A new study published in Science Translational Medicine describes how a chimeric antigen receptor T-cell (CAR-T) therapy has been engineered to express a peptide from scorpion venom. In certain models, the addition of a venom component to a CAR-T construct allowed the engineered cells to home more efficiently to glioma cells.1
The preclinical work utilized both patient glioma samples and mouse models to show that the peptide chlorotoxin (CLTX) — originally derived from the venom of the deathstalker scorpion — binds to glioma cells with high specificity and increases the binding and killing capability of CAR-T cells engineered to express the peptide.
The researchers first used 23 glioma samples from 15 patients to show that CLTX had a high affinity for the majority of patient tumor samples and also high proportions of cells within the samples. When tested alongside other clinically relevant targets under investigation such as HER2 and EGFR, CLTX compared favorably.
Continue Reading
The researchers then used a recognized chimeric antigen receptor (CAR) targeted against CD19 with an excellent safety and clinical activity profile and modified it to express CLTX and CD28 for costimulation, before engineering T cells to express this CAR.
CLTX-CAR-T cells were cocultured with glioma cells, and the CAR-T constructs killed the cancer cells within 48 hours. The engineered T cells were also tested in mouse models with both subcutaneous and orthotopic engraftment of 2 patient-derived glioma cell cultures. In both models, compared with mock T-cell treatments, the CLTX-CAR-T cells resulted in tumor regressions and prolonged survival, with some of the mice remaining tumor-free for up to 170 days.
CLTX-CAR-T also exhibited minimal off-target effects when tested on a panel of several different human cell types, and mice treated with the cells showed no adverse effects or toxicities from the therapy.
These promising preclinical safety results are echoed by other similar studies in humans, for example, assessing the use of chlorotoxin as a surgical imaging reagent.2
The first phase 1 clinical trial of CLTX-CAR-T cells (ClinicalTrials.gov Identifier: NCT04214392) has recently started and is recruiting patients with recurring or progressive glioblastoma.
References
- Wang D, Starr R, Chang W-C, et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Trans Med. 2020;12(533):eaaw2672. doi: 10.1126/scitranslmed.aaw2672
- Patil CG, Walker DG, Miller DM, et al. Phase 1 safety, pharmacokinetics, and fluorescence imaging study of tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas. Neurosurgery. 2019
