PDL1-PD1 blockade therapies are demonstrating promising clinical outcomes in NSCLC (non-small cell lung carcinoma) patients. However, a significant proportion of patients are intrinsically resistant to these therapies. Moreover, instead of raising efficacious anti-tumor immunity, this therapy might accelerate disease carrying hyperprogression. Hence, stratification of patients into hyperprogressors, non-responders and potential responders is a critical issue in oncology.
Peripheral blood samples from 34 NSCLC patients treated with PD-L1/PD-1 immune checkpoint inhibitors were obtained previous to the initiation of the immunotherapy and before the administration of each cycle of treatment. Baseline CD4+ Tsen numbers and their dynamic changes during treatment were quantified by flow cytometry and correlated to responses and survival.
In our cohort study, patients with baseline Tsen values below 40% (negative profile) had an ORR of 0% and all experienced progression by week 9; in contrast to patients with Tsen values above 40% with ORR accounted to 38.9% and a 12-week PFS of 44%. Moreover, two main systemic T cell dynamic patterns were identified. Increase in Tsens after the first cycle of therapy was always associated to hyperprogression and intrinsic non-responders (pattern 1, Tsen “burst”), while decrease (pattern 2) significantly correlated with responders. Here, we demonstrate that a Tsen baseline value <40% associated to significant “Tsens bursts” thorough therapy objectively characterized hyperprogressive disease. ROC analysis demonstrated the robustness of Tsen quantification with clinical output (R = 0.84, P = 0.006), with a cut-off value of < 57.7% baseline Tsens to achieve 100% specificity with a 75% sensitivity for identification of non-responders prior to therapy.
This study uncovers the central role of CD4+ Tsen cells in anti-PD-L1/PD-1 immunotherapy efficacy, and provides a highly accurate predictive biomarker of responses to PD-L1/PD-1 blockade. Baseline CD4+ Tsen values unequivocally identify hyperprogressors and intrinsic non-responders before therapy administration.
Clinical trial identification
Legal entity responsible for the study
Navarrabiomed-Fundación Miguel Servet.
Asociación Española Contra el Cáncer; Instituto de Salud Carlos III, Spain; FECYT, Spain.
All authors have declared no conflicts of interest.