Abstract 4478: Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation
Authors: Matsumoto Seiji , Matsutani Takaji , Fujita Yoshiko , Takahashi Ryo , Yokoi Takashi , Kodama Hiroshi , Inao Yoshie , Kitaura Kazutaka , Nakamichi Tohoru , Nakamura Akifumi , Kuroda Ayumi , Kobayashi Aki , Hashimoto Masaki , Kondo Nobuyuki , Suzuki Ryuji , Yamakado Koichiro , Kijima Takashi , Hasegawa Seiki 
Published: September 2020

Background: Programmed death 1 (PD-1) blockade with Nivolumab are effective in patients with malignant pleural mesothelioma (MPM), however; successful predictive biomarker has not been available. Unlike invasive test with tumor biopsy, peripheral blood is safe and easily obtainable source of biomarkers. We have previously reported that T cell receptor (TCR) diversity of CD8+PD-1+ T cells were effective to predict response to anti-PD-1 antibody treatment in non-small cell lung cancer (NSCLC) patients (AACR2019: Abstract nr 2230). In this study, Next generation sequence(NGS)-based TCR α and β repertoires were examined with peripheral CD8+PD-1+ T cells isolated from 11 patients with MPM and treatment responses were evaluated 2 months after anti-PD-1 antibody treatment.

Methods: Peripheral blood mononuclear cells were collected from 11 MPM patients enrolled in this study before administration of anti-PD-1 antibody (Nivolumab). NGS-based TCR α and β repertoire analysis were performed with CD8+PD-1+ T cells isolated with FACS sorting by Repertoire Genesis Inc. TCR diversity was statistically evaluated by Shannon, Simpson and Diversity Evenness 50 (DE50) indices. CT scan was performed during week 8 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine.

Results: Three of 11 (27.3%) MPM patients responded to anti-PD-1 treatment. There were good correlation of all diversity indices between TCRα and TCRβ. TCRβ diversity was significantly higher among responders than non-responders based on DE50 (0.0019 ± 0.00032 vs 0.0011 ± 0.00042, P &lt; 0.05). Also, responders exhibited a clear trend to have higher TCR diversity of CD8+PD-1+ T cells in terms of Shannon, normalized Shannon and Simpson indices.

Conclusion: Like NSCLC patients, PD-1 blockade was more effective in MPM patients who had higher levels of TCR diversity in peripheral CD8+PD-1+ T cells. This result suggested the TCR diversity of peripheral CD8+PD-1+ T cells has potential to predict response to immune checkpoint inhibitors in various tumor patient. Further clinical study would be needed to verify effectiveness of this biomarker.

Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Ryo Takahashi, Takashi Yokoi, Hiroshi Kodama, Yoshie Inao, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Aki Kobayashi, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Koichiro Yamakado, Takashi Kijima, Seiki Hasegawa. Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4478.