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Cancer Res. 2018 Dec 12. pii: canres.1127.2018. doi: 10.1158/0008-5472.CAN-18-1127. [Epub ahead of print]

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 vanagno1@jhmi.edu.
2
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine.
3
Institute for Computational Medicine, Johns Hopkins University.
4
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine.
5
Computer Science, Applied Physics Laboratory, Institute for Computational Medicine, Johns Hopkins University.
6
Department of Internal Medicine, Johns Hopkins University School of Medicine.
7
Pathology, Johns Hopkins University.
8
Oncology, Johns Hopkins University School of Medicine.
9
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
10
Johns Hopkins Sidney Kimmel Cancer Center.
11
Radiology and Surgery, Johns Hopkins University School of Medicine.
12
Radiology, Johns Hopkins University School of Medicine.
13
Pathology, Johns Hopkins University School of Medicine.
14
Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center.
15
Department of Pathology, Memorial Sloan Kettering Cancer Center.
16
Johns Hopkins University.
17
Immunology and Hematopoiesis Division, Department of Oncology, Johns Hopkins University School of Medicine.
18
Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College.
19
Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center.

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, non-responders 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 to molecular responders (5.2 vs 14.5 and 8.4 vs 18.7 months, HR=5.36, 95% 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 (TCR) productive frequencies mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of early stage NSCLC patients (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.

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