Cargo Therapeutics announces ASH 2024 abstract on CRG-023

CARGO Therapeutics (CRGX) announced that its first abstract on CRG-023 will be presented as a poster at the upcoming 66th American Society of Hematology Annual Meeting and Exposition, taking place December 7-10, 2024, in San Diego, California. CRG-023 is designed with the goal of providing more patients with durable responses by addressing several known causes of relapse associated with existing CAR T-cell therapies, such as tumor antigen loss, loss of co-stimulation and T-cell exhaustion. CRG-023 is a first of its kind CAR T product candidate with a construct that targets three B-cell lineage antigens via three separately expressed CARs. For the CD19 and CD20 CARs, new scFv binders were selected for optimal CAR-mediated activity following an extensive antibody discovery and screening campaign. Each CAR has a CD3 signaling domain and a distinct co-stimulatory domain. The CD20 CAR design, which incorporates a CD2 costimulatory domain, was informed by observations that CD58 expression loss is associated with poor response outcomes to CD19 CAR T-cell therapy. Intentional engineering and optimization of the final construct sought to limit onset of functional T-cell exhaustion and to sustain performance across a range of antigen expression profiles in order to prevent antigen escape. The abstract reviews the CRG-023 construct design, including the discovery of novel CD19 and CD20 scFv binders, selected for enhanced CAR performance, that were combined with the existing CD22 scFv binder used in firicabtagene autoleucel. The iterative engineering of the construct allowed for the selection of the optimal costimulatory domain configuration and optimal assemblage in a unique tri-cistronic lentiviral vector designed to maximize durable anti-tumor response. Importantly, in these mouse models, CRG-023 CAR T cells were able to sustain durable in vitro anti-tumor activity despite repeated tumor challenge against tumor cells expressing all or any one of the three antigens. Superior tumor control was observed as compared to benchmark CAR T cells, without increased cytokine secretion and while sustaining a less effector-differentiated phenotype. In vivo studies showed that CRG-023 CAR T cells were highly active and able to clear Raji lymphoma tumor cells expressing the three target antigens in a dose-response manner and down to the lowest dose tested. Additionally, the data showed that CRG-023 T cells were able to durably clear tumor cells in models mimicking antigen loss in contrast to mono-CAR T cells such as FMC63-containing CD19 CAR T cells.