5226 - Pre-treatment CD4 senescent T cells accurately predicts lack of response to PD-L1/PD-1 immune checkpoint blockade in non small cell lung cancer, and correlates with risk of hyperprogression

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Funding

Asociación Española Contra el Cáncer; Instituto de Salud Carlos III, Spain; FECYT, Spain.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.