Abstract 5185: First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination
Authors: Harano Kenichi , Kaneko Shin , Nakatsura Tetsuya , Yuda Junichiro , Fuse Nozomu , Sato Akihiro , Watanabe Reiko , Ishii Genichiro , Mukohara Toru , Tanabe Hiroshi , Ishiguro Yukiko , Furuya Hideki , Wakabayashi Masashi , Fukutani Miki , Shimomura Manami , Ueda Tatsuki , Iriguchi Shoichi , Kumagai Ayako , Nakagoshi Kengo , Sasaki Aki , Doi Toshihiko 
Published: June 2022

Abstract
Background: The development of chimeric antigen receptor (CAR) T cell therapy has introduced an effective strategy to guide and promote the immune response. Also, gene-engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be directed against target tumor antigen. However, these autologous applications are limited by toxicities, restricted trafficking and infiltration into tumor, suboptimal persistence, and exhausted status of immune cells that may cause manufacturing failure. One approach to overcome those limitations is the development of “off-the-shelf” iPS-cell sources. The iCAR-ILC-N101 is an allogeneic human leukocyte antigen (HLA)-homozygous induced pluripotent stem cell (iPSC)-derived anti-glypican-3 (GPC3) CAR-expressing innate lymphoid cells/natural killer cell (ILC/NK), which has both antigen-specific and NK activating receptor-mediated cytotoxicity. The iCAR-ILC-N101 is produced from the established iPSC strain QHJI01s04, and there is theoretically no risk of developing graft-versus host disease because the product dose not have T cell receptor. The product has a relevant living period in the body, thereby has little concern about residual toxicity and reduces systemic side effects by topical treatment. GPC3 is a cancer-specific membranous protein that is expressed in hepatoblastoma, hepatocellular carcinoma and ovarian clear cell carcinoma (OCCC) but is not expressed in normal tissue. OCCC is a relatively rare malignancy and is associated with poor prognosis. Intraperitoneal administration of iCAR-ILC-N101 is expected to show antitumor activity for OCCC patients with peritoneal dissemination that express GPC3 and reduce systemic side effects, thereby ensuring safety and improving therapeutic efficacy. Preclinical study showed that intraperitoneal injection of iCAR-ILC-N101 for GPC3-positive ovarian tumor-bearing immunodeficient mouse model showed suppressed tumor growth.
Method: This is a first-in human phase 1 study to evaluate safety, toxicity and efficacy of the iCAR-ILC-N101 in patients with GPC3-positive advanced or recurrent OCCC harboring peritoneal dissemination. Major inclusion criteria include histologically diagnosed GPC3-positive advanced or recurrent OCCC with peritoneal dissemination who are resistant to standard therapy and have matched HLA-A24 or B52. The study includes 3 cohorts (cohort -1, 0.5x106 cells/kg; cohort 1, 1x106 cells/kg; cohort 2, 3x106 cells/kg) and starts with cohort 1. The iCAR-ILC-N101 is administered intraperitoneally once a week for 4 weeks; for the first patient in each cohort, patient is observed for 14 days for safety evaluation after the first administration and then receive iCAR-ILC-N101 on day15 and 22. Enrollment initiated in July 2021 and one patient was enrolled. No dose-limiting toxicity was observed. Clinical trial registry number: jRCT2033200431
Citation Format: Kenichi Harano, Shin Kaneko, Tetsuya Nakatsura, Junichiro Yuda, Nozomu Fuse, Akihiro Sato, Reiko Watanabe, Genichiro Ishii, Toru Mukohara, Hiroshi Tanabe, Yukiko Ishiguro, Hideki Furuya, Masashi Wakabayashi, Miki Fukutani, Manami Shimomura, Tatsuki Ueda, Shoichi Iriguchi, Ayako Kumagai, Kengo Nakagoshi, Aki Sasaki, Toshihiko Doi. First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5185.