First-in-human quad-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial

@misc{ronsley2026firstinhuman,
  title = {{First-in-human quad-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial}},
  author = {Rebecca Ronsley and Marlena Bannick and Prabha Narayanaswamy and Adam Beebe and Christopher Brown and Wenjun Huang and Stephanie Rawlings-Rhea and Jeffrey Whiteaker and Shrabanti Chowdhury and Andrea Timpanaro and Edward Song and Leonel Elena-Sanchez and Michael Meechan and Audrey Alderman and Madison Beam and Tiffany Sad and Sam Bakotich and Matthew Macquivey and Daniel Runco and Erin Crotty and Sarah Leary and Joelle Straehla and Juliane Gust and Alison Thomsen and Amy Beckstrom and Susan Holtzclaw and Corinne Hoeppner and Samuel Browd and Hannah Goldstein and Jason Hauptman and Amy Lee and Jeffrey Ojemann and Jason Wright and On Ho and Sowmya Pattabhi and Jason Wendler and Kamila Gwiazda and Pei Wang and Amanda Paulovich and Joshua Gustafson and Rebecca Gardner and Corinne Summers and Colleen Annesley and Julie Park and Michael Jensen and Nicholas Vitanza},
  howpublished = {Research Square},
  year = {2026},
  month = oct,
  doi = {10.21203/rs.3.rs-11447687/v1},
  url = {https://doi.org/10.21203/rs.3.rs-11447687/v1},
  note = {CC BY 4.0},
}

TY  - UNPB
TI  - First-in-human quad-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial
AU  - Rebecca Ronsley
AU  - Marlena Bannick
AU  - Prabha Narayanaswamy
AU  - Adam Beebe
AU  - Christopher Brown
AU  - Wenjun Huang
AU  - Stephanie Rawlings-Rhea
AU  - Jeffrey Whiteaker
AU  - Shrabanti Chowdhury
AU  - Andrea Timpanaro
AU  - Edward Song
AU  - Leonel Elena-Sanchez
AU  - Michael Meechan
AU  - Audrey Alderman
AU  - Madison Beam
AU  - Tiffany Sad
AU  - Sam Bakotich
AU  - Matthew Macquivey
AU  - Daniel Runco
AU  - Erin Crotty
AU  - Sarah Leary
AU  - Joelle Straehla
AU  - Juliane Gust
AU  - Alison Thomsen
AU  - Amy Beckstrom
AU  - Susan Holtzclaw
AU  - Corinne Hoeppner
AU  - Samuel Browd
AU  - Hannah Goldstein
AU  - Jason Hauptman
AU  - Amy Lee
AU  - Jeffrey Ojemann
AU  - Jason Wright
AU  - On Ho
AU  - Sowmya Pattabhi
AU  - Jason Wendler
AU  - Kamila Gwiazda
AU  - Pei Wang
AU  - Amanda Paulovich
AU  - Joshua Gustafson
AU  - Rebecca Gardner
AU  - Corinne Summers
AU  - Colleen Annesley
AU  - Julie Park
AU  - Michael Jensen
AU  - Nicholas Vitanza
PY  - 2026
DA  - 2026/10/27
PB  - Research Square
DO  - 10.21203/rs.3.rs-11447687/v1
UR  - https://doi.org/10.21203/rs.3.rs-11447687/v1
AB  - Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are lethal pediatric central nervous system (CNS) tumors with a median survival of 11 months. Despite advancements in translating chimeric antigen receptor (CAR) T cells for these patients, efficacy may be constrained by antigen heterogeneity and immune escape. We conducted a first-in-human, phase 1 trial (BrainChild-04; NCT05768880) evaluating repetitive intracerebroventricular (ICV) administration of a multi-antigen targeting CAR T cell product directed against B7-H3, EGFR806, HER2 and IL13Rα2 (quad-CAR T cells) for children and young adults with DIPG/pontine DMG (Arm A) and recurrent or refractory CNS tumors (Arm B). Here we report results from Arm A. Primary endpoints were feasibility, safety, and determination of the maximally tolerated dose regimen (MTDR). Secondary endpoints included CAR T cell distribution and preliminary clinical activity. Correlative analyses assessed CAR T cell kinetics and cytokine dynamics in cerebrospinal fluid (CSF). Twenty-six patients were enrolled with 100% manufacturing success rate. Twenty-one patients received at least one infusion (median 8/patient, range 3-56). No dose-limiting toxicities occurred in the dose-finding period, and treatment was tolerable with predominantly grade 1-2 adverse events, including fever (95%), headache (86%), and fatigue (81%). One dose-limiting toxicity (acoustic nerve disorder) occurred outside the evaluation window. Repetitive ICV dosing was feasible, and most of the infused patients (86%) initiated two or more treatment courses (median 4). CAR T cells were detected in CSF in 100% of patients, across serial courses in 76% of patients, with evidence of detection across sequential courses, particularly at higher dose levels. Cytokine profiling demonstrated dynamic immune activation within the CNS. Median survival from initial CAR T infusion was 8.6 months (95% CI: 5.2-10.3). All deaths were due to disease progression. Repetitive ICV administration of quad-CAR T cells is feasible and tolerable in children and young adults with DIPG/DMG. This study represents the first clinical application of quad-antigen targeting CAR T cells and confirmed feasibility in manufacturing and preliminary evidence of biologic activity in the CNS. These findings support further evaluation of multi-antigen CAR T strategies to address tumor heterogeneity of antigen expression as a likely barrier to CAR T cell efficacy in patients with CNS tumors.
SN  - 2693-5015
ER  -