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. 2025 Jul 18;7(1):vdaf160.
doi: 10.1093/noajnl/vdaf160. eCollection 2025 Jan-Dec.

First-in-human study of an EGFRvIII x CD3 T cell bispecific antibody in the treatment of newly diagnosed glioblastoma

James R Whittle  1 , Maria Vieito  2 , Kristoffer Rohrberg  3 , Maria E Rodriguez-Ruiz  4 , Eduardo Castanon  4 , Ingo K Mellinghoff  5 , Myra Van Linde  6 , Timothy Cloughesy  7 , David A Reardon  8 , Robert A Chong  7 , Mark Rosenthal  1 , Antje Wick  9 , Inja Waldhauer  10 , Nina Henkel  11 , Barbara Romagnoli  12 , Vincent Wolowski  12 , Shuva Dey  13 , Florian Heil  11 , Christian Heichinger  12 , Nick Flinn  13 , Jean-Philippe Gou  12 , Lance Smith  13 , Frederic Prince  12 , Michael Derks  13 , Andreas Roller  12 , Christina Schiff  12 , Meike Schneider  12 , Warren Mason  14
Affiliations

First-in-human study of an EGFRvIII x CD3 T cell bispecific antibody in the treatment of newly diagnosed glioblastoma

James R Whittle et al. Neurooncol Adv. .

Abstract

Background: This first-in-human study evaluated EGFRvIII × CD3 TCB, a novel T cell bispecific antibody, in patients with newly diagnosed EGFRvIII-positive glioblastoma.

Methods: Patients with newly diagnosed glioblastoma received escalating doses of EGFRvIII × CD3 TCB following chemoradiation. The primary objectives were to evaluate safety/tolerability and define the maximum tolerated dose (MTD); secondary objectives included pharmacokinetics (PK), immunogenicity, pharmacodynamics, and clinical activity.

Results: Thirty-six patients were enrolled, 32 with unmethylated and 4 with methylated MGMT promoter. EGFRvIII × CD3 TCB doses ranged from 0.004 to 10 mg Q3W, administered either on a flat or step-up dose schedule. One DLT occurred (grade 3 seizure). The MTD was not reached. Most adverse events (AEs) were of grade 1-2 severity, with headache being the most common treatment-related AE (22%). EGFRvIII × CD3 TCB showed dose-proportional PK in serum and cerebrospinal fluid (CSF), with a CSF/serum ratio of 0.08. At the highest dose tested, 10 mg Q3W, maximum serum concentrations remained 6-fold below the lower boundary of the predicted anticipated therapeutic dose.

Conclusions: The administration of EGFRvIII × CD3 TCB in a maintenance setting, following standard of care treatment, was safe and well tolerated up to the highest tested dose of 10 mg Q3W. However, evidence of efficacy was not observed at the evaluated doses, suggesting that a study of higher dose levels may be warranted.

Keywords: EGFR; T cell bispecific antibody; glioblastoma; immune therapy; phase 1.

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Figures

Figure 1.
Figure 1.
Tornado plot of the most common AEs (AEs that were considered related in ≥ 1 patient).
Figure 2.
Figure 2.
EGFRvIII × CD3 TCB pharmacokinetics and EGFRvIII staining intensity. (A) Linear regression analysis of EGFRvIII × CD3 TCB concentrations in serum and CSF for the tested dose range. (B) Distribution of EGFRvIII staining intensity. Representative examples for low, medium, and high EGFRvIII staining intensity are shown in Supplementary Figure S3.
Figure 3.
Figure 3.
Clinical outcomes following treatment with EGFRvIII × CD3 TCB. (A) Swimlane plot for exposure to EGFRvIII × CD3 TCB and response over time based on RANO criteria for all 36 enrolled patients. (B) Kaplan-Meier estimate of progression-free survival for the 32 patients with an unmethylated MGMT promoter.
Figure 4.
Figure 4.
Characterization of the patient with tumor flare. (A) Magnetic resonance imaging and (B) measurements of peripheral blood CD 8 T cells (upper panel) and cytokines (lower panels) in this patient. C, cycle; D, day. (C) Serum EGFRvIII × CD3 TCB concentration data from this (yellow) and the other three patients included in the 6.5 mg cohort.
See this image and copyright information in PMC

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