CAR T-cell therapy guided by scorpion toxin for glioblastoma
The first chimeric antigen receptor T-cell (CAR T-cell) therapy using chlorotoxin (CLTX), a toxin found in the venom of scorpions, demonstrated antitumor activity in a preclinical study recently published in Science Translational Medicine. As a result, a first-in-human clinical trial has opened at the City of Hope, Duarte, CA, for patients with recurrent or progressive glioblastoma (NCT04214392).1
Glioblastoma is the most common brain tumor to occur in adults. Few advances have been made in its treatment, and the prognosis for patients remains poor. One of the key obstacles limiting current glioblastoma therapies is its highly heterogeneous nature, between patients and within a single tumor.2,3
In this study, a CAR T-cell product incorporating the CLTX peptide in the tumor-targeting domain was developed, exploiting the glioblastoma-binding potential of CLTX shown in previous studies. In this preclinical study, the antitumor activity was robust and specific in mouse models. Results showed tumor regression in orthotopic xenograft tumor models after treatment with CLTX-CAR T-cells.4
Furthermore, CLTX binding was observed in a higher proportion of tumors and cells within these tumors when compared with the expression of other CAR T-cell targets, including IL13Rα2, HER2 and EGFR. Encouragingly, the study demonstrated that CLTX-CAR T-cells are highly effective at selectively killing human glioblastoma cells in both cell-based assays and animal models. CLTX-CAR T-cells were able to recognize and kill broad populations of glioblastoma cells while ignoring non-tumor cells in the brain and other organs, supporting efficacy and suggesting limited off-tumor targeting and toxicity.4
Tumor recurrence is another barrier limiting successful therapies for glioblastoma, and it is highly associated with the presence of cancer stem cells that contribute to tumor initiation and therapeutic resistance.4,5 CLTX binding included the glioblastoma stem-like cells linked to tumor recurrence. 4
The phase I clinical trial at the City of Hope will assess the feasibility and safety of CLTX-CAR T-cell therapy for patients with recurrent or progressive glioblastoma.6
Written by Marta Palhas
Edited by Thomas Southgate
- City of Hope. From scorpion to immunotherapy: city of hope scientists repurpose nature’s toxin for first-of-its kind car t-cell therapy to treat brain tumors (2020). Available from: https://www.cityofhope.org/news/from-scorpion-to-immunotherapy. Last accessed 17/03/2020.
- Tirosh I, Suvà M. Tackling the Many Facets of Glioblastoma Heterogeneity. Cell Stem Cell. 2020 Mar;26(3):303-304.
- Hatoum A, Mohammed R, Zakieh O. The unique invasiveness of glioblastoma and possible drug targets on extracellular matrix. Cancer Manag Res. 2019 Feb;11:1843-1855.
- Wang D, Starr R, Chang W et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. 2020 Mar;12(533):eaaw2672.
- Lathia J, Mack S, Mulkearns-Hubert E et al. Cancer stem cells in glioblastoma. Genes Dev. 2015 Jun;29(12):1203-1217.
- ClinicalTrials.gov. Chimeric Antigen Receptor (CAR) T-Cells With a Chlorotoxin Tumor-Targeting Domain for the Treatment of Recurrent or Progressive Glioblastoma (2020). Available from: https://www.clinicaltrials.gov/ct2/show/NCT04214392. Last accessed 17/03/2020