B7-H3 CAR-T

Our study highlights the importance of understanding tumor-specific factors that limit CAR T-cell response and using this information to design superior next-generation CAR T-cells. Specifically, we identify cytoskeleton remodeling and T cell motility as therapeutically actionable targets for future engineering approaches.

This study retrospectively applies TIAN criteria to patients with DIPG/pontine DMG treated with intraventricular B7-H3 CAR T cells in the BrainChild-03 (BC-03) trial (NCT04185038)...TIAN was common within this cohort but mostly low-grade and transient. Refining its classification and understanding its clinical impact will aid safety assessments and trial comparisons for CNS-directed CAR T therapies.

P2, N=41, Not yet recruiting, St. Jude Children's Research Hospital

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.