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Clinical Trial
. 2025 Aug;31(8):2778-2787.
doi: 10.1038/s41591-025-03745-0. Epub 2025 Jun 1.

Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial

Stephen J Bagley  1   2   3 , Arati S Desai  4   5   6 , Joseph A Fraietta  7   8 , Dana Silverbush  9 , Daniel Chafamo  6 , Nelson F Freeburg  9 , Gayathri Konanur Gopikrishna  9 , Andrew J Rech  7   10 , Ali Nabavizadeh  11 , Linda J Bagley  6   11 , Jungmin Park  5   6   7 , Danuta Jarocha  7 , Rene Martins  7 , Nicolas Sarmiento  7 , Eileen Maloney  5   6 , Lester Lledo  7 , Carly Stein  7 , Amy Marshall  7 , Rachel M Leskowitz  7 , Julie K Jadlowsky  7 , Shane Mackey  7 , Shannon Christensen  7 , Bike Su Oner  7 , Gabriela Plesa  7 , Andrea Brennan  7 , Vanessa Gonzalez  7 , Fang Chen  7 , David Barrett  12 , Robert Colbourn  10 , MacLean P Nasrallah  5   10 , Zissimos Mourelatos  10 , Wei-Ting Hwang  13 , Cecile Alanio  14   15 , Donald L Siegel  5   7   10 , Carl H June  7   10 , Elizabeth O Hexner  4   7 , Zev A Binder  5   6   7 , Donald M O'Rourke  16   17   18
Affiliations
Clinical Trial

Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial

Stephen J Bagley et al. Nat Med. 2025 Aug.

Erratum in

  • Author Correction: Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial.
    Bagley SJ, Desai AS, Fraietta JA, Silverbush D, Chafamo D, Freeburg NF, Gopikrishna GK, Rech AJ, Nabavizadeh A, Bagley LJ, Park J, Jarocha D, Martins R, Sarmiento N, Maloney E, Lledo L, Stein C, Marshall A, Leskowitz RM, Jadlowsky JK, Mackey S, Christensen S, Oner BS, Plesa G, Brennan A, Gonzalez V, Chen F, Barrett D, Colbourn R, Nasrallah MP, Mourelatos Z, Hwang WT, Alanio C, Siegel DL, June CH, Hexner EO, Binder ZA, O'Rourke DM. Bagley SJ, et al. Nat Med. 2025 Sep;31(9):3205. doi: 10.1038/s41591-025-03824-2. Nat Med. 2025. PMID: 40500416 No abstract available.

Abstract

Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12-15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13Rα2), or CART-EGFR-IL13Rα2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13Rα2 cells. The maximum tolerated dose was determined to be 2.5 × 107 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity; none had grade 4-5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%; 90% confidence interval, 0-32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1-3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13Rα2 is feasible and appears safe. CART-EGFR-IL13Rα2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. ClinicalTrials.gov registration: NCT05168423 .

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Conflict of interest statement

Competing interests: S.J.B. has received consulting fees from Modifi Bio, Telix, Servier, Kiyatec, Novocure and Bayer and has received research funding from Kite (a Gilead Company) related to the submitted work and from Incyte, Novocure, GSK and Eli Lilly, all outside of the submitted work. J.A.F. is a member of the scientific advisory boards of Cartography Bio and Shennon Biotechnologies Inc and has patents, royalties and other intellectual property. A.J.R. is a cofounder and shareholder in Cellformatica. J.J. has received consulting fees from Bluewhale Bio, outside of the submitted work. D.B. is an employee of Kite Pharma (a Gilead company). D.L.S. holds founder’s equity and has licensed intellectual property to Verismo Therapeutics and Vetigenics, Inc. and has intellectual property licensing to Chimeric Therapeutics, Ltd. C.H.J. and the University of Pennsylvania have patents pending or issued related to the use of gene modification in T cells for adoptive T cell therapy. C.H.J. is a cofounder of Tmunity (acquired by Kite Pharma, a Gilead company); is a scientific cofounder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics and Bluewhale Bio; serves on the board of AC Immune; is a scientific advisor to BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Cellcarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite, Poseida, Verismo, Viracta, Vittoria Bio and WIRB-Copernicus group; and is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and Kite and may receive license revenue from such licenses. Z.A.B. has received research funding from Kite Pharma, has inventorship interest in intellectual property owned by the University of Pennsylvania and has received royalties related to CAR T therapy in solid tumors. D.M.O. reports previous or active roles as consultant and scientific advisory board member for Celldex Therapeutics, Prescient Therapeutics, Century Therapeutics and Chimeric Therapeutics, and has an advisory role and holds equity in Kiragen and Cellula Therapeutics. He has received research funding from Celldex Therapeutics, Novartis, Tmunity Therapeutics and Gilead Sciences/ Kite Pharma. D.M.O. is an inventor of intellectual property (US patent numbers 7,625,558 and 6,417,168 and related families) and has received royalties related to targeted ErbB therapy in solid cancers previously licensed by the University of Pennsylvania. D.M.O. is also an inventor on multiple patents related to CART cell therapy in solid tumors that have been licensed by the University of Pennsylvania and has received royalties from these license agreements. The other authors declare no competing interests.

References

    1. Price, M. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2017–2021. Neuro. Oncol. 26, vi1–vi85 (2024). - PubMed
    1. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005). - PubMed
    1. Taslimi, S., Ye, V. C., Wen, P. Y. & Zadeh, G. Lessons learned from contemporary glioblastoma randomized clinical trials through systematic review and network meta-analysis: part 2 recurrent glioblastoma. Neurooncol. Adv. 3, vdab029 (2021). - PubMed - PMC
    1. Reardon, D. A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 6, 1003–1010 (2020). - PubMed
    1. Chen, A. T. C. et al. Prospective randomized phase 2 trial of hypofractionated stereotactic radiation therapy of 25 Gy in 5 fractions compared with 35 Gy in 5 fractions in the reirradiation of recurrent glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 119, 1122–1132 (2024). - PubMed

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