Abstract
Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423.
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Data availability
The data that support the findings of this study are included in the paper or may be available from the corresponding author, recognizing that certain patient-related data not included in the paper were generated as part of the clinical trial and may be subject to patient confidentiality. It is estimated that the corresponding author will respond to external data requests within 2 weeks of receipt of request. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Source data are provided with this paper.
Change history
22 March 2024
In the version of the article initially published an incorrect version of the Supplementary Information was included. This has now been updated in the HTML version of the article.
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Acknowledgements
The authors would like to thank the patients who participated in this study and their families for their dedication to furthering GBM treatment. The authors also thank the Neurosurgery Clinical Research Division, the Translational and Correlative Sciences Laboratory and the Clinical Cell and Vaccine Production Facility at the University of Pennsylvania Perelman School of Medicine for all of their clinical trial contributions and support. This work was funded by Kite Pharma (a Gilead company), the Abramson Cancer Center Glioblastoma Translational Center of Excellence to D.M.O., the Templeton Family Initiative in Neuro-Oncology to D.M.O., the Maria and Gabriele Troiano Brain Cancer Immunotherapy Fund to D.M.O., National Institutes of Health grants R35NS116843 to H.S. and R35NS097370 to G.-L.M. and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to G.-L.M. Kite Pharma had an advisory role in the design of the study and review of the final manuscript but had no role in data collection, analysis, decision to publish or preparation of the manuscript.
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Authors and Affiliations
Contributions
Study design: S.J.B., A.S.D., E.M., L.L., A.M., R.L, J.K.J., S.C, B.S.O., G.P., A.B., W.G., D.B., W.-T.H., E.O.H., Z.A.B. and D.M.O. Patient recruitment and treatment: S.J.B., A.S.D., R.M. and E.M. Data generation, curation and analyses: S.J.B., M.L., J.A.F., X.W., A.S.D., L.J.B., A.N., D.J., R.M., C.S., R.L., J.K.J., S.C., V.G., F.C., Y.S., M.P.N., W.-T.H., G.-L.M., H.S., D.L.S., E.O.H., Z.A.B. and D.M.O. Writing—original draft: S.J.B. and Z.A.B. Writing—review and editing: S.J.B., C.H.J., E.O.H., Z.A.B. and D.M.O. Supervision: S.J.B., E.M., L.L., C.S., G.P., A.B., H.S., D.L.S., C.H.J., E.O.H., Z.A.B. and D.M.O. Funding support: W.G. and D.B.
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Competing interests
S.J.B. has received consulting fees from Telix, Servier, Kiyatec, Novocure and Bayer and has received research funding from Kite Pharma (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 and has patents, royalties and other intellectual property (IP). W.G. is an employee of Kite Pharma (a Gilead company). D.B. is an employee of Kite Pharma (a Gilead company). D.L.S. holds founder’s equity and has licensed IP to Verismo Therapeutics and Vetigenics and has IP licensing to Chimeric Therapeutics. 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 co-founder of Tmunity (acquired by Kite Pharma, a Gilead company); is a scientific co-founder 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 Pharma, Poseida, Verismo, Viracta, Vittoria Biotherapeutics and WIRB-Copernicus group; and is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and Kite Pharma and may receive license revenue from such licenses. Z.A.B. has inventorship interest in IP owned by the University of Pennsylvania and has received royalties related to CAR T therapy in solid tumors. D.M.O. reports prior or active roles as consultant/scientific advisory board member for Celldex Therapeutics, Prescient Therapeutics, Century Therapeutics and Chimeric Therapeutics and has received research funding from Celldex Therapeutics, Novartis, Tmunity Therapeutics and Gilead Sciences/Kite Pharma. D.M.O is an inventor of IP (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 CAR T cell therapy in solid tumors that have been licensed by the University of Pennsylvania and has received royalties from these license agreements. The remaining authors declare no competing interests.
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Extended data
Extended Data Fig. 1 CART-EGFR-IL13Rα2 construct, CONSORT diagram, and study schema.
(a). The illustration depicts two parallel CARs with 4-1BBζ intracellular signaling domains. (b) CONSORT flow diagram for the patients included in this report. (c). Study schema.
Extended Data Fig. 2 Flow cytometry plots of optimized CAR detection assay.
For each patient, histograms depict EGFR CAR (left column) and IL13Rα2 CAR (center column) expression. Dual CAR expression is quantified in dot plots (right column). CAR expression values in patient infusion products based on these flow cytometry plots are displayed in Supplementary Table 1.
Extended Data Fig. 3 Immunofluorescence staining of EGFR CAR and IL13Ra2 CAR targets in patient pre-infusion tumor tissue.
Tumor tissue obtained at the time of Ommaya placement was stained for both CAR targets. All 6 patients treated demonstrated expression of one or both targets throughout their tumor. All images taken at 20x magnification. Staining was performed in duplicate. Scale bar = 100 μm.
Supplementary information
Supplementary Information
Full Study Protocol
Supplementary Tables 1–5
Optimized CAR T cell expression values on patient infusion product. CRS grading system. University of Pennsylvania modified CAR neurotoxicity grading system for patients with GBM. CSF and blood cytokine analyses (pg ml−1). CSF and blood cytokine fold change.
Source data
Source Data Fig. 3
Source data Fig. 3.
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Bagley, S.J., Logun, M., Fraietta, J.A. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med (2024). https://doi.org/10.1038/s41591-024-02893-z
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DOI: https://doi.org/10.1038/s41591-024-02893-z
