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Abstract Incidences of early-onset colorectal cancer (CRC) have been accelerating worldwide. To begin to address the lack of therapeutic options for CRC, we have developed a CAR-T cell therapy specific for leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). LGR5 is known to potentiate Wnt/Β-catenin signaling and mark cells-of-origin in intestinal cancers. Extensive screening has demonstrated elevated expression of LGR5 in CRC, which is correlated with reduced patient survival. In CRC, LGR5 has been intimately linked with metastasis, cell survival and perturbation of chemotherapeutic interventions. We have developed a 9-day preclinical manufacturing method to generate LGR5-targeting CAR-T cells with a minimally differentiated T cell phenotype, which was concomitant with significant cytotoxic and activation marker expression. In human CRC xenograft mouse models, LGR5-targeting CAR-T cells eradicated tumors at doses as low as 800, 000 CAR+ cells, and were capable of significantly inhibiting advanced tumor growth following delayed administration. Robust CAR-T cell-mediated immunological protection was observed in rechallenge experiments, in which secondary tumor growth was undetectable in mice which had tumors rejected following previous CAR-T cell administration. LGR5 protein and mRNA expression was also detected in a diverse range of cancer families, including ovarian, brain, liver and stomach, expanding upon the clinical indications with which LGR5-targeting CAR-T cells may be harnessed. These results contribute to a preclinical body of work that culminated in a Phase I/IIa clinical trial in metastatic colorectal cancer patients, which was approved for initiation by the FDA and commenced in 2023 (NCT05759728). Citation Format: Jade Foeng, Timona Tyllis, Caitlin Abbott, Dylan McPeake, Emma Thompson, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Claudine Bonder, Iain Comerford, Tim Sadlon, Simon Barry, Shaun McColl. Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a cancer immunotherapy 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 (6Suppl): Abstract nr 56.
Foeng et al. (Fri,) studied this question.