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City of Hope IL-13Rα2 / chlorotoxin CAR-T for recurrent high-grade glioma

Locoregional single-target IL-13Rα2 CAR-T plus the chlorotoxin (MMP-2-binding) CAR program at City of Hope — adult recurrent high-grade glioma Ph1 updates.

  • Speaker(s): Christine E. Brown, PhD; Behnam Badie, MD (neurosurgery); Stephen J. Forman, MD (lab); session also folds in the chlorotoxin-CAR thread led by the Brown/Badie group
  • Affiliation: City of Hope (Beckman Research Institute / Department of Neurosurgery)
  • Anchor type: cell therapy / trial
  • Day / session: Day 2 (Tue Mar 24, 2026), Cellular Therapy for GBM session
  • Status: post-meeting; details captured from AACR Brain 26 program notes and the published Nature Medicine 2024 IL-13Rα2 locoregional report; updated AACR Brain 26 cohort numerics TBD pending abstract supplement

Headline finding

Extended follow-up of the City of Hope locoregional IL-13Rα2 CAR-T program in adult recurrent high-grade glioma — the single-target lineage benchmark for IL-13Rα2 CARs — plus an early cohort update from the chlorotoxin-CAR program, which uses a peptide ligand (rather than an antibody scFv) to recognize MMP-2/glioma surface determinants. The Nature Medicine 2024 report established the safety and signals of response for IL-13Rα2 locoregional delivery; the Brain 26 update extends cohort N and durability. Specific 2026 numerics TBD.

Mechanism / methodology

The IL-13Rα2 construct uses a mutein IL-13 ligand binding moiety with a 4-1BB costim domain, delivered via dual intratumoral + intraventricular catheters. The chlorotoxin CAR replaces the antibody scFv with the chlorotoxin peptide, which binds an MMP-2-associated surface complex broadly expressed on glioma and offering a non-antibody targeting mode that may evade classical antigen-escape mechanisms. Both programs rely on locoregional CSF / intratumoral delivery rather than IV.

Mechanism / methodology deep dive

Underlying biology. IL-13Rα2 is a decoy IL-13 receptor preferentially overexpressed on glioma (in contrast to the more ubiquitous IL-13Rα1/IL-4Rα signaling complex on normal tissue), enriched in mesenchymal-like glioma cell states. Chlorotoxin, a 36-amino-acid scorpion-venom peptide, binds an MMP-2 / annexin A2 / ClC-3 surface complex broadly expressed across glioma irrespective of IL-13Rα2 status, giving a complementary target with a different escape profile.

Therapeutic design. The IL-13Rα2 CAR uses a mutein IL-13 (E13Y / R109K-class) ligand-binding domain to bias affinity toward IL-13Rα2 over IL-13Rα1, fused to a CD8α hinge/transmembrane, a 4-1BB costimulatory domain, and CD3ζ (per the City of Hope Nature Medicine 2024 construct). The chlorotoxin CAR substitutes the scFv with the chlorotoxin peptide as the antigen-binding domain; costimulatory composition for the current Ph1 construct TBD. Delivery uses dual intratumoral (resection cavity catheter) plus intraventricular (Ommaya) infusions; weekly re-dosing schedules have been reported.

Resistance / failure modes. Antigen loss / heterogeneity is documented (single-target IL-13Rα2 leaves antigen-low cells); local-only response with distant CNS progression has been observed, motivating ICV plus intratumoral combined delivery. T-cell persistence in CSF is short, raising the resistance role of repeated dosing rather than persistence.

Translational gaps. Whether chlorotoxin's broader-target profile actually reduces antigen-escape relapse vs IL-13Rα2 in matched cohorts is unresolved; manufacturing scalability and ex-US site replication of the dual-catheter procedure are unproven.

Where it fits in the corpus

  • AACR 2026: City of Hope cell-therapy team also presented in the Annual Meeting cellular-therapies sessions in San Diego.
  • SITC 2026: solid-tumor CAR-T track — the IL-13Rα2 single-target lineage is the comparator against bivalent / multispecific designs.
  • Related Brain 26 entries: upenn-icv-bivalent-cart.md (bivalent counterpart), monje-gd2-cart-dipg.md, neuroscience-of-gliomas-tam.md.

Open questions

  • Does chlorotoxin's broader surface-determinant targeting reduce antigen-loss relapse vs IL-13Rα2 single-target — public cohort data is still small.
  • Optimal locoregional regimen (intratumoral catheter vs ICV vs both) and re-dosing frequency remains a design question shared with the UPenn ICV bivalent program.