Vitanza Nicholas A, Ronsley Rebecca, Choe Michelle, Seidel Kristy, Huang Wenjun, Rawlings-Rhea Stephanie D, Beam Madison, Steinmetzer Leonel, Wilson Ashley L, Brown Christopher, Beebe Adam, Lindgren Catherine, Gustafson Joshua A, Wein Amy, Holtzclaw Susan, Hoeppner Corrine, Goldstein Hannah E, Browd Samuel R, Hauptman Jason S, Lee Amy, Ojemann Jeffrey G, Crotty Erin E, Leary Sarah E S, Perez Francisco A, Wright Jason N, Alonso Marta M, Dun Matthew D, Foster Jessica B, Hurst Diana, Kong Ada, Thomsen Alison, Orentas Rimas J, Albert Catherine M, Pinto Navin, Annesley Colleen, Gardner Rebecca A, Ho On, Pattabhi Sowmya, Gust Juliane, Wendler Jason P, Park Julie R, Jensen Michael C
Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA.
Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
Nat Med. 2025 Mar;31(3):861-868. doi: 10.1038/s41591-024-03451-3. Epub 2025 Jan 7.
Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 10 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038 .
弥漫性脑桥内在型胶质瘤（DIPG）是一种致命的中枢神经系统（CNS）肿瘤，中位生存期为11个月。由于B7-H3在儿童中枢神经系统肿瘤中表达，我们开展了BrainChild-03研究，这是一项针对复发或难治性中枢神经系统肿瘤及DIPG儿童患者的单中心、剂量递增的1期临床试验，采用重复脑室内（ICV）注射靶向B7-H3的嵌合抗原受体T细胞（B7-H3 CAR T细胞）。在此，我们报告C组的结果，该组仅限于DIPG患者。主要目标是评估可行性和耐受性，这两个目标均已达成。次要目标包括评估CAR T细胞的分布和存活情况。共有23例DIPG患者入组，21例患者采用患者内剂量递增方案接受重复剂量的ICV B7-H3 CAR T细胞治疗，之前未进行淋巴细胞清除。在方案治疗期间，不允许同时进行包括再照射在内的肿瘤定向治疗。我们总共注射了253次ICV剂量，并确定了最高计划剂量方案DR4，即每次剂量递增至10×10⁶细胞，作为最大耐受剂量方案。常见的不良事件包括头痛、疲劳和发热。在DR2期间发生了1例剂量限制性毒性反应（瘤内出血）。对于所有接受治疗的患者（n = 21），从首次CAR T细胞输注起的中位生存期为10.7个月，从诊断起的中位生存期为19.8个月，3例患者在诊断后44、45和52个月时仍存活。最终，这项完成的首例人体试验表明，在患有DIPG的儿科和年轻成人患者中，重复ICV注射B7-H3 CAR T细胞是可耐受的，包括多年重复给药，并且可能具有临床疗效，值得在多中心2期试验中进一步研究。ClinicalTrials.gov注册号：NCT04185038 。
