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Published on: February 16, 2015
Chlorotoxin-directed CAR T cell therapy for recurrent glioblastoma: Interim clinical experience demonstrating
Michael E Barish1, Maryam Aftabizadeh2, Jonathan Hibbard2
1Department of Stem Cell Biology & Regenerative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, CA 91010, USA.
Abstract:
A challenge in treating glioblastoma (GBM) is its phenotypic heterogeneity between patients and within tumors. Chlorotoxin (CLTX), a peptide from scorpion venom, broadly binds glioma cells through a mechanism involving surface matrix metalloproteinase-2 (MMP-2). We previously developed chimeric antigen receptor (CAR) T cells incorporating CLTX as the GBM recognition domain. Here, we report interim clinical experience of a phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells in four patients with MMP-2-expressing recurrent GBM (NCT04214392), with the primary objectives of feasibility and safety. The therapy is well tolerated with no dose-limiting toxicities. Three of the four participants (75%) exhibit a best response of stable disease. CLTX-CAR T cells are detected in the tumor cavity fluid and at lower levels in the blood. Human anti-CAR antibody assays do not detect humoral immunogenicity against the CLTX-CAR. These observations support further clinical evaluation of CLTX-CAR therapy.
Insights
This study shows that chlorotoxin (CLTX)-chimeric antigen receptor (CAR) T-cell therapy is safe and feasible for recurrent glioblastoma (GBM). Most patients experienced stable disease, with no significant immune reactions observed.
Area of Science:
- Oncology
- Immunotherapy
- Neuroscience
Background:
- Glioblastoma (GBM) presents significant treatment challenges due to its heterogeneity.
- Chlorotoxin (CLTX), a scorpion venom peptide, targets glioma cells via matrix metalloproteinase-2 (MMP-2).
- Previous work established CLTX-based chimeric antigen receptor (CAR) T cells for GBM recognition.
Purpose of the Study:
- To evaluate the feasibility and safety of intracavity/intratumoral (ICT) CLTX-CAR T-cell therapy.
- To assess the preliminary efficacy of this novel GBM treatment approach.
Main Methods:
- Phase 1 clinical trial of ICT CLTX-CAR T cells in recurrent GBM patients (NCT04214392).
- Monitoring for safety, feasibility, dose-limiting toxicities, and immune response.
- Detection of CLTX-CAR T cells in tumor fluid and blood.
Main Results:
- The CLTX-CAR T-cell therapy was well tolerated with no dose-limiting toxicities observed.
- Three out of four participants (75%) achieved stable disease as their best response.
- CLTX-CAR T cells were detected in tumor cavities and blood; no humoral immunogenicity was detected.
Conclusions:
- Intracavity/intratumoral CLTX-CAR T-cell therapy demonstrates safety and feasibility in recurrent GBM.
- The therapy shows promising preliminary efficacy, supporting further clinical investigation.
- This approach warrants continued evaluation for GBM treatment.
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