Switchable CD123-Specific CAR-T: A Promising Therapeutic Approach for Acute Leukemia

3 June 2024
The abstract discusses the use of autologous T cells modified to carry CD19-specific chimeric antigen receptors (CAR-T) for treating B cell cancers. It notes the difficulty of applying CAR-T therapy to targets other than CD19 due to challenges in managing CAR-T cell activity and the scarcity of antigens unique to malignant cells. The CD123 antigen, linked to leukemia, is highlighted as a potential target for immunotherapy but is also expressed in healthy stem cells and blood vessels, making it a risky target.

A new platform called UniCAR has been introduced to address these issues. It is composed of two parts: a non-reactive, inducible second-generation CAR designed for safe manipulation (UniCAR-T), and soluble targeting modules that activate UniCAR-T cells in a target-specific way.

The study presents data on the use of UniCAR-T with a CD123-specific targeting module (TM123) for treating acute leukemia. It shows that UniCAR-T cells, when redirected by TM123, can effectively eliminate CD123-positive leukemic cells both in vitro and in vivo. The activation and response of these cells are strictly controlled, and they exhibit comparable anti-leukemic effects to traditional CAR-T cells.

Importantly, UniCAR-T cells are able to distinguish between high-expressing malignant cells and low-expressing healthy cells, reducing toxicity to stem cells. A new targeting module with a bound 4-1BB ligand has been created to enhance CAR-T activity at the site of the tumor. This module, TM123-4-1BBL, showed specific binding to both 4-1BB and CD123-positive cells and improved the killing capability of UniCAR-T in tumor eradication models.

The study concludes that UniCAR-T cells maintain high efficacy against leukemia while providing a mechanism for immediate control, enhancing safety and versatility. The ability to switch between different targeting modules with varying plasma half-lives allows for personalized treatment strategies and minimizes adverse effects.

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