-18-1127. Epub 2018 Dec 12.

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Author information

1
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. vanagno1@jhmi.edu velculescu@jhmi.edu.
2
The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
5
Applied Physics Laboratory, Laurel, Maryland.
6
Department of Internal Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland.
7
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
8
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
9
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
10
Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, New York.
11
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
12
Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
#
Contributed equally

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 = 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 = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 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 = 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.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

PMID:
30541742
PMCID:
PMC6432636
DOI:
10.1158/0008-5472.CAN-18-1127
[Indexed for MEDLINE]
Free PMC Article

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