Dynamic Testing of Stimulative and Suppressive Biomarkers on Peripheral Blood Cells at Early Stages of Immunotherapy Predicts Response in Advanced Cancer Patients

Purpose: Immunotherapy against malignant tumors has shown considerable clinical efficacy, especially agents targeting the programmed death 1 (PD-1) pathway. In this study, we set out to dynamically determine the relationships between clinical benefit and changes in immune biomarkers on peripheral blood monocular cells (PBMCs) and try to establish a model to predict the response at an early stage of treatment. Experimental design: All patients recruited from December 2016 to July 2017 were treated in the Cancer Center of the Chinese People's Liberation Army General Hospital with nivolumab or pembrolizumab, and with or without chemotherapy. We investigated nine checkpoint molecules PD-1, CTLA-4, TIM-3, LAG-3, BTLA, CD160, Ki-67, OX40, and GITR on CD4+, CD8+, and NK cells by flow cytometry in patients before and after receiving each treatment of anti-PD-1 agents. Results: We found that the responder group showed higher expressions of PD-1 on CD4+ and NK cells than the non-responder group after the first cycle of immunotherapy, and lower expression of CTLA-4, GITR, and OX40 after the second cycle of immunotherapy. A simple model of the combination of biomarkers was generated to predict the immunotherapeutic effect, revealing that elevation of key biomarkers after the first cycle of immunotherapy, followed by a decrease in their expression after the second cycle, was associated with a better outcome from immunotherapy at an early stage of treatment of cancer. Conclusion: Our work indicates that by testing biomarkers on patients' PBMCs at an early stage of treatment, the immunotherapeutic effect can be predicted, thus improving patient outcomes and cost efficiency.