Yoshihiro Ohue1, Koji Kurose1, Takahiro Karasaki2, Midori Isobe1, Takaaki Yamaoka1, Junichiro Futami3, Isao Irei4, Takeshi Masuda5, Masaaki Fukuda6, Akitoshi Kinoshita7, Hirokazu Matsushita8, Katsuhiko Shimizu9, Masao Nakata9, Noboru Hattori5, Hiroyuki Yamaguchi10, Minoru Fukuda11, Ryohei Nozawa12, Kazuhiro Kakimi8, Mikio Oka13. 1. Department of Respiratory Medicine, Kawasaki Medical School, Okayama, Japan. 2. Department of Thoracic Surgery, The University of Tokyo, Tokyo, Japan. 3. Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan. 4. Department of Pathology, Kawasaki Medical School, Okayama, Japan. 5. Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan. 6. Department of Respiratory Medicine, The Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan. 7. Department of Respiratory Medicine, Nagasaki Prefecture Shimabara Hospital, Nagasaki, Japan. 8. Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation Hub Program, RIKEN, Tokyo, Japan. 9. Department of General Thoracic Surgery, Kawasaki Medical School, Okayama, Japan. 10. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 11. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan. 12. Faculty of Health and Welfare Services Administration, Kawasaki University of Medical Welfare, Okayama, Japan. 13. Department of Immuno-Oncology, Kawasaki Medical School, Okayama, Japan. Electronic address: moom@med.kawasaki-m.ac.jp.
Abstract
INTRODUCTION: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. METHODS: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. RESULTS: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). CONCLUSIONS: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.
INTRODUCTION: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. METHODS: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. RESULTS: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). CONCLUSIONS: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.
Authors: Annika Rähni; Mariliis Jaago; Helle Sadam; Nadežda Pupina; Arno Pihlak; Jürgen Tuvikene; Margus Annuk; Andrus Mägi; Tõnis Timmusk; Amir M Ghaemmaghami; Kaia Palm Journal: Commun Med (Lond) Date: 2022-05-11