CAR T cells for diffuse intrinsic pontine gliomas - a phase 1 trial
A Phase 1 trial of T-cell mediated immunotherapy for diffuse intrinsic pontine gliomas (DIPGs) from Seattle
A Seattle team published a paper on a phase 1 trial of intraventricularly administered Chimeric Antigen Receptor T cells (CAR T Cells) targeting B7-H4 protein in patients with diffuse intrinsic pontine gliomas (DIPG) in Nature Medicine on January 25, 2025 (1).
The principal purpose of Phase I trials is to assess the safety, dosage, and pharmacokinetics of drugs or agents for treating a specific disease. B7-H4 is a checkpoint protein. Checkpoint proteins can modulate the immune system to prevent the immune system from attacking normal tissue. However, tumours could also use checkpoint proteins to evade the immune system. The checkpoint protein B7-H4 is found in DIPG.
Chimeric Antigen Receptor T cells (CAR T cells) are the patient’s T cells harvested from the patient’s blood. In this study, the harvested (apheresis) CD4+ and CD8+ T-cells were engineered (transduced) by lentivirus to express receptors (chimeric antigen receptors) for B7-H4. Then, these cells were allowed to proliferate before they were administered intraventricularly in those patients in this study. These CAR T cells would directly recognise tumour cells carrying B7-H4 proteins.
The maximum dose they could administer was 100 million CAR T cells/dose. In the study, 21 patients received CAR T cells. One patient had an intratumoral haemorrhage. Headache was noted in 81%, nausea and vomiting in 81%, fatigue in 62% and fever in 57% of the patients.
The study was not powered to investigate the efficacy of this immunotherapy. However, the authors report that the median survival was 19.8 months, in contrast to historical outcomes for DIPGs of 11.2 months. The authors qualify the better prognosis in this study by pointing out the difficulty of comparing historical outcomes.
The authors also examined the subset of patients who had entered the trial after the progression following radiotherapy. These patients had a median survival of 9.4 months after CART T cell therapy. Historically, patients with disease progression survive for less than 3 months.
This study is the first on CAR T cells for DIPGs only, where the CAR T cells were exclusively administered intraventricularly. The paper on this impressively sophisticated study had been published as an open-access paper. Naturally, the authors need to be congratulated on their groundbreaking work. The authors are now planning for a Phase II trial (efficacy).
Vitanza NA, Ronsley R, Choe M, Seidel K, Huang W, Rawlings-Rhea SD, Beam M, Steinmetzer L, Wilson AL, Brown C, Beebe A, Lindgren C, Gustafson JA, Wein A, Holtzclaw S, Hoeppner C, Goldstein HE, Browd SR, Hauptman JS, Lee A, Ojemann JG, Crotty EE, Leary SES, Perez FA, Wright JN, Alonso MM, Dun MD, Foster JB, Hurst D, Kong A, Thomsen A, Orentas RJ, Albert CM, Pinto N, Annesley C, Gardner RA, Ho O, Pattabhi S, Gust J, Wendler JP, Park JR, Jensen MC. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial. Nat Med. 2025 Mar;31(3):861-868. doi: 10.1038/s41591-024-03451-3. Epub 2025 Jan 7. PMID: 39775044; PMCID: PMC11922736. [Download]