Mp04-13 immunophenotype analysis of tumor-infiltrating immune cells to elucidate the mechanism of antitumor effect of il-7 and ccl19 producing car-t cells against solid cancer

You have accessJournal of UrologyCME1 Apr 2023MP04-13 IMMUNOPHENOTYPE ANALYSIS OF TUMOR-INFILTRATING IMMUNE CELLS TO ELUCIDATE THE MECHANISM OF ANTITUMOR EFFECT OF IL-7 AND CCL19 PRODUCING CAR-T CELLS 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.0000000000003215.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Chimeric antigen receptor (CAR)-T cell therapy against solid cancer is challenging. We reported that mouse CAR-T cells modified to produce interleukin- (IL)-7 and CCL19 (7×19 CAR-T) enhance the therapeutic efficacy against solid tumors by recruiting not only administered CAR-T cells but also endogenous T cells and DCs into tumors and inducing long-term antitumor memory responses. Furthermore, we reported that human 7×19 CAR-T cells show enhanced antitumor efficacy against patient-derived xenograft (PDX) tumor expressing mesothelin, for which 10% of renal cell carcinoma are positive. In this research, we explore 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, especially focusing on the immunophenotype of tumor-infiltrating lymphocytes (TILs). 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 and a pancreatic cancer PDX models. Tumor was resected after the administration of Conv. or 7×19 CAR-T cells and analyzed TILs by flowcytometry focusing on the number, exhaustion marker, phenotype and cytokine producing ability. RESULTS: 7×19 CAR-T cells showed superior antitumor efficacy compared to Conv. CAR-T cells in the orthotopic and PDX tumor models. In the PDX treatment model, TIL analysis revealed that not only CAR-T cells but also non-CAR-T cells were infiltrated effectively into tumors by 7×19 treatment compared to Conv. Exhaustion marker expressions such as PD-1 and TIGIT were significantly downregulated in 7×19 than Conv. The examination of the ability of TILs to express cytokines and effector molecules showed that significant increases of TNF-α and Granzyme B, as well as a trend of increased IFN-γ in 7×19 CAR-T cells. The analysis of splenocyte after the treatment revealed that 7×19 CAR-T cells maintained their effector memory phenotype. CONCLUSIONS: It was found that 7×19 CAR-T cells showed enhanced antitumor potential by the maintenance of their effector functions. These data support the foresight of this therapy as a treatment option for patients with mesothelin-positive renal cell carcinoma. Source of Funding: 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) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e38 Advertisement Copyright & Permissions© 2023 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 ...