Abstract 3247: Dynamic clonality of T cell receptor differentiate atypical progression in NSCLC patients treated with PD-1/PD-L1inhibitors
Authors: Jiefei Han, Zhijie Wang, Yuqi Wang, Si Chen, Hua Bai, Jianchun Duan, Jie Wang
Journal: Cancer Research (2019)

Abstract Background:The advent of immune checkpoint inhibitors (ICI) has radically changed the paradigm of care for patients with non-small cell lung cancer (NSCLC). However, response patterns of tumors treated with immunotherapies may differ compared with conventional chemotherapeutic agents or targeted therapies, and accurate assessment of the response can be radiologically challenging. Most of the current immune-related response criteria are designed to identify pseudoprogression but not hyperprogressive disease (HPD). The objective of the current analysis was to explore the biomarkers which can distinguish different patterns of responses of in ICI-treated NSCLC patients.Methods:Among patients with NSCLC treated with ICI at our Institute, at least 2 CT scans before ICI therapy (baseline and the most recent scan before baseline) and 1 CT scan during treatment were mandatory for radiological evaluation. The tumor growth rate (TGR) was calculated from the sum of the largest diameters of the target lesions as per RECIST version 1.1 to evaluate the percentage increase in tumor volume per month. HPD was defined as delta TGR exceeding 50%. Pseudoprogression was defined as initial progression, followed by complete response or partial response or stable disease. Flow cytometry was used to obtain CD3+CD8+ T cells from peripheral blood mononuclearcells. Immunosequencing of the CDR3 regions of TCRb chains was performed. TCR clonality is compared pre-therapy to initial evaluation. Results:A total of 51 patients were included in our study. By the time of first radiological assessment,11 cases were defined as Responders (21.6%), 16 patients with Stable Disease (31.4%), 24 cases defined as Progressors (47.1%).Six patients meet the criteria for HPD. During the following treatment, 3 of 24 progressors were confirmed to have pseudoprogression. The degree of TCR clonality change ranged from 2.17 to 0.64 times in all patients. Clinical response is significantly correlated with increased repertoire clonality of CD3+CD8+ T cells (P = 0.01). Among three kinds of disease progression, pseudoprogression showed an increase in TCR clonality than true progression patients (1.47 vs. 0.79, P=0.01). Interestingly, the decrease of TCR clonality is greater in patients developed typical PD than in HPD (-0.19 vs. -0.05, P=0.03). Our further analysis showed that Patients who demonstrated RECIST-PD with an increased clonality had a longer median PFS compared to patients with a declined clonality (8.9 versus 2.4 months, p = 0.01).Conclusion: The results demonstrate that the change in clonality of CD3+CD8+ T cell receptor can differentiate atypical patterns of progression in patients with NSCLC treated with ICI. Results of this TCR test performed at regular intervals during ICI treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response. Citation Format: Jiefei Han, Zhijie Wang, Yuqi Wang, Si Chen, Hua Bai, Jianchun Duan, Jie Wang. Dynamic clonality of T cell receptor differentiate atypical progression in NSCLC patients treated with PD-1/PD-L1inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3247.