Abstract 4084: Globo H-targeted CAR T cell cancer immunotherapy

Abstract

Abstract Background: Globo H (GH), a Globo-series glycosphingolipid (GSL), is highly expressed in epithelial tumors, such as colon, endometrial, gastric, pancreatic, lung, prostate, and breast cancers. Aberrant expression of Globo H has been reported to be associated with the metastatic potential and poor prognosis of these cancers. However, in normal tissues, GH expression is limited to the secretory borders of apical epithelial cells, making it difficult to access by the immune system. GH is therefore a promising target for anticancer therapeutics. Clinical studies with the Globo H vaccines (OBI-822 and OBI-833) and the humanized anti-Globo H antibody (OBI-888) demonstrating an excellent safety profile. In recent years, cell therapy using chimeric antigen receptor T (CAR T) cells have shown impressive clinical outcomes. As a result, development of CAR T targeting GH may offer a novel anticancer therapeutic agent. Aim: The aim of this study was to develop a CAR T cell therapy targeted against Globo H (obi-R007) using lentivirus-mediated genetic engineering with a proprietary Globo H-specific antibody. Methods: We conducted in vitro and in vivo studies to determine the characteristics of GH CAR T obi-R007. Results: Ex vivo expansion of obi-R007 from healthy donors ranged from 40- to 200-fold post-activation for 10 days. Previous studies have suggested that less differentiation and fewer exhaustion markers of CAR T cells are beneficial for therapeutic persistence. In our study, there was less differentiation in the CD62L+ population (TSCM and TCM) in greater than 80% of obi-R007 cells, and no significant exhaustion markers (PD-1, LAG-3, etc.) were detected. obi-R007 showed specific cytotoxicity against Globo H-positive tumor cells with an E/T ratio of 0.5:1~2:1 and exhibited Globo H-specific activation through the expression of CD69, CD25, and Granzyme B as well as the release of Interferon γ and IL-2. Moreover, the activation and proliferation of obi-R007 were dependent on the presence of target cells. All the in vitro results indicate the specific targeting of obi-R007 to Globo H resulting in cytotoxic T cell responses. In the in vivo study, the efficacy of obi-R007 was demonstrated by adoptive cell transfer in several xenograft models and obi-R007 was shown to be persistent under multiple tumor challenges in the NCI-N87 gastric cancer model. Luminance labelling of CAR T cells showed that the distribution of CAR T cells in mice was specific to the tumor site and lymphoid organs suggesting a homing activity of the CAR T cells. Furthermore, no obviously physiological toxicity was observed in vivo. Conclusion: In conclusion, our in vitro and in vivo pharmacology and preliminary toxicology studies support clinical development of Globo H CAR T immunotherapy for patients with cancer. Citation Format: Jiann-Shiun Lai, Shiou-Ling Jian, Woan-Eng Chan, Ming-Tain Lai. Globo H-targeted CAR T cell cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4084.