B7-H3 CAR-T

P1, N=42, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

P1, N=42, Not yet recruiting, St. Jude Children's Research Hospital

GPC2-CARs lead to significant in vivo tumor regression in orthotopic tumor models via intravenous or intraventricular administration route and had equivalent activity to the B7-H3-CAR against D283 and enhanced activity than GD2-CAR in both models in vivo. T cell kinetic studies revealed that GPC2-CAR T cells home to the area of the primary tumor, expand, and upregulate genes critical for cytotoxicity and T cell homing. These results provide a preclinical rationale for including children with GPC2+ MB in our upcoming clinical GPC2-CAR T cell trial.

P1, N=48, Recruiting, St. Jude Children's Research Hospital | N=36 --> 48

Our results support ongoing clinical evaluation of B7-H3.CAR T-cells for EPNs and provide model systems for further studying determinants of anti-EPN CAR T-cell treatment efficacy and resistance.

Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for OS patients.

We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.

This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

Using an immunocompetent glioma model, we evaluated a panel of seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, and activation domains...Indeed, complete brain macrophage depletion using a CSF1R inhibitor abrogated CAR T-cell anti-tumor activity. In sum, our study highlights the critical role of CAR design and its modulation of the TIME in mediating the efficacy of adoptive immunotherapy for high-grade glioma.

We have developed a simple thaw/wash procedure to prepare B7-H3-CAR T cells for their locoregional delivery to the neural axis. While we focus here on CAR T cells, the methods could be readily adapted to other cryopreserved immune effector cell products.

P1, N=32, Recruiting, St. Jude Children's Research Hospital | Trial completion date: Feb 2026 --> Mar 2027 | Trial primary completion date: Mar 2025 --> Mar 2026