City of Hope investigators initiated a Phase I (first-in-man) clinical trial evaluating a (CAR) T cell therapy for glioblastoma (GBM) utilizing a scorpion venom peptide called chlorotoxin (CLTX) to direct T cells to target brain tumor cells. Preclinical research involving mice models reveal that the CLTX-CAR T cells result in tumor regression with no evidence of off-target effects.
TrialSite News breaks this information down to what is hopefully an easier translation to a larger audience. The research, led by City of Hope investigators, had their preclinical studies published in Science Translational Medicine in a paper titled “Chlorortoxin-directed CAR T cells for specific and effective targeting of glioblastoma.”
What is glioblastoma, and why is it a Problem?
The most common form of primary brain tumor (PBT), glioblastoma, is also the deadliest. Often difficult to treat as tumors are disseminated throughout the brain. The most recent treatment breakthroughs—such as immunotherapies including CAR T cells—must contend with a high degree of heterogeneity within the tumors. Unfortunately, despite all the breakthroughs from surgery and chemotherapy to radiotherapy, GBM survival has only modestly improved over the past decades.
What is the significance of the City of Hope research here?
This chlorotoxin-based CAR T cell therapy can potentially help glioblastoma (brain cancer) patients that are difficult to treat. Moreover, this targeting strategy, based on CAR T, represents a new targeting strategy for CAR T therapy
How is the City of Hope experimental CAR T treatment different?
With typical CAR T, therapy typically incorporates a monoclonal antibody sequence in the targeting domain—enabling the CAR T to seek out and kill tumor cells—the City of Hope-based experimental CAR T exploits the tumor-binding propensity of the 36-amino acid CLTX peptide (originally isolated from deathstalker scorpion called Leiurus quinquestriatus). As reported in Genetic Engineering & Biotechnology News, the City of Hope scientists noted: “CLTX has been established to bind broadly and specifically to GBM and other neuroectodermal tumors while showing minimal cross-reactivity with non-malignant cells in the brain and elsewhere.”
This approach brings a more mobile component where the chlorotoxin is used to direct the T cells to constantly survey the brain on the look-out for appropriate targets. The hope is that this novel therapy will seek out and target a wider variety of GBM tumor cells that other antibody-based CARs.
Has the CLTX-based CAR T shown promise?
Yes. Experiments in human GBM cells in cell-based assays and in animal models reveal that the CLTX-CAR T cells recognized and killed broad populations of GBM cells, however, avoided non-tumor cells in the brain and other organs.
The Phase I studies the side effects and best dose of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain in treating patients with glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells.
The study will include 36 participants for this open-label, single-group assessment study. The study commences in March 2020 and concludes in 2023.
Christine Brown, Ph.D., City of Hope’s Heritage Provider Network Professor in immunotherapy, deputy director T Cell Therapeutics Research Laboratory
Michael Barish, Ph.D., City of Hope professor and chair of the department of development and stem cell biology
Behnam Badie, MD Neurosurgeon
Dongrui Wang, Doctoral candidate, City of Hope’s Irell & Manella Graduate School of Biological Sciences