CTP-07. Phase I study of intravenous and intracerebroventricular C7R-GD2.CAR T cell therapy for pediatric central nervous system (CNS) tumors

Abstract H3K27-altered diffuse midline gliomas (DMGs) and recurrent high-grade CNS tumors have poor prognoses and limited treatment options. GD2-CAR T cells (GD2.CARTs) armored with constitutively active IL7 receptor (C7R) have demonstrated early signs of therapeutic efficacy. We conducted a Phase I study to assess the feasibility, safety, and clinical activity of this approach using 3 different delivery strategies, all with preceding lymphodepleting chemotherapy. With the IV-only schedule, we treated eight patients (6 with DMG and 2 with recurrent medulloblastoma: n=3 at dose level 1 (DL1, 10 million cells/m²) and n=6 at dose level 2 (30 million cells/m²/2 doses, including one treated at both DLs) without dose-limiting toxicities (DLTs), and only low-grade tumor inflammation-associated neurotoxicity (TIAN) (gr 1 in 7/8) and low-grade cytokine release syndrome (CRS) (gr 1 in 5/8). Only one patient experienced transient grade 4 CRS. Of 7 patients with preexisting neurologic deficits, 6 showed clinical improvement; 2 demonstrated partial imaging responses, including one sustained >2 years. We then evaluated concurrent intracerebroventricular (ICV)-IV C7R-GD2.CAR T infusions, with one ICV dose (5×106 cells) and two IV doses (15 million cells/m2) given one week apart. Three patients with DMG received this regimen, of whom two experienced DLTs secondary to grade 3 TIAN (1 with concurrent grade 3 CRS), lasting several weeks and requiring anakinra and dexamethasone. One patient experienced a mixed response with transient clinical improvement and stable disease burden; two had clinical and radiographic progression. Due to neurotoxicity associated with concurrent ICV-IV administration, we adopted a staggered q4 week regimen of an initial IV cycle followed by single ICV cycles. To date, two patients have tolerated >/= 4 cycles with low-grade TIAN/CRS and clinical stability. Thus, while back-to-back ICV-IV dosing resulted in increased toxicity compared to IV-only therapy, sequential dosing was better tolerated, potentially indicative of the negative sequelae of compounded inflammation.