Scientists at UC San Francisco have built immune cells that stay switched off as they travel through the body and turn on only once they reach the brain. In mice, these cells cleared diffuse midline glioma, often shortened to DMG, a childhood brain cancer that grows into healthy tissue1. The work appeared in the journal Science Translational Medicine on October 281. The team is now preparing the therapy, called B-SYNC CAR-T, for a first trial in patients at UCSF Health that may begin as early as April 20271.
The results come from mice only. No child has received the treatment, and one report on the study noted that the team’s hopes rest on lab results, since human trials have not begun2.
What happened
CAR-T cell therapies are made from immune cells called T cells. In the lab, the cells are given a new receptor, called a CAR, that senses proteins on tumor cells and prompts the T cells to attack1. These therapies have so far failed against brain cancer1.
The UCSF version adds a safety catch. A sensor called synNotch sits on the cell and waits for a protein called brevican, which is found throughout the brain. Only when the sensor detects brevican does the cell start making its attack receptor1. Once switched on, the cells search the brain for tumor cells carrying either of two proteins, EphA2 or IL13Rα21.
Hideho Okada, a professor of neurological surgery at UCSF and a senior author of the paper, described the goal this way:
“It’s been a struggle to make CAR-T cells that overcome DMG without causing unacceptable side effects. By limiting B-SYNC’s CAR expression to when and where it matters—in the brain—we saw consistent, total shutdown of DMG tumors in the lab.”
That quote comes from the university’s announcement1.
The evidence so far
Postdoctoral researcher Senthilnath Lakshmanachetty, in Okada’s lab, ran the experiments in mice that had been implanted with human DMG cells1. The team reported three main findings.
- Given into a vein: some of the engineered cells crossed into the brain, made the attack receptor and went after the cancer. Cells found outside the brain, including in the blood and spleen, did not make the receptor, “just as we designed it,” Lakshmanachetty said1.
- Injected directly into the brain: using an injection into the fluid-filled spaces of the brain, the treatment cleared tumors in every mouse tested in two human DMG models. Standard CAR-T cells failed to control the cancer1.
- Lasting protection: nearly seven weeks later, the researchers gave already-treated mice a second dose of tumor cells. Every mouse that had received B-SYNC rejected the new tumors1.
“We didn’t expect B-SYNC CAR-T cells to necessarily persist,” Lakshmanachetty said. “But they are still patrolling for cancer over 70 days out—and they’re still very functional.”1
The researchers say they are not sure why the brain-only cells did better than standard ones. They suspect that keeping the cells switched off until they reach the brain may stop them from becoming “exhausted,” or worn out, before they reach the cancer. That could explain why other CAR-T therapies have failed1. This is an idea the team offered, not something the study proved.
What it does not show yet
Mice carrying human tumor cells are a standard early test, but they are not children. The study cannot show whether the cells will be safe in people, whether they will clear tumors in patients, or how long any benefit might last. The published accounts do not give the number of mice per group12.
The main safety claim is that the cells did not make their attack receptor outside the brain1. One report described this as the central safety feature of the design, because the cells do not build their tumor-killing machinery while they circulate in the rest of the body2. Even so, whether brain-only activation avoids harmful side effects in people can only be learned in a trial. The cells switch on in response to a protein found throughout the brain, not only in tumors. The available accounts do not describe whether the switched-on cells harmed healthy brain tissue in the mice12.
Who is behind it
B-SYNC is the latest version of an approach developed by Okada and Wendell Lim, a professor of cellular and molecular pharmacology at UCSF1. In 2021 the pair announced lab results for an earlier version, E-SYNC, built for glioblastoma, a different brain cancer1. E-SYNC switched on after detecting EGFRvIII, a mutant protein found on some glioblastomas. But only about 20% of patients have tumors with that protein, and tumors can lose it as the treatment kills the cells that carry it1. The team switched to brevican to find a steadier signal that would work in more patients1. Because glioblastoma and DMG share the target proteins EphA2 and IL13Rα2 on many of their tumor cells, the approach also seemed suited to DMG1.
The planned first trial will be led by UCSF doctors Marie Jaeger-Krause and Sabine Mueller1. Mueller already leads other UCSF trials in brain tumors of young people3. The sources available to Biohack do not describe who funded the mouse study or whether any company holds rights to the therapy.
How it fits the field
DMG is very hard to treat because it grows into the brainstem, the part of the brain that controls breathing, heartbeat and swallowing. Children almost always die within a year of diagnosis1. A research foundation focused on the disease describes DMG, including the form called DIPG, as universally fatal, with median survival of just 11 months4.
Other cell therapies are already being tested in children. According to the same foundation, early results from a trial of CAR-T cells aimed at a protein called GD2 showed improvements in symptoms and on scans, including one long-term survivor. But responses varied and most patients still relapsed4. Researchers point to the tumor’s surroundings as one reason: the tissue around DMG suppresses the immune system and contains few of the immune cells that normally fight disease4. A Stanford project funded by the foundation is now studying why tumors grow back after GD2 CAR-T treatment4.
The UCSF approach takes a different route. Instead of finding a new tumor target, it changes when and where the cells switch on. One report described it as a redesign built on the idea that the timing and location of activation may matter as much as the target itself2.
What to watch next
The team plans a trial in which each patient’s own T cells are turned into B-SYNC cells1. The first trial will test both delivery into a vein and delivery into the brain, in different combinations1. For brain delivery, doctors will implant a small tube, called a shunt, that links the brain’s fluid-filled spaces to a reservoir under the scalp, so patients can receive several rounds of treatment1.
Key questions for that trial include whether the brain-only switch holds up in people, what side effects appear, and whether the tumor shrinkage and lasting protection seen in mice carry over to children. The earliest possible start is April 20271.
