Abstract B050: A novel approach and model to limit cytokine release syndrome and off-tumor toxicity of synthetically enhanced CEA CAR-T cells

Abstract Background: Despite the potential for tumor-specific T cells to mediate durable complete responses, even in advanced disease, no CAR-T cell treatment is currently approved for use against any solid cancers [1–3]. While a large majority of solid cancers express tumor-associated antigens (TAAs) that are vulnerable to CAR T cell recognition, in nearly all cases TAAs are present in healthy tissues [4]. Since CAR T cells cannot differentiate between cancer and normal cells, CAR T cell recognition of TAAs on healthy tissues provokes dose-limiting ‘on-target off-tumor’ toxicities at sites of endogenous expression, most commonly the lungs [5–8]. Metastatic patterns of solid cancer are heterogenous, and in some cases lethal disease is limited to a single organ throughout a patient’s entire disease course – i.e. oligometastasis. For example, the liver is the sole site of metastasis in approximately 20,000 colorectal cancer deaths per year in the United States and the most common site of visceral metastasis from solid cancer overall [9–11]. We sought to capitalize on the oligometastatic biology of some cancers by genetically encoding CAR-T cells to restrict their activity to the cancer involved-organ while limiting CAR-T cell trafficking and associated toxicity to non-cancer sites. Methods: We develop two immunocompetent murine models of CAR T cell transfer targeting TAAs abundant in metastatic colorectal cancer and pancreatic cancer (EpCAM and CEA). Conventional TAA-specific CAR T cells affected tumor shrinkage but also infiltrated and damaged non-cancerous organs that expressed the TAA (lung, pancreas, & colon) [12]. The respiratory system was the site of greatest pathology in both models, with massive CAR T cell accumulation and tissue destruction, resulting in dose-limiting lethality. To mitigate off-tumor toxicity, we developed a multiparameter genetically encoded program that leverages endogenous chemokine and tissue resident systems to imbue CAR-T cells with liver tropism and enhanced functionality (Figure 1). Results: Liver-directed programming of CAR T cells in both CEA and EpCAM CAR models resulted in highly preferential trafficking of CAR T cells to liver tumors and limited CAR T cell trafficking and toxicity in non-cancerous tissues that share expression of the tumor associated antigen. Conclusions: Organ-directed targeting of TAA specific CAR-T cells is a promising approach to treat oligo-metastatic disease while avoiding off-tumor toxicities. Based on these results we are preparing to initiate phase 1b clinical (3+3) trial using liver-directed CEA specific CAR T cells in patients with colorectal liver metastasis. Citation Format: Alexandra Bartlett, Robert MD Eil. A novel approach and model to limit cytokine release syndrome and off-tumor toxicity of synthetically enhanced CEA CAR-T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B050.