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Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer
Valsamo Anagnostou1,2, Patrick M Forde3,2, James R White3
1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. vanagno1@jhmi.edu velculescu@jhmi.edu.
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.
Insights
Ultrasensitive monitoring of circulating tumor DNA (ctDNA) and T-cell expansion can predict lung cancer patient response to immunotherapy. Early ctDNA changes offer a faster, more accurate assessment of treatment effectiveness than CT scans.
Area of Science:
- Oncology
- Immunology
- Molecular Diagnostics
Background:
- Immunotherapy has shown success in treating metastatic lung cancer, but identifying responders remains a challenge.
- There is a clinical need for molecular assays to predict patient response to immune checkpoint blockade therapy.
- Current methods like CT imaging have limitations in early prediction of therapeutic outcomes.
Purpose of the Study:
- To investigate the utility of ultrasensitive circulating tumor DNA (ctDNA) and T-cell expansion as biomarkers for assessing response to immune checkpoint blockade in lung cancer.
- To compare the predictive value of ctDNA dynamics with CT imaging for treatment outcomes.
- To validate the findings in an independent cohort of early-stage non-small cell lung cancer patients.
Main Methods:
- Ultrasensitive measurement of ctDNA levels in patients with metastatic lung cancer (N=24) undergoing immune checkpoint blockade.
- Monitoring T-cell expansion via T-cell receptor productive frequencies.
- Assessing pathologic response in early-stage non-small cell lung cancer patients (N=14) treated with anti-PD1 therapy.
- Comparing ctDNA dynamics and CT imaging for prediction of progression-free and overall survival.
Main Results:
- Complete reduction in ctDNA levels correlated with clinical response to therapy.
- Non-responders showed no significant change or an increase in ctDNA.
- Acquired resistance was indicated by ctDNA recrudescence after an initial drop.
- Molecular non-responders had significantly shorter progression-free and overall survival compared to responders.
- ctDNA dynamics predicted response 8.7 weeks earlier than CT imaging and were more predictive of clinical benefit.
- T-cell expansion mirrored ctDNA reduction, validating the molecular response assessment.
- Early ctDNA dynamics successfully predicted pathologic response in an independent cohort.
Conclusions:
- Ultrasensitive ctDNA and T-cell expansion measurements provide a rapid and accurate method for assessing response to immune checkpoint inhibitors in lung cancer.
- This molecular assay approach can guide personalized immune-targeted strategies.
- Early detection of ctDNA dynamics has significant implications for clinical decision-making and drug development in lung cancer immunotherapy.
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