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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Association of Tumor Mutational Burden and Immune Gene Expression with Response to PD-1 Blockade by Sasanlimab Across
Siwen Hu-Lieskovan1, Fadi Braiteh2, Juneko E Grilley-Olson3
1Division of Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, HCI-RS-2703, Salt Lake City, UT, 84112, USA. Siwen.Hu-Lieskovan@hci.utah.edu.
Background:
Sasanlimab is a monoclonal antibody that binds to the programmed cell death receptor 1 (PD-1). Anti-PD-1 monoclonal antibodies have improved patient clinical outcomes; however, not all treated patients derive clinical benefit. Further insights on potential biomarkers beyond PD-L1 expression levels would help to identify the patients most likely to respond to treatment.
Objective:
This study evaluated tumor biopsies from patients treated with intravenous or subcutaneous sasanlimab to identify biomarkers of response and characterize pharmacodynamic activity.
Methods:
Anti-PD-1/PD-ligand 1 (PD-L1)-naive patients with advanced solid tumors received sasanlimab intravenously at 1, 3, or 10 mg/kg every 3 weeks (n = 23) or subcutaneously at 300 mg every 4 weeks (n = 15). Best tumor percentage change from baseline was determined by RECIST. Whole-exome DNA and RNA sequencing were performed in tumor samples collected from treated patients at protocol-defined timepoints. PD-L1 and CD8 protein expression were evaluated in tumor biopsies by immunohistochemistry. Associations with response were assessed by linear regression analysis.
Results:
Baseline tumor mutational burden (TMB), as well as PD-L1 and CD8 expression, were significantly associated with response to sasanlimab across the multiple dose levels, routes of administration, and range of tumor types evaluated. TMB is an independent biomarker from the various tumor inflammatory genes and signatures evaluated. Gene set enrichment analysis showed that higher baseline expression levels of genes related to the interferon-γ and PD-1 signaling pathways and the cell cycle were significantly associated with response to sasanlimab across tumor types. No differences were observed between routes of administration with regard to response to sasanlimab for the biomarkers of interest (TMB, PD-L1, CD8, and interferon-γ signature). Evaluation of pharmacodynamic changes showed increased tumor expression of genes enriched in adaptive immune response pathways.
Conclusions:
Our findings indicate an active, immunomodulatory mechanism for the anti-PD-1 antibody sasanlimab across different tumor types and routes of administration.
Trial Registration:
ClinicalTrials.gov identifier NCT02573259; registered October 2015.
Insights
This study identified tumor mutational burden (TMB) and interferon-gamma pathway gene expression as key biomarkers for sasanlimab (anti-PD-1) response in advanced solid tumors. These findings help predict patient benefit from immunotherapy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Sasanlimab, a programmed cell death receptor 1 (PD-1) inhibitor, shows promise in improving clinical outcomes for cancer patients.
- However, not all patients benefit from anti-PD-1 therapy, necessitating better biomarkers for treatment selection.
- Identifying predictive biomarkers beyond PD-L1 expression is crucial for optimizing patient response.
Purpose of the Study:
- To identify biomarkers associated with response to sasanlimab treatment.
- To characterize the pharmacodynamic activity of sasanlimab.
- To evaluate biomarkers in patients with advanced solid tumors receiving intravenous or subcutaneous sasanlimab.
Main Methods:
- Patients with advanced solid tumors received sasanlimab intravenously or subcutaneously.
- Tumor biopsies were analyzed using whole-exome DNA and RNA sequencing.
- Immunohistochemistry was used to assess PD-L1 and CD8 protein expression.
- Associations between biomarkers and response were evaluated using linear regression.
Main Results:
- Baseline tumor mutational burden (TMB), PD-L1, and CD8 expression were significantly associated with sasanlimab response.
- Higher baseline expression of interferon-gamma and PD-1 signaling pathway genes, and cell cycle genes correlated with response.
- No significant differences in biomarker-response associations were observed between intravenous and subcutaneous administration routes.
- Pharmacodynamic analysis revealed increased tumor expression of adaptive immune response genes post-treatment.
Conclusions:
- Sasanlimab demonstrates an active immunomodulatory mechanism across various tumor types and administration routes.
- TMB and specific gene expression signatures (interferon-gamma, PD-1 pathway, cell cycle) are promising biomarkers for predicting sasanlimab response.
- These findings support the potential of sasanlimab in diverse patient populations and highlight the importance of comprehensive biomarker analysis in immunotherapy.
