Abstract LB090: IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma

Abstract Over the last decade, immunotherapy has revolutionized the way we treat cancer primarily by boosting the body’s own immune system to help fight cancer. In particular, an engineered T cell therapy, namely chimeric antigen receptor (CAR) T cell therapy, is a more aggressive way to modify T cells to recognize cancer cells and destroy them. Although these CAR-T therapies have shown remarkable clinical responses in patients with hematological malignancies, their efficacy in solid tumor treatment has been disappointing due to many challenges: lack of tumor-specific antigen targets, loss of the CAR T-cell persistence, the inability of CAR-T cells to effectively infiltrate into solid tumors, toxicities of cytokine release syndrome and neurologic toxicity, and the immunosuppressive tumor microenvironment (TME). In this regard, we report here that we have successfully developed a CAR-T cell therapy, referred to as EU307, to treat one type of solid tumor, hepatocellular carcinoma (HCC). EU307 is a fourth-generation CAR-T therapy that targets the HCC-specific tumor antigen of glypican-3 (GPC3), and also secretes IL-18 which results in autocrine co-stimulation of CAR-T cells and reprogramming of the TME into a tumor-killing environment. Through a sophistically optimized manufacturing process in our good manufacturing practices (GMP) facility, we are able to manufacture CAR-T cells with stem cell memory (TSCM) and central memory (TCM) phenotypes. Functionally, EU307, when infused with as little as 0.1 × 106 total cells per animal, showed superior in vivo persistence and antitumor immunity in an HCC tumor-bearing mouse model. Furthermore, a single dose toxicity study in the same disease mouse model determined the no observed adverse effect level (NOAEL) as 5.0 × 105 total cells per male and 1.0 × 106 total cells per female. Taken together, our studies demonstrate that we have a developed a novel fourth-generation CAR-T therapy to treat HCC, a solid tumor that expresses a high-level of tumor-specific GPC3, by overcoming previously limiting factors in the development of CAR-T therapies against solid tumors. Citation Format: Joseph H. Jeong, Young-Kyun Chang, You-Yeon Kang, Jeong-Yun Lee, Sae-Rom Lee, Yun-Kyung Lee, Young-Ho Kim, Byoung S. Kwon. IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB090.