H3K27M-mutant diffuse midline glioma (DMG) primarily affects children and young adults, arising from midline structures of the central nervous system. It is a highly aggressive CNS malignancy with a poor prognosis and limited response to conventional therapies. The most common subtype of DMG is diffuse intrinsic pontine glioma (DIPG), with a median overall survival of 11 months from diagnosis and a 5-year survival rate below 1%. In recent years, CART cell therapy has shown great promise across various cancers, and GD2-targeted CAR-T cells have demonstrated significant efficacy in preclinical models of DMG.

In November 2024, Nature published a clinical study titled "Intravenous and intracranial GD2CAR T cells for H3K27M+ diffuse midline gliomas." The study showed that following intravenous (IV) infusion followed by intracerebroventricular (ICV) infusion of CART cells, tumor shrinkage was observed in patients with DIPG and spinal DMG (sDMG), with sustained antitumor effects in some patients [1]. The GD2 CAR construct incorporates a scFv derived from the 14g2a monoclonal antibody, a CD8 transmembrane domain, and 4-1BB and TCR zeta signaling domains, and is transduced into T cells via a retroviral vector [2].

This study aimed to uate the safety and preliminary efficacy of intravenous and intracranial GD2 CAR-T cell administration in H3K27M+ DMG. The trial was conducted in two phases: patients first received intravenous GD2-CAR-T cells (at dose levels of 1×10⁶/kg and 3×10⁶/kg), followed by intracranial infusion in those showing clinical or radiological improvement. CAR-T cell products were successfully manufactured for all patients. In terms of safety, no dose-limiting toxicities (DLTs) were observed in the DL1 cohort; however, three patients in the DL2 cohort experienced DLT cytokine release syndrome, establishing 1×10⁶/kg as the maximum tolerated IV dose. Nine patients received ICV infusions, with no DLTs observed. All patients developed tumorinflammation-associated neurotoxicity, which was safely managed under close monitoring and supportive care.

 Figure 1: Summary of tumor progression changes and CAR-T toxicity reactions in the patient

Regarding efficacy, four patients demonstrated significant tumor volume reductions (52%, 54%, 91%, and 100%, respectively), while three others showed minor reductions. One patient remained in complete remission for over 30 months after enrollment. Nine patients exhibited marked neurological improvement following treatment, with some regaining the ability to walk. Patients who received intracranial infusion immediately following IV infusion showed more pronounced tumor regression and neurological improvement.

This study represents one of the first successful applications of CAR-T cell therapy in solid tumors, offering new hope for the treatment of H3K27M+ DMG, a fatal brain tumor. It demonstrates the safety and efficacy of GD2-directed CAR-T cell therapy in H3K27M+ DMG patients. The results indicate that the combination of intravenous and intracranial GD2-CAR-T cell infusion is not only safe and feasible but also capable of significantly reducing tumor burden and improving neurological function.

More recently, Nature Medicine published a report of a pediatric neuroblastoma patient who has remained in remission for over 18 years following GD2-directed CAR-T cell therapy, with no additional treatment required during the complete remission period (NCT00085930). This GD2 CAR also utilizes the 14G2A scFv and is prepared using retroviral vector technology.

Shenzhen Cell Valley employs its proprietary industrial-scale retroviral vectors to manufacture CAR-T cells targeting GD2, Claudin18.2, GPC3, EGFR, MUC1, and other solid tumor targets, supporting the clinical application of CAR-T cells in solid tumors. The transduction efficiency for CAR-T cells can reach over 60%, and the company provides end-to-end services covering T-cell activation, retroviral vector transduction, CAR-T cell expansion, quality testing, and product release. Leveraging its core retroviral vector platform, Shenzhen Cell Valley has developed GD2 CAR-T cell products with transduction efficiencies exceeding 50%, which have been validated in preclinical studies. This article provides an overview of clinical research on GD2 CART for DMG.

Figure 2: Detection of killing efficiency of Shenzhen Cell Valley GD2 CAR-T cells

Shenzhen Cell Valley is currently collaborating with leading domestic tertiary hospitals on clinical research in cell therapy, providing highstandard CAR-T/CARNK cell products with notable clinical efficacy. From the day of receiving patient blood samples, cell manufacturing can be completed in approximately 12 days. For patients who are refractory, relapsed, or resistant to prior treatments, CAR-T cell therapy has achieved an overall response rate (ORR) of 100% for Tcell acute lymphoblastic leukemia (T-ALL), 87.5% for multiple myeloma (MM), and 80% for B-cell acute lymphoblastic leukemia (B-ALL). These GMP-grade CAR-T products, manufactured using retroviral vectors, have proven safe and effective, earning high recognition from physicians. We welcome collaboration to benefit more patients!

References

[1] Monje M, Mahdi J, Majzner R, et al. Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature. 2025 Jan;637(8046):708-715. doi: 10.1038/s41586-024-08171-9. Epub 2024 Nov 13. Erratum in: Nature. 2024 Dec;636(8043):E6.

[2] Mount CW, Majzner RG, Sundaresh S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat Med. 2018 May;24(5):572579.

[3] Li CH, Sharma S, Heczey AA, et al. Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma. Nat Med. 2025.