Abstract LB363: Multi-mechanism human B7H3 CAR-T effectively overcome tumor microenvironment resistance in treatment of solid tumors

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological cancers, but its application for solid tumors remains limited. Tumor antigen heterogeneity, insufficient T cell trafficking, and immunosuppressive tumor microenvironment (TME) are the key challenges of resistance. Several approaches such as engineering CAR-T to express chemokines to support trafficking to tumors, expression of checkpoint inhibitor pathway blockers, and modification of T cell metabolism to overcome TME have been reported. To deliver an integrated solution, Elpis has developed a B7H3 CAR-T armored with a precision engineered multi-mechanism armor to simultaneously overcome multiple TME resistant mechanisms. B7H3 is overexpressed on a wide range of solid tumors, including skin, pancreatic, lung, breast, colon, kidney and other cancers. Importantly, B7H3 is highly expressed on differentiated malignant cells and cancer-initiating cells, with limited B7H3 heterogeneity, and low level of expression on normal tissues. Methods: We have discovered a panel of human anti-B7H3 and anti-PD-L1 single-chain variable fragments (scFvs) with a broad affinity range and extensive epitope coverage. This was achieved using our proprietary mRNADis™ mRNA display technology, combined with live-cell selection from proprietary human B cell libraries. To enhance therapeutic efficacy, we engineered a multi-mechanism armor by fusing an anti-PD-L1 scFv with a fine-tuned IL-2 variant, optimized via our mSCAFold™ cytokine engineering platform. We have developed EPC-002, a next-generation fully human anti-B7H3 armored CAR-T, aiming to treat a broad range of solid tumors with enhanced efficacy, favorable safety, and improved persistence. EPC-002 secretes a multi-mechanism armor, designed to augment the immune cell function in the TME. The anti-PD-L1 scFv blocks inhibitory checkpoint signaling, while the engineered IL-2 suppresses Treg activation, activates T central memory (TCM) cells, drives the proliferation of CAR-T, and improves the anti-tumor immunity of the CAR-T therapy. Results: EPC-002 demonstrated robust cancer cell engagement, leading to effective cytotoxic killing of cancer cells. In A375 melanoma mouse model, as low as 3x105 CAR-T cells mediated complete tumor regression. When these mice were rechallenged with Capan-2, a pancreatic cancer line expressing B7H3, these treated mice resisted new Capan-2 tumor growth and persisted through 110 days of treatment course. Pharmacodynamic studies demonstrated robust CAR-T and bystander T cell infiltration. The expanded TCM CAR-T phenotype was observed from PBMCs and splenocytes, enhances anti-tumor activity while improving CAR-T cell persistence. Conclusion: EPC-002 is a promising candidate that potentially enhances anti-tumor activity, reduces multiple immunosuppression mechanisms within the TME. These novel mechanisms could potentially translate into durable clinical efficacy for treating solid tumors. Citation Format: Keming Zhang, Katie O'Callaghan, Ning Jiang, Ryan Feng, Tony Ruan, Jenna Nguyen, Sam Hassan, Kehao Zhao, Yan Chen. Multi-mechanism human B7H3 CAR-T effectively overcome tumor microenvironment resistance in treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB363.