PDTM-39. GD2-DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELLS AS A POTENT IMMUNOTHERAPY REGIMEN IN XENOGRAFT MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor with a median survival of approximately 10 months. Despite advances in understanding the molecular origins of DIPG, translations to improvement in clinical outcomes have yet to materialize. To date, there has been little target exploration for immunotherapy applications in DIPG. Here we report substantial preclinical efficacy of chimeric antigen receptor (CAR)-bearing T cells targeting the disialoganglioside GD2 as an immunotherapy regimen in patient-derived orthotopic xenograft models of Histone 3 K27M (H3K27M) mutated DIPG. GD2 is highly and uniformly expressed in patient-derived H3K27M DIPG cultures, and in vitro assays demonstrate substantial target-dependent cytokine generation and target cell killing. H3 WT pediatric high-grade gliomas (HGGs), including one case diagnosed as DIPG, do not express significant levels of GD2, and the H3K27M mutation is associated with increased synthesis of ganglioside pathway synthesis enzymes, suggesting expression of the GD2 antigen is driven by H3K27M-induced transcriptional dysregulation. Single-dose systemic administration of GD2-directed CAR T cells in multiple orthotopic xenograft models of DIPG achieves potent and lasting antitumor efficacy within a 4 week period of administration compared to a CD19-directed CAR control cohort. Universal response was observed across multiple cohorts, and treatment-associated toxicity was transient and tolerated during the period of peak anti-tumor activity. If these results are predictive of human response, GD2-directed CAR T cell therapy could have a transformative impact upon DIPG outcomes.