B7-H3–Directed CAR T-Cell Therapy Has Acceptable Safety Profile in Recurrent Glioblastoma

Intraventricular infusion of B7-H3–directed CAR T-cell therapy was well tolerated at doses up to 1 x 10⁷ CAR T cells per infusion in patients with recurrent glioblastoma, meeting the primary safety objective of the interim analysis of a first-in-human phase 1 LCCC 2059 study (NCT05366179), which were presented at the 2025 Society for Neuro-Oncology Annual Meeting.¹

Among 9 evaluable patients who were enrolled across 3 dose levels (2 x 10⁶, n = 3; 5 x 10⁶, n = 3; 1 x 10⁷, n = 3) of CAR T-cells per infusion, no dose-limiting toxicities (DLTs) were reported. A total of 2 patients developed mild cytokine release syndrome (CRS); no patients experienced moderate or severe CRS. No patients had immune effector cell–associated neurotoxicity syndrome of any grade, and no grade 3 or higher adverse effects were deemed related to CAR T-cell infusion. Notably, 2 patients had moderate headaches. No patients needed to be admitted to the intensive care unit or receive toxicity management treatment with anakinra (Kineret) or tocilizumab (Actemra).

Among the 9 evaluable patients, the median age was 49 years, and 78% of patients were male. All patients completed the scheduled 3 weekly infusions. Best radiographic responses included partial response (PR; 22%; n = 2) and stable disease (22%; n = 2), translating to a disease control rate of 44%. One of the patients with PR achieved this response by 24 weeks and remained in response for 8 months after infusion. The other patient with PR achieved this response by the end of the DLT period. The median overall survival was 10.2 months.

“This is an ongoing clinical trial, and we are enrolling on dose level 5, [which is 6 x 10⁷ CAR T cells], at this time,” lead study author Yasmeen Rauf, MD, stated in the presentation.

Rauf is an assistant professor of neurology and neurosurgery at the University of North Caroline (UNC) School of Medicine, as well as the interim division chief of Neuro-Oncology at the UNC Lineberger Comprehensive Cancer Center in Chapel Hill.

What is currently known about the story of B7-H3 targeted therapy in brain cancer?

Currently, patients with glioblastoma have a median survival of approximately 14.6 months and 5-year survival rates below 5%. B7-H3 is widely expressed in glioblastoma and has minimal expression in normal brain tissue, making it an attractive therapeutic target.

B7-H3–directed CAR T-cell therapy is under investigation in other brain cancer populations as well. For instance, in May 2025, the FDA granted regenerative medicine advanced therapy designation to the CAR T-cell therapy BCB-276, which targets B7-H3, for the treatment of patients with diffuse intrinsic pontine glioma.²

What was the design of the phase 1 trial investigating B7-H3–directed CAR T-cell therapy in patients with glioblastoma?

This dose-escalation study used a 3+3 design.¹ It enrolled patients at least 18 years of age with histologically confirmed recurrent glioblastoma, a Karnofsky performance score of greater than 60, and measurable disease of at least 1 cm. Patients were not permitted to have prior bevacizumab treatment.

Patients received 3 weekly intraventricular infusions across 6 planned dose levels ranging from 1 x 10⁶ CAR T cells to 1 x 10⁸ CAR T cells, followed by a 2-week DLT period. Autologous CAR T cells were manufactured through RNA electroporation. Radiographic responses were measured every 8 weeks per Immunotherapy Response Assessment in Neuro-Oncology criteria. Notably, patients who progressed on this study treatment received additional treatment.

“It takes us about 3 to 4 weeks, sometimes 5 weeks, for manufacturing of the CAR T cells,” Rauf noted.

Safety and tolerability served as the primary end point of the trial. Secondary end points were feasibility and preliminary efficacy.

What did a case study show about the efficacy of B7-H3–directed CAR T-cell therapy in a specific patient?

Rauf presented findings from a case of a 46-year-old patient with IDH wild-type glioblastoma who received 6 weeks of concurrent radiation and temozolomide (Temodar), followed by 5 cycles of adjuvant temozolomide. After presenting with progression, this patient received 2 cycles of lomustine. Upon second progression, the patient was enrolled onto LCCC 2059 and received 3 weekly infusions of CAR T cells at dose level 3 x 10⁷ CAR T cells. Following the DLT period, this patient’s brain MRI appeared stable, and a subsequent MRI displayed a durable PR.

References

1. Rauf Y, Higgins D, Buchannan B, et al. Safety and tolerability of intraventricular infusion of B7-H3.CAR-T cells in recurrent glioblastoma. Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, Hawaii. Abstract CTIM-32.
2. FDA grants regenerative medicine advanced therapy designation for BrainChild Bio’s B7-H3 CAR T-cell therapy for incurable pediatric brain tumors. News release. BrainChild Bio. May 15, 2025. Accessed May 19, 2025. https://brainchildbio.com/wp-content/uploads/2025/05/BrainChild-Bio-RMAT-PR_FINAL.pdf