Abstract B081: Serum antibody against NY-ESO-1 and XAGE1 predicts clinical responses to anti-PD-1 therapy in non-small cell lung cancer
Authors: Kurose Koji , Ohue Yoshihiro , Karasaki Takahiro , Futami Junichiro , Irei Isao , Masuda Takeshi , Fukuda Masaaki , Kinoshita Akitoshi , Matsushita Hirokazu , Shimizu Katsuhiko , Yamaguchi Hiroyuki , Fukuda Minoru , Kakimi Kazuhiro , Oka Mikio 
Published: February 2019

Abstract
Introduction: Lung cancer is the leading cause of death from cancer worldwide. Most lung cancers, especially non-small-cell lung cancer (NSCLC), are diagnosed in the advanced stages and are resistant to conventional chemotherapy, resulting in poor prognosis. Programmed death-1 (PD-1) inhibitors effectively treat NSCLC; however, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified. NSCLC expresses NY-ESO-1 and/or XAGE1 antigens which belongs to cancer-testis (CT) antigen. NY-ESO-1 is broadly expressed in various human malignancies and has been extensively investigated as a target of cancer vaccines and T-cell therapy, because it exhibits the highest immunogenicity among CT antigens. XAGE1 is expressed in approximately 40~60% of lung adenocarcinoma (LAD), and the XAGE1 serum antibody is a good prognostic marker in advanced LAD patients, as we reported previously. Thus, NY-ESO-1 and XAGE1 may be major immuno-dominant antigens in NSCLC, and spontaneous immune responses against these antigens are considered to play important roles in the immune surveillance of NSCLC. Then, we hypothesized that NY-ESO-1 and XAGE1 antibody have potential as response and monitoring biomarkers in anti-PD-1 therapy for NSCLC, and conducted a prospective study to verify this hypothesis. Methods: A prospective study of biomarkers for anti-PD-1 therapy was performed using patients with advanced NSCLC from five medical centers in Japan. Prior to the administration of nivolumab or pembrolizumab, serum NY-ESO-1 and XAGE1 antibody responses were measured using ELISA, and patients in the discovery cohort were then stratified by their antibody status for enrollment in observational study. To assess the status of the antibody response, sera from patients were collected within two months before anti-PD-1 therapy, and antibody titers were serially measured during anti-PD-1 therapy. In the multicenter study (the validation and the additional cohorts), clinical responses to anti-PD-1 therapy and the antibody status were double-blinded with each other by clinicians and laboratory scientists. The primary endpoint was the objective responses rate (ORR) to anti-PD-1 therapy according to the NY-ESO-1 and XAGE1 antibody status. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In the discovery cohort (n=13), NY-ESO-1 and/or XAGE1 antibody-positive NSCLC responded to anti-PD-1 therapy, whereas antibody-negative NSCLC did not. Furthermore, the antibody titers before anti-PD-1 therapy strongly correlated with tumor reduction rates (P&lt;0.0001), and the titers in responders gradually decreased with tumor shrinkage. Antibody-positive patients obtained clinical benefits with anti-PD-1 therapy; Hazard ratios (HR) of OS and PFS between antibody-positive and -negative patients were 0.15 (95% CI 0.03 to 0.51, P=0.005) and 0.17 (95% CI 0.02 to 0.31, P=0.001), respectively. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 (PD-L1) expression, mutation burden, and CD8 T-cell infiltration. In independent multicenter study (n=40), five (50%; 3 CR and 2 PR) out of ten antibody-positive patients responded to anti-PD-1 therapy, in contrast to only two (6.7%; 2 PR) out of 30 antibody-negative patients (ORR 50% vs. 6.7%, P&lt;0.006), resulting in 18% (7/40) ORR in the multicenter study. OS in antibody-positive patients were significantly longer than those in antibody-negative patients (HR 0.20, 95% CI 0.13 to 0.76, P=0.01). CT antibody-positive NSCLC patients recognized and responded to significantly more tumor antigens than CT antibody-negative patients. Conclusions: NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC.
Citation Format: Koji Kurose, Yoshihiro Ohue, Takahiro Karasaki, Junichiro Futami, Isao Irei, Takeshi Masuda, Masaaki Fukuda, Akitoshi Kinoshita, Hirokazu Matsushita, Katsuhiko Shimizu, Hiroyuki Yamaguchi, Minoru Fukuda, Kazuhiro Kakimi, Mikio Oka. Serum antibody against NY-ESO-1 and XAGE1 predicts clinical responses to anti-PD-1 therapy in non-small cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B081.