B7-H3 CAR T cells following initial radiation for children and young adults with diffuse intrinsic pontine glioma - PROJECT SUMMARY: B7-H3 CAR T cells following initial radiation for children and young adults with diffuse intrinsic pontine glioma Central nervous system (CNS) tumors cause the most childhood cancer deaths. Diffuse intrinsic pontine glioma (DIPG) is a universally fatal CNS tumor responsible for the death of ~400 children each year in the US with hundreds of failed Phase 1 trials unable to advance to Phase 2 because of the lack of preliminary efficacy. Our team has demonstrated the preclinical efficacy of B7-H3-specific chimeric antigen receptor (CAR) T cells and translated them to a completed first-in-human clinical trial, BrainChild-03 (BC-03), that found the highest planned dose level (10x107 cells/dose) to be the maximally tolerated dose (MTD). Patients were eligible to enroll at any clinical timepoint (e.g. after initial radiation or after progression) with some patients enrolling after multiply metastatic recurrences, complicated efficacy analyses. Notably, 10 of 21 treated patients enrolled after their initial radiation (i.e. before progression) and have a median overall survival (OS) of 17 months (versus 11 months historically) with 5/10 patients still alive. Therefore, we will open BrainChild-05 (BC-05), a Phase 2 clinical trial of repeatedly intracranially dosed B7-H3 CAR T cells at the confirmed MTD in patients with DIPG following their initial radiation. We will also develop advanced neuroimaging automated analysis and CSF correlative biomarkers to create a centralized pipeline that can be leveraged to distinguish treatment response from treatment failure in future multi-site trials. Our long-term goal is to create a paradigm of effective locoregional CAR T cell therapy and monitoring for DMG and all pediatric CNS tumors. Our overall objective is to define the efficacy of B7-H3 CAR T cells for children with DIPG that incorporates correlative studies able to define signals of therapeutic benefit. Our central hypothesis, building off our phase 1 experience, is that B7-H3 CAR T cells will extend OS compared to historical controls; advanced neuroimaging assessments will improve the validity, reproducibility, and biologic understanding of our therapy; and serial CSF biomarker evaluations will identify markers of treatment response. Specifically, in AIM 1 we will open BC-05 delivering repeatedly dosed locoregional B7-H3 CAR T cells at the MTD in patients with DIPG following initial radiation in order to define the efficacy of this therapy. These activities will be supported end-to-end by our vertically integrated infrastructure that has launched 16 IND-supported pediatric CAR T trials. In AIM 2, we will define the ability for programmed volumetric and diffusion pontine measurements to create a more valid, reproducible assessment pipeline and to define changes in response to cellular therapy. In AIM 3, we will perform quantitative CAR T cell detection, CSF cytokine analyses, and targeted mass spectrometry on serial patient biospecimens to quantify immunomodulatory proteins and CAR T target antigens.
