MP12-03 IL-7 AND CCL19 PRODUCING CAR-T CELLS PREVENT ANTIGEN-LOSS TUMOR RELAPSE AND ENHANCE ANTITUMOR EFFICACY AGAINST SOLID CANCER

Abstract

You have accessJournal of UrologyCME1 May 2022MP12-03 IL-7 AND CCL19 PRODUCING CAR-T CELLS PREVENT ANTIGEN-LOSS TUMOR RELAPSE AND ENHANCE ANTITUMOR EFFICACY AGAINST SOLID CANCER Shunsuke Goto, Koji Tamada, and Masatoshi Eto Shunsuke GotoShunsuke Goto More articles by this author , Koji TamadaKoji Tamada More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002534.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: While chimeric antigen receptor (CAR)-T cell brought a breakthrough to the treatment for hematological cancer, most CAR-T cell therapies failed to treat solid cancers. We recently reported that mouse CAR-T cells modified to produce interleukin- (IL)-7 and CCL19 (7×19 CAR-T cells) enhance the therapeutic efficacy against solid tumors by recruiting not only administered CAR-T cells but also endogenous T cells and DCs into tumors. Further, we reported that human 7×19 CAR-T cells show enhanced antitumor efficacy against PDX tumor expressing mesothelin, for which 10% of renal cell carcinoma are positive. In this research, we focus on the mechanism of antitumor activity of 7×19 CAR-T cells and object to prevail the difference between conventional CAR-T cells (Conv.) and 7×19. Another hurdle of CAR-T cell therapy is adverse event arising from unspecific reaction to normal tissues and organs. In this regard, we investigated the antigen-specific activity of 7×19 CAR-T cells by conducting a tumor rechallenge experiment. METHODS: We produced a novel anti-human mesothelin 7×19 CAR-T cells, then assessed the antitumor activity against solid tumor in vivo using a malignant mesothelioma orthotopic tumor model. Tumor was resected after the administration of CAR-T cells and surface expression levels of mesothelin were measured by flowcytometry. Tumor rechallenge experiment was done using PDX tumor model. RESULTS: 7×19 CAR-T cells rejected the orthotopic tumor, while Conv. CAR-T cells allowed the tumor relapse. The surface expression of mesothelin on those relapsing tumors were declined from original tumors, which suggested that 7×19 CAR-T cells prevented the relapse of antigen-loss tumors. In the rechallenge trial, mesothelin-positive tumor progression was specifically suppressed in mice which had rejected mesothelin positive PDX tumors by the treatment with 7×19 CAR-T cells. CONCLUSIONS: It was found that the enhanced antitumor potential of human anti-mesothelin 7×19 CAR-T cells are antigen-specific and show a long-term memory effect. Further, 7×19 CAR-T cells can solve one of the important clinical problems, antigen-loss tumor relapse. These data support that this therapy will be a new treatment option for patients with mesothelin-positive renal cell carcinoma. Source of Funding: This study was supported by Practical Research for Innovative Cancer Control, and Project for Cancer Research and Therapeutic Evolution (P-CREATE) 16770206 by Japan Agency for Medical Research and Development (AMED), and Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (C) Grant Number 19K07625 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e166 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shunsuke Goto More articles by this author Koji Tamada More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement PDF DownloadLoading ...