Abstract 5255: A B7-H3-CAR-modified Vδ1 T cells showed potentanti-solid tumor potential
Authors: Licui Jiang, Changsong Qi, Fengtao You, Shufen Xiang, Ping Zhang, Min Wang, Hai Wu, Kunmin Yan, Jiequn Huang, Huimin Meng, Nan Yang, Shirley Zhang, Lin Shen, Lin Yang
Journal: Cancer Research (2024)

Abstract Background: CAR-αβT cells have made limited advancement in treating solid tumors. Vδ1 T cells, a subtype of γδT cells, are rare in human peripheral blood, but they are the main tissue-resident immune cells found in epithelial and mucosal tissues. This suggests that Vδ1 T cells might be a potential modality for treating solid tumors. To explore this possibility, we hypothesized that Vδ1 T cells modified with B7-H3 CAR (B7-H3-CAR-Vδ1 T) could have great potential of anti-solid tumor activity, making them a promising candidate for further development as a universal cellular therapy product. Methods: A proprietary manufacturing procedure to produce Vδ1 T cells from the leukopak of healthy donors has been established under GMP compliance. The immune checkpoint molecule B7-H3 was selected as the target. The allogeneic B7-H3-CAR-Vδ1 T cells carrying IL-2 (UTAA06), which displayed the most prolonged anti-tumor activity, were chosen for comprehensive functional validation. Single-cell sequencing and mass spectrometry flow cytometry were utilized to characterize the biology of UTAA06. In vivo effectiveness of UTAA06 was confirmed in animal models. Results: A clinical-grade manufacturing process for Vδ1 T cells is developed. This process results in a purity of over 95% of Vδ1 T cells, with an expansion of more than 20,000-fold, and a CAR lentiviral transduction efficiency of over 50%.žSingle-cell sequencing and mass cytometry analysis both demonstrated that the Vδ1 T cells produced by our approach exhibited high expression levels of natural cytotoxic receptors (including NKG2D, DNAM1, and NKp series receptors), chemokine receptors (such as CXCR3 and CXCR6), anti-tumor related molecules (such as CD27 and CD137), and low expression levels of inhibitory molecules (such as PD1 and LAG3).ž UTAA06 cells did not produce IL17A, which is a signal protein with pro-tumor activity. Meanwhile, UTAA06 demonstrated significant and specific inhibitory effects on the growth of various solid tumor cell lines.žUTAA06 cells were found to significantly suppress tumor cell growth in solid tumor mouse models. The complete remission (CR) for each tumor model was 83.3% of neuroblastoma (SK-N-AS, N=6), 66.7% of pancreatic cancer (SW1990, N=6), 100% of lung cancer (A549, N=6), and 70% of colorectal cancer (HCT-15, N=10) respectively. In addition, a potent capacity of UTAA06 to penetrate tumor tissues with a favorable safety profile in mice was observed. Conclusion: UTAA06 exhibited extraordinary anticancer properties both in vitro and in vivo against solid tumors. Additionally, the outstanding manufacturing process of UTAA06 will facilitate the clinical application of this product. Citation Format: Licui Jiang, Changsong Qi, Fengtao You, Shufen Xiang, Ping Zhang, Min Wang, Hai Wu, Kunmin Yan, Jiequn Huang, Huimin Meng, Nan Yang, Shirley Zhang, Lin Shen, Lin Yang. A B7-H3-CAR-modified Vδ1 T cells showed potentanti-solid tumor potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5255.