Identifying and targeting the cell to cell interactions driving diffuse intrinsic pontine glioma growth after GD2-CAR T cell treatment

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) with histone H3K27M mutations are universally fatal pediatric brain cancers, with an average survival of just 11 months.

These tumors are challenging to treat due to their location in the brainstem and their tumor-supportive microenvironment.

Recent findings suggest that cell-to-cell interactions between the tumor, nervous system, and immune system play a critical role in driving tumor progression, and targeting these interactions has shown promise in preclinical models.

A phase I trial (NCT04196413) using GD2-specific CAR T-cells demonstrated initial clinical improvements, but all patients ultimately relapsed.

This study aims to investigate the molecular and cellular mechanisms underlying tumor progression following GD2 CAR T-cell therapy, with a focus on identifying therapeutic vulnerabilities within the tumor microenvironment. The project will be conducted in two phases over three years.

First, we will analyze patient samples using single-cell and spatial transcriptomics to identify key therapeutic targets.

In the second phase, we will validate these targets in DIPG cell cultures and xenograft models, with the ultimate goal of translating these findings into more effective treatment strategies for DIPG and other gliomas.