Abstract LB-C010: Flare: A clinical stage platform designed to overcome challenges of the tumor microenvironment and universally target tumors of epithelial origin

Abstract Treatments that yield deep and durable responses against solid tumors remain elusive. CAR T cell therapy has shown promise, but is hindered by a lack of tumor-specific targets, leading to a narrow therapeutic window due to negative effects on normal tissues. In addition, the solid tumor microenvironment is hostile to the immune system, leading to exhaustion and dysfunction of engineered and endogenous immune cells. To overcome these limitations, we use a tumor-specific virus to deliver a specific CAR T antigen, termed a Flare, to universally target epithelial tumor types, while also creating an inflammatory microenvironment that amplifies CAR T cell function. We explored Flare molecules derived from both natural and synthetic origins, and confirmed activity of the platform across multiple Flare targets in multiple tumor types. The delivery of Flare relies on a virus that is a replicating, tumor-selective adenovirus, clinically validated for systemic administration. Viral infection with our Flare viruses leads to expression of Flare in cancer cells but not primary normal cells. When CAR T cells lyse virally infected cancer cells, it drives the release of mature viral particles. These viral particles reinfect the surrounding tumor cells, targeting them for clearance and creating a positive feedback loop of cell clearance. We demonstrate that tumor cells are effectively and specifically infected by our engineered viruses and are made to express a Flare molecule for CAR T cell targeted clearance. In addition to target delivery, viral infection produces an inflammatory signature supportive of CAR T cell activity in NSG mouse models. Infected cells were recognized and cleared by Flare-targeted CAR T cells, followed by ongoing cycles of viral replication and T cell killing, demonstrating combination activity in vitro and in vivo. Together the data establishes our Flare platform as an effective means to create a supportive microenvironment, while specifically tagging cancer cells of epithelial origin for CAR T targeting without damaging healthy tissue. Our first Flare program (DISP-10) uses an engineered form of BCMA as a Flare and will be tested with clinically validated BCMA CAR Ts across a range of epithelial tumors. The DISP-10 IND has been cleared by FDA for clinical initiation in gastrointestinal cancers where there remains a substantial unmet medical need, and patient dosing will begin in the near future. Citation Format: Lex Johnson. Flare: A clinical stage platform designed to overcome challenges of the tumor microenvironment and universally target tumors of epithelial origin [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C010.