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Venom-Aided Immunotherapy Designed for Brain Tumors

Death stalker scorpion

Death stalker scorpion (Tola Kokoza, Wikimedia Commons)

5 Mar. 2020. Cancer researchers developed engineered immune-system cells, helped by peptides from scorpion venom, that in lab mice bind more reliably to brain tumor cells. A team from City of Hope medical center in Duarte, California describe their techniques in yesterday’s issue of the journal Science Translational Medicine (paid subscription required).

A growing form of cancer treatment uses T-cells from the immune system, genetically engineered to express added cancer-killing proteins called chimeric antigen receptors. These engineered T-cells, known as CAR T-cells, are shown in lab studies and clinical trials to attract antibodies that bind to and destroy cancer cells, particularly with blood-related cancers such as leukemia and lymphoma.

For solid tumor cancers, however, CAR T-cells have a more mixed record. Solid tumor cancers, such as the brain cancer glioblastoma, are often more complex than blood-related cancers and mutate to a greater extent, making these tumors more difficult to treat. These tumor mutations mean the original antigen targets escape, and thus require more versatile CAR T-cells to be effective.

A team at City of Hope led by immunotherapy professor Christine Brown is seeking to boost the reliability of CAR T-cells for treating glioblastoma and other solid tumor cancers. Glioblastoma is a cancer that forms in the brain’s glial cells that support the functioning of neurons in the brain sending and receiving nerve signals. The cancer generally grows and spreads quickly, often resulting death within 15 months of diagnosis. National Cancer Institute estimates nearly 23,000 adults in the U.S. were diagnosed with glioblastoma in 2015, resulting in more than 15,000 deaths.

Brown and colleagues supplemented CAR T-cells with chlorotoxin, a peptide isolated from the venom of Leiurus quinquestriatus, also known as the death stalker scorpion. The peptide derived from this venom has 36 amino acids and is already shown to bind to cancer cells. On its own, the peptide is non-toxic to both cancer and other tissue cells, and used today to identify cancer cells for surgery and radioisotope therapy.

For this therapy, the researchers take advantage of chlorotoxin’s binding ability to cancer cells, leaving the CAR T-cells to attack and destroy brain tumors. Doctoral candidate and first author Dongrui Wang observed that chlorotoxin specifically interacts with an enzyme called matrix metallopeptidase 2 on the surface of cells, making up some of the cellular framework.

In tests on lab mice with grafted glioblastoma tumors, the team combined chlorotoxin and CAR T-cells, where chlorotoxin provides the cancer cell targeting and binding, with CAR T-cells attacking the tumors. The results show the chlorotoxin captures a wider variety of tumor cells than conventional staining techniques. And with CAR T-cells, the therapy results in regression of the brain tumors. In addition, the researchers found no off-target effects in the organs of test mice.

“Our chlorotoxin-incorporating CAR expands the populations of solid tumors potentially targeted by CAR T-cell therapy,” says Brown in a City of Hope statement, “which is particularly needed for patients with cancers that are difficult to treat such as glioblastoma.” Brown adds, “This is a completely new targeting strategy for CAR T therapy with CARs incorporating a recognition structure different from other CARs.”

City of Hope is collaborating with National Cancer Institute on early-stage clinical trial of chlorotoxin-aided CAR T-cells to treat patients with glioblastoma.

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