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Updated: Jun 14, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition
Barzin Y Nabet1, Mohammad S Esfahani2, Everett J Moding1
1Department of Radiation Oncology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
Abstract:
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
Insights
Predicting durable clinical benefit in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) is challenging. A new noninvasive assay integrating circulating tumor DNA (ctDNA) and immune cell profiling accurately forecasts patient outcomes early.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Diagnostics
Background:
- Immune checkpoint inhibitors (ICIs) offer durable responses in non-small cell lung cancer (NSCLC), but most patients experience early progression.
- Conventional imaging lacks accuracy in predicting durable clinical benefit (DCB) from ICIs.
- Identifying patients likely to benefit from ICIs remains a critical unmet need.
Purpose of the Study:
- To identify noninvasive biomarkers for predicting durable clinical benefit (DCB) in NSCLC patients receiving ICIs.
- To develop and validate a multiparameter assay for early and accurate outcome prediction.
Main Methods:
- Analysis of pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels.
- Monitoring ctDNA dynamics after the first ICI infusion.
- Development and validation of the noninvasive DIREct-On assay integrating these biomarkers.
Main Results:
- Pre-treatment ctDNA and CD8 T cell levels were independently associated with DCB.
- ctDNA dynamics post-infusion further aided in identifying patients with DCB.
- The integrated DIREct-On assay demonstrated higher accuracy in predicting DCB than individual markers.
Conclusions:
- Integrated ctDNA and immune cell profiling provide accurate, noninvasive, and early prediction of outcomes for NSCLC patients on ICIs.
- The DIREct-On assay offers a promising tool for optimizing immunotherapy selection and management in NSCLC.
- This approach may improve treatment strategies by enabling early identification of patients likely to achieve durable responses.
