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Background Diffuse intrinsic pontine glioma (DIPG) remains one of the most lethal pediatric brain tumors, with a median survival of approximately 11 months. B7-H3 is commonly expressed on DIPG cells, and early-phase clinical trials targeting B7-H3 with chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy. We developed CMD03, a novel B7-H3-targeting CAR T cell incorporating interleukin-7 receptor alpha (IL-7Rα) signaling. Preclinical studies showed that CMD03 CAR T cells exhibit a less differentiated memory phenotype, enhanced T cell proliferation, reduced activation-induced cell death, and improved tumor control with prolonged survival in murine models. 1 Methods We initiated a single-center, dose-escalation Phase I clinical trial evaluating repeated locoregional infusions of CMD03 CAR T cells without lymphodepletion in pediatric patients with DIPG ( NCT06221553). Approval was granted by the IRB committee, Chulalongkorn University (COA#1647/2024). Dose levels include 1×107, 3×107, and 1×108 CAR T cells per infusion. Infusions are administered every two weeks via an indwelling CNS catheter. The primary objective is to assess safety and tolerability; secondary objectives include evaluation of preliminary efficacy and CAR T cell biodistribution. Dose-limiting toxicities (DLTs) are assessed for up to 8 weeks following initiation of therapy. Radiographic response is evaluated according to RANO criteria for glioma.Results As of June 23, 2025, we report data from the first three patients enrolled at dose level 1 following radiographic progression. A total of 10 intracerebroventricular infusions were administered without any DLTs. The first patient received three doses before experiencing disease progression. The second patient received four doses and achieved stable disease at the two-month MRI follow-up. The third patient has received three doses and continues on schedule; imaging evaluation is planned for July 2025. Common adverse events included transient fever and headache. Two patients developed grade 3 tumor inflammation-associated neurotoxicity (TIAN), which resolved within 24 to 72 hours following treatment with dexamethasone and anakinra. CMD03 CAR T cells were monitored weekly in the cerebrospinal fluid (CSF) and were detected at levels ranging from 5–20% of total lymphocytes in the first two patients. As expected with locoregional delivery, CAR T cells were not detected in peripheral blood.Conclusions Preliminary findings suggest that repeated locoregional delivery of CMD03 CAR T cells is feasible and well tolerated at the initial dose level. Continued clinical investigation is warranted to further explore the therapeutic potential of IL-7Rα-enhanced B7-H3-targeting CAR T cells in improving outcomes for children with DIPG.Reference Sakunrangsit N, Khuisangeam N, Inthanachai T, Yodsurang V, Taechawattananant P, Suppipat K, Tawinwung S. Incorporating IL7 receptor alpha signaling in the endodomain of B7H3-targeting chimeric antigen receptor T cells mediates antitumor activity in glioblastoma. Cancer Immunol Immunother. 2024 Apr 15;73(6):98. doi: 10.1007/s00262-024-03685-7. PMID: 38619641; PMCID: PMC11018726.