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The sequential intracerebroventricular (ICV) and intraventricular (IV) administration of CR7-GD2 CAR T-cell therapy was found to be better tolerated vs concurrent administration in pediatric patients with central nervous system (CNS) tumors, according to data from a phase 1 study (NCT04099797) presented at the 2025 Society of Neuro-Oncology Annual Meeting.¹

During the study, investigators at Baylor College of Medicine in Houston, Texas, evaluated 3 administration techniques for the CR7-GD2 CAR T-cell therapy: IV only; concurrent ICV and IV; and sequential ICV and IV.

Findings showed that in patients treated with IV-only administration (n = 8) at 10 million cells/m² (n = 3) or 30 million cells/m² (n = 6), no dose-limiting toxicities (DLTs) were reported, and instances of tumor inflammation–associated neurotoxicity (TIAN) were low grade, occurring in 7 patients. One patient experienced transient grade 4 cytokine release syndrome (CRS); 5 experienced grade 1 CRS. Among patients treated via IV alone who had preexisting neurological defects (n = 7), 6 achieved clinical improvement, including 2 partial responses on imaging, which 1 patient maintained for more than 2 years.

In patients who received concurrent ICV/IV administration (n = 3), with doses given 1 week apart, 2 experienced DLTs secondary to grade 3 TIAN, including 1 patient with concurrent grade 3 CRS. These DLTs persisted for several weeks and required intervention with anakinra and dexamethasone. In this group, 1 patient achieved a mixed response with transient clinical improvement and stable disease burden. The remaining 2 patients had clinical and radiographic progression.

The neurotoxicity observed with concurrent administration prompted investigators to adopt a sequential strategy, with ICV administration given 4 weeks after IV treatment. In patients treated with this strategy (n = 3), treatment was well tolerated for at least 3 cycles each, with no DLTs reported; these patients experienced low-grade TIAN/CRS and clinical stability.

“While back-to-back ICV/IV dosing resulted in increased toxicity compared [with] IV-only therapy, sequential dosing was better tolerated, potentially indicative of the negative sequelae of compounded inflammation,” lead study author Jasia Mahdi, MD, and colleagues wrote in a poster presentation of the data. Mahdi is a pediatric neurologist and neuro-oncologist, and director of Neuro-Oncology for the Division of Pediatric Neurology at Texas Children’s Hospital, as well as an assistant professor of pediatrics-neurology at Baylor College of Medicine.

How was the phase 1 study conducted?

The single-center trial enrolled 2 cohorts of patients between 12 months and 22 years of age.² The first included patients with histologically confirmed, GD2-expressing or H3K27-altered, diffuse midline glioma (DMG) or high-grade glioma (HGG) that was newly diagnosed, defined as prior to radiographic progression or recurrence; patients with histologically confirmed, GD2-expressing or H3K27-altered, recurrent, refractory, or progressive DMG/HGG; and those with recurrent, refractory, or progressive high-grade CNS tumors with confirmed GD2-expression. Cohort 2 included patients with recurrent, refractory, or progressive pontine HGG with confirmed GD2-expression or H3K27-altered DMG.

All patients needed to have tumors less than 5 cm in maximum dimension, measurable disease on at least 2 dimensions per MRI, and a Karnofsky/Lansky performance status of at least 50.

The C7R-GD2 CAR T-cell therapy was administered after lymphodepleting chemotherapy in all arms and cohorts, comprising 2 days of cyclophosphamide and 3 days of fludarabine.¹ In patients who received combined dosing, the CAR T-cell therapy was given at 5 x 10⁶ cells/m² ICV, followed by 15 x 10⁶ cells/m² IV, then another IV dose at the same level. In the sequential cohort, patients received an IV dose at 10 million cells/m², followed by an ICV dosing in cycle 2 and beyond, starting at 2 million cells and escalating to 5 million cells.

In both ICV arms, patients remained for inpatient monitoring for 6 to 10 days, followed by close outpatient follow-up. Disease evaluation occurred at week 6.

The incidence of DLTs was the trial’s primary end point.² Response rate was a secondary end point.

In the combined ICV/IV arm, 1 male patient and 2 female patients had a median age of 15 years (range, 4-17).¹ Tumor locations included thalamus and midbrain (n = 1), pons (n = 1), and C1-C7/T1 (n = 1). All had H3K27-altered DMG. Patients had a median time since diagnosis before enrollment of 9.4 months, and they had a median time from the end of radiation to enrollment of 6.5 months. These patients received a median of 1 ICV infusion.

In the sequential cohort, all 3 patients were male with a median age of 16 years (range, 14-17). Tumor locations comprised the thalamus (n = 2) and the temporal lobe (n = 1). Tumor types included H3K27-altered DMG (n = 2) and H3 wild-type, IDH wild-type diffuse HGG (n = 1). Patients had a median time from diagnosis to enrollment of 7.4 months, and a median time from the end of radiation to enrollment of 2.3 months. This group received a median of 3 ICV infusions.

What were the toxicity profiles of combined and sequential ICV/IV CAR T-cell therapy administration?

In the combined ICV/IV arm, adverse effects included CRS (grade 1, n = 2 infusions; grade 3, n = 1 infusion), immune effector cell–associated neurotoxicity syndrome (ICANS; grade 0, n = 3 infusions), and TIAN (grade 1, n = 1 infusion; grade 3, n = 2 infusions). Two patients received tocilizumab (Actemra), and all 3 were given dexamethasone, which continued upon hospital discharge.

In the sequential group, toxicities included CRS (grade 0, n = 13 infusions; grade 1, n = 3 infusions), ICANS (grade 0, n = 16), and TIAN (grade 0, n = 2 infusions; grade 1, n = 14 infusions). All patients required tocilizumab, but no patients received dexamethasone.

What was reported from a trial case study?

Investigators highlighted a 16-year-old male patient with H3K27-altered thalamic and periventricular occipital lobe DMG who underwent 9 cycles of treatment in the sequential ICV/IV arm, including 1 IV infusion and 8 ICV infusions. This patient remained on treatment as of data cutoff, and he has experienced CRS and TIAN at a maximum grade of 1. MRI revealed stable disease, and the patient was also stable on a neurological exam.

References

1. Mahdi J, Stuckert A, Tat C, et al. Phase I study of intravenous and intracerebroventricular C7R-GD2.CAR T cell therapy for pediatric central nervous system (CNS) tumors. Presented at 2025 Society of Neuro-Oncology Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTP-07.
2. C7R-GD2.CAR T cells for patients with GD2-expressing brain tumors (GAIL-B). ClinicalTrials.gov. Updated September 4, 2025. Accessed November 23, 2025. https://clinicaltrials.gov/study/NCT04099797