Tumors of the brain and spinal cord, H3K27M-mutated diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPG), occur in children and young adults and have a median overall survival of 11-13 months from diagnosis. Palliative radiotherapy is currently the standard of care for these cancers, which cannot be surgically excised and are incurable. Researchers led by Ludwig Stanford’s Michelle Monje and Crystal Mackall reported in Nature last November the final results for Arm A of an ongoing Phase 1 trial evaluating the use of CAR-T cells directed against the ganglioside GD2—which the researchers previously had shown to be highly expressed in H3K27M+ DMGs—for these cancers. Thirteen patients with spinal DMG (3) and DIPG (10) enrolled in the trial, with eleven treated on trial, receiving CAR-T therapy intravenously. Nine patients received subsequent intracranial CAR-T infusions, which provoked fewer side effects. (Two patients progressed too rapidly to receive the experimental therapy.) Associated neuroinflammation was both expected and clinically manageable. Remarkably, nine patients showed neurological improvement, while tumors in three patients shrank by more than half (52, 54 and 91%) with a further three patients exhibiting smaller reductions. One patient exhibited a complete response—with tumors undetectable in brain scans—that was ongoing for over 30 months since enrollment. This is the first such response recorded for a cancer that has resisted all other treatment strategies.
Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas
Nature, 2024 November 13