Harnessing iMC Costimulation for Targeted CD123-Specific CAR T Cell Therapy in Leukemia

The abstract discusses a novel CAR-T cell platform termed "GoCAR-T," which targets CD123/IL-3Rα, a protein highly expressed on AML cells and stem cells. This platform is designed to mitigate the risk of toxicity to normal stem cells, which also express CD123, albeit at lower levels. The GoCAR-T platform includes a first-generation CD123-specific CAR that is proliferation-deficient and a costimulatory switch that is activated by the ligand rimiducid (Rim). This allows for physician-controlled elimination of CD123+ tumor cells and regulation of CAR-T cell engraftment.

The methodology involved activating T cells with antibodies and transducing them with a retrovirus that carries the costimulatory switch and the CD123-targeting CAR. The efficacy of this system was tested in vitro using coculture assays with leukemic cell lines and in vivo using an immune-deficient mouse model with CD123+ tumor cells. The results showed that antigen-specific cytolytic function was observed, and both CAR antigen recognition and Rim-dependent costimulation were necessary for optimal IL-2 production, CAR-T cell proliferation, and tumor cell killing.

In the mouse model, only those treated with the modified T cells and Rim showed significant tumor growth control. Furthermore, the study found that the absence of costimulatory signals led to a decrease in CAR-T cell persistence, suggesting that the GoCAR-T system provides a controllable approach to managing the persistence and safety of CD123-specific CAR-T cells.