B7H3 specific CAR T cell with IL-7Ra signaling domain

The B7H3 specific CAR T cell with IL-7Ra signaling domain (also known as CMD03) is a novel chimeric antigen receptor T cell therapy that targets B7H3 (CD276) antigen on tumor cells while incorporating the IL-7 receptor alpha signaling domain to enhance T cell function and persistence[1][2]. This therapy represents an advancement in CAR-T cell design by including a third signaling domain (IL-7Rα) alongside the traditional CD3ζ (signal 1) and 41BB (signal 2) components[1]. ## Mechanism of Action The B7H3-targeting CAR construct works by recognizing and binding to B7H3 (CD276) protein expressed on tumor cells. What makes this therapy unique is the incorporation of the IL-7 receptor alpha (IL-7Rα) cytoplasmic domain as a third signaling component[1]. Research has shown that the short length (IL7R-S) of the IL-7Rα cytoplasmic domain provides superior results by: 1. Maintaining pSTAT5 activation 2. Increasing T-cell proliferation 3. Reducing activation-induced cell death 4. Downregulating proapoptotic genes 5. Upregulating genes associated with T-cell proliferation[1] This constitutive IL-7Rα signaling helps overcome the limitation of conventional CAR-T cells, which often face challenges in treating solid tumors due to impaired T-cell function in the tumor microenvironment[1][7]. ## Clinical Development The therapy is currently being evaluated in Phase 1 clinical trials for: 1. Relapsed and refractory pediatric solid tumors (NCT06612645) - started April 2025[2] 2. Diffuse intrinsic pontine glioma (DIPG) (NCT06221553) - using intraventricular infusion[2][4] These trials aim to assess both safety and early efficacy in pediatric patients who have completed standard treatments[2][4]. ## Preclinical Results In animal models, B7H3-IL7R-S CAR-T cells demonstrated: * Effective elimination of B7H3-positive glioblastoma in vitro * Suppression of tumor growth * Prolonged overall survival compared to conventional CAR-T cells * Maintenance of a less differentiated T cell phenotype, which is associated with better persistence and function[1] ## Advantages Over Conventional CAR-T Approaches The integration of IL-7Rα signaling provides several advantages: 1. **Enhanced persistence**: The IL-7 signaling pathway is critical for T cell survival and memory formation[6][7] 2. **Reduced exhaustion**: The therapy helps maintain T cell function during repeated antigen exposure[7] 3. **Targeted signaling**: Unlike approaches that use systemic cytokine administration, this design provides cell-intrinsic cytokine support only to the modified T cells, potentially reducing toxicity[7][8] 4. **Improved solid tumor efficacy**: The enhanced persistence and function may help overcome the challenges CAR-T cells face in solid tumor environments[1][7] This approach represents a promising strategy for augmenting the effectiveness of CAR-T cell therapy, particularly for challenging solid tumors like glioblastoma and DIPG where conventional treatments have limited efficacy[1][4].

Other names

B7H3-targeting CAR constructB-7H3-targeting CAR constructB 7H3-targeting CAR constructB7H3-IL7R-S CAR-T cellsB-7H3-IL7R-S CAR-T cellsB 7H3-IL7R-S CAR-T cells