Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients

Elliot Naidus,David Y Oh,Lawrence Fong,Hai Yang,Nathan E Standifer,Timothy J Looney,Jerome Bouquet,Li Zhang

doi:10.1007/s00262-020-02833-z

Abstract

Immune checkpoint inhibitors (ICI) are designed to activate exhausted tumor-reactive T cells thereby leading to tumor regression. Durvalumab, an ICI that binds to the programmed death ligand-1 (PD-L1) molecule, is approved as a consolidation therapy for treatment of patients with stage III, unresectable, non-small cell lung cancer (NSCLC). Immunophenotypic analysis of circulating immune cells revealed increases in circulating proliferating CD4 + and CD8 + T cells earlier after durvalumab treatment. To examine durvalumab’s mechanism of action and identify potential predictive biomarkers, we assessed the circulating T cells phenotypes and TCR genes of 71 NSCLC patients receiving durvalumab enrolled in a Phase I trial (NCT01693562, September 14, 2012). Next-generation sequencing of TCR repertoire was performed on these NSCLC patients’ peripheral blood samples at baseline and day 15. Though patients’ TCR repertoire diversity showed mixed responses to the treatment, patients exhibiting increased diversity on day 15 attained significantly longer overall survival (OS) (median OS was not reached vs 17.2 months for those with decreased diversity, p = 0.015). We applied network analysis to assess convergent T cell clonotypes indicative of an antigen-driven immune response. Patients with larger TCR clusters had improved OS (median OS was not reached vs 13.1 months for patients with smaller TCR clusters, p = 0.013). Early TCR repertoire diversification after durvalumab therapy for NSCLC may be predictive of increased survival and provides a mechanistic basis for durvalumab pharmacodynamic activity.

Highlights

The approval of anti-PD-1 and anti-programmed death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) represents a key innovation in the treatment of non-small cell lung cancer (NSCLC)
We evaluated peripheral blood T cell receptor (TCR)-ß chain repertoires in advanced NSCLC before and after treatment with durvalumab to identify how TCR repertoires are associated with outcome
We took C1D1 as the baseline to ensure a consistent interval of 14 days to assess changes in peripheral TCR repertoire after durvalumab exposure

Summary

Introduction

The approval of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors (ICIs) represents a key innovation in the treatment of NSCLC. III–IV NSCLC [1,2,3,4]. Objective response rates to ICIs remain low at 15–30% [5]. Increased expression of PD-L1 by tumor cells augments response to immunotherapy as well as survival [5]. The successes and shortcomings of ICI therapy in stage III–IV NSCLC have motivated research into alternate immune checkpoint targets and combination ICI therapies [7]. Responses to anti-PD-1/PD-L1 antibodies occur even with low PD-L1 tumor expression [2], yet little is known about the immunologic determinants of such responses

Methods

Results

Conclusion