UCSF CAR-T Cells Clear Deadly Child Brain Tumor in Two Mouse Models

An engineered immune cell therapy cleared diffuse midline glioma from every mouse it was given to in two mouse models of the disease, researchers at the University of California, San Francisco reported Oct. 28 in the journal Science Translational Medicine. The cells are built to stay switched off until they reach the brain.

Diffuse midline glioma, or DMG, is a childhood brain cancer that grows into the brainstem, the region that runs breathing, heartbeat and swallowing. Nearly all children diagnosed with it die within a year, and current treatments have done little to slow it. The new therapy, called B-SYNC CAR-T, has not been tested for effectiveness in people.

A sensor that waits for a brain protein

CAR-T therapy takes a patient’s T cells, a type of immune cell, and fits them with receptors called CARs. The receptors latch onto proteins on cancer cells and set off an attack. The method has worked against some cancers and has struggled against brain tumors.

B-SYNC adds a step before that attack. A molecular sensing system called synNotch looks for brevican, a protein found throughout the brain. Only when the sensor meets brevican do the cells start making CARs, which then go after two proteins carried by many DMG and glioblastoma tumor cells, EphA2 and IL13Rα2.

The design grew out of an earlier UCSF therapy for glioblastoma, called E-SYNC, reported in 2021 by Hideho Okada, a professor of neurological surgery, and Wendell Lim, a professor of cellular and molecular pharmacology. E-SYNC keyed on EGFRvIII, a mutated protein, but only about 20% of patients have tumors that carry it, and tumors can lose it as the cells holding it are killed off. Brevican gave the team a signal that does not depend on a tumor mutation.

What the mouse experiments showed

Senthilnath Lakshmanachetty, a postdoctoral researcher in Okada’s laboratory, led the work. The team first gave B-SYNC cells intravenously to mice carrying human DMG cells. Some of the cells crossed into the brain and began producing CARs there. Cells circulating in the blood and sitting in the spleen did not.

The researchers then injected the cells straight into the fluid-filled ventricles of the brain, a route called intracerebroventricular delivery. In two mouse models carrying human DMG tumors, that wiped out the cancer in every animal. Conventional CAR-T cells could not bring the same tumors under control.

Nearly seven weeks later, the team injected a fresh round of DMG cells into treated mice. Every one of those mice rejected the new cancer cells, and the engineered cells were still working more than 70 days after treatment. “They are still patrolling for cancer over 70 days out,” Lakshmanachetty said.

Why it matters, and what is still unknown

Why the brain switch helps is not settled. The researchers suspect it has to do with T cell exhaustion, the loss of killing power that sets in when immune cells stay switched on for long stretches. Holding off CAR production until the cells reach the brain may keep them fresher for the tumor.

These are animal results. Mouse tumors are implanted human cells in an animal immune system, and therapies that clear them often fall short in patients. The study reports no measure of how B-SYNC behaves in a human brain, and no safety record in children. The paper carries the DOI 10.1126/scitranslmed.aed9994.

What happens next

UCSF says it is preparing clinical trials at UCSF Health that could start as early as April 2027. The first will be led by UCSF physicians Marie Jaeger-Krause and Sabine Mueller, and will test combinations of intravenous delivery and delivery into the brain. Each patient’s own T cells would be modified into B-SYNC cells.

For the brain route, surgeons would implant a shunt running from the ventricles to a reservoir under the scalp, so repeat doses can be given without new surgery. “This preclinical data is very promising,” said Mueller, director of the UCSF Pediatric Brain Tumor Center.

Source: ScienceDaily