Researchers with City of Hope have developed a chimeric antigen receptor (CAR) T cell therapy leveraging chlorotoxin, a component of scorpion venom.
Venom, whether in snakes, scorpions or Gila monsters, are very complex chemicals. And in more than one instance, research into them has led to effective drugs.
Researchers with City of Hope have developed a chimeric antigen receptor (CAR) T cell therapy leveraging chlorotoxin (CLTX), a component of scorpion venom. In preclinical research published in Science Translational Medicine, they demonstrated that the therapeutics directed T cells to target brain tumor cells.
Currently, the two approved CAR T therapies are Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel). They basically are living therapies, where T cells are drawn from a cancer patient, treated in the laboratory to be supercharged for specific cancer markers, and infused back into the patient. There, they actively grow, engage the target tumor cells and kill them. They are largely approved for use in blood cancers and lymphomas but have been less successful in solid tumors.
A typical CAR T uses a monoclonal antibody sequence to help target the antigens in question. The new compound, CLTX-CAR, utilizes a 36-amino acid peptide sequence that was isolated from death stalker scorpion venom. It was then engineered to act as the CAR recognition domain.
Glioblastoma (GBM) is the most common type of brain cancer and one of the most deadly cancers. Because of the way the tumors spread throughout the brain, it is very difficult to treat.
The researchers used the CLTX binding in resection samples from patients with GBM to evaluate how effectively it bound to known CAR-T targets, including IL13R alpha2, HER2 and EGFR. The CLTX bound to more tumors and to cells within those tumors. The binding also appeared to include GBM stem-like cells that are believed to act as seeds for tumor recurrence.
“Our chlorotoxin-incorporating CAR expands the populations of solid tumors potentially targeted by CAR T cell therapy, which is particularly needed for patients with cancers that are difficult to treat such as glioblastoma,” said Christine Brown, City of Hope’s Heritage Provider Network Professor in Immunotherapy and deputy director of T Cell Therapeutics Research Laboratory. “This is a completely new targeting strategy for CAR T therapy with CARs incorporating a recognition structure different from other CARs.”
The peptide developed from scorpions has been used as an imaging agent to help guide surgery in glioblastoma as well as to carry radioisotopes and other drugs to GBM tumors. This effort was to improve immunotherapy.
“Much like a scorpion uses toxin components of its venom to target and kill its prey, we’re using chlorotoxin to direct the T cells to target the tumor cells with the added advantage that the CLTX-CAR T cells are mobile and actively surveilling the brain looking for appropriate targets,” said Michael Barish, City of Hope professor and chair of the Department of Developmental and Stem Cell Biology. “We are not actually injecting a toxin but exploiting CLTX’s binding properties in the design of the CAR. The idea was to develop a CAR that would target T cells to a wider variety of GBM tumor cells than the other antibody-based CARs.”
Another example of venom leading to therapeutics is an entire class of drugs, GLP-1 agonists that are used to treat diabetes. They were originally discovered by John Eng while working in the laboratory of Rosalyn Yalow at the Mount Sinai School of Medicine. His research was on peptide hormones, and in the late 1980s he was advancing Yalow’s research by developing more sensitive tests to help identify hormones. He began with guinea pigs and then chinchillas. He was looking for more difficult test subjects, when he read about earlier work on snake venom and lizard venom, especially the venom of the Gila monster. In 1982, he identified two compounds in Gila monster venom, one which he named exendin-4. It was similar to GLP-1 and was eventually licensed to Amylin Pharmaceuticals to develop into Exenatide, the first GLP-1 analogue, which was approved in the U.S. in 2005.
Examples of this class of drug include AstraZeneca’s Byetta (exenatide), Novo Nordisk’s Victoza (liraglutide) and Ozempic (semaglutide), Sanofi’s Lyxumia (lixisenatide), GlaxoSmithKline’s Tanzeum (albiglutide), and Eli Lilly’s Trulicity (dulaglutide).
