Abstract Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal pediatric tumors of the central nervous system. Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CAR T) have demonstrated promise in preclinical studies and in an ongoing Phase I clinical trial (NCT04196413). In a recently published report of the first arm of this trial, tumor responses exhibited a Gaussian distribution of responses ranging from no response to a complete and durable response. Taken together, these results indicate great potential of this therapeutic approach and the need to understand mechanisms of treatment resistance. To better understand GD2-CAR T cell effects on DIPG and the pontine tumor microenvironment, in this study we focus on single-nucleus RNA sequencing (snRNA-seq) analyses performed on autopsy samples from 8 trial participants and 17 autopsy samples from DIPG patients with no prior CAR T-cell therapy. In total, we sequenced over 320,000 cells, representing DIPG malignant cells, microglia, neurons, astrocytes, oligodendrocytes, and vascular cells within the DIPG tumor microenvironment. Using this comprehensive dataset, we aim to elucidate how CAR T cell therapy alters the state of malignant cells and the tumor microenvironment in DIPG. These analyses will elucidate possible biomarkers of response and mechanisms of treatment resistance, with the aim of optimizing this promising therapy.
Gavish et al. (2025) studied this question.