Scientists at UC San Francisco have engineered CAR-T cells that stay dormant until they reach the brain, where they switch on and destroy tumor cells.
In mice, these CAR-T cells were able to clear diffuse midline glioma (DMG), a lethal form of childhood brain cancer that integrates into healthy tissue.
The cells also had staying power. When scientists introduced another round of cancer several weeks later, the cells were still able to fight.
DMG is exceptionally hard to treat because it infiltrates the brainstem, which controls essential functions like breathing, heartbeat, and swallowing. Children almost always die within a year of diagnosis.
The new therapy, however, has the potential to succeed where standard CAR-T cell therapy failed.
Scientists aren't sure why, but they suspect that focusing the CAR-Ts on the brain somehow made them more potent.
Thanks to strong results in the laboratory, the team is now preparing the therapy, called B-SYNC CAR-T, for clinical trials at UCSF Health that may begin as early as April 2027.
"It's been a struggle to make CAR-T cells that overcome DMG without causing unacceptable side-effects," said Hideho Okada , MD, PhD, a professor of Neurological Surgery at UCSF and co-corresponding author of the paper, which appeared in Science Translational Medicine on Oct. 28. "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."
A better CAR T for DMG
B-SYNC is the latest iteration of a CAR-T cell approach developed by Okada and his colleague Wendell Lim , PhD, professor of Cellular and Molecular Pharmacology at UCSF.
CAR-T cell therapies are made of immune T cells engineered to have receptors, or CARs, that sense proteins on tumor cells and prompt the T cells to attack. So far, though, they've failed to overcome brain cancer.
In 2021, Okada and Lim announced promising laboratory results for E-SYNC, a CAR-T cell therapy they developed for a different brain cancer called glioblastoma. E-SYNC uses a cellular sensor called synNotch to detect EGFRvIII, a mutant protein found on some glioblastomas. The synNotch spurs the production of a CAR that target EphA2 and IL13Rα2, proteins that dot many tumor cells. The two-step approach was better than one-step CAR T.
But only about 20% of patients have tumors with EGFRvIII. And even among those patients, the tumors can lose EGFRvIII as E-SYNC eliminates the cells that carry it. So, the researchers next looked for a more stable signal that would work in more patients.
The team settled on brevican, a protein found throughout the brain. They engineered synNotch to activate the CAR only in response to brevican. These "B-SYNC" CAR- T cells then roamed the brain looking for cells that carried EphA2 or IL13Rα2, even if they did not have EGFRviii.
The approach, designed for glioblastoma, also seemed well suited to DMG, since the two brain cancers shared EphA2 and IL13Rα2on many of their tumor cells. Postdoctoral researcher Senthilnath Lakshmanachetty , PhD, in Okada's lab, put the idea to the test.
B-SYNC clears DMG — and persists
Lakshmanachetty gave B-SYNC CAR- T cells intravenously (IV) to mice that had been implanted with human DMG cells. Some of the B-SYNC cells crossed into the brain, where they made the CAR and attacked the cancer.
The experiment showed that the therapeutic activity was restricted to the brain. B-SYNC cells found outside the brain, including in the blood and spleen, did not express the CAR, "just as we designed it," Lakshmanachetty said.
The team then tried injecting B-SYNC directly into the brain with an intracerebroventricular (ICV) injection. The treatment cleared tumors in every mouse tested in two human DMG models, while conventional CAR-T cells again failed to control the cancer.
The researchers finally tested whether B-SYNC could provide long-lasting protection from cancer. Nearly seven weeks later, the team gave already-treated mice a second round of DMG cells. Every mouse that had received B-SYNC rejected the new tumors.
The scientists said that controlling where the B-SYNC T cells become active may prevent them from becoming "exhausted" before they've reached the cancer. It could explain why other CAR-T cell therapies have failed.
"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."
Ready for impact
In partnership with UCSF oncologists, Okada, Lim, and Lakshmanachetty are preparing for clinical trials in which each patient's T-cells are transformed into the B-SYNC CAR-T cell therapy. It's a rapid turnaround for such a recent laboratory advance.
The first trial, which will be led by UCSF's Marie Jaeger-Krause , MD, and Sabine Mueller , MD, PhD, will test both ICV and IV delivery of the therapy in different combinations. For ICV, a shunt will be implanted to connect the brain ventricles with a reservoir on the scalp, enabling multiple rounds of therapy.
"Diffuse midline glioma is a heartbreaking diagnosis for patients and their families," said Mueller, director of the UCSF Pediatric Brain Tumor Center, UCSF professor of Neurology, Neurosurgery, and Pediatrics, and co-founder of the Pediatric Neuro-Oncology Consortium (PNOC). "This preclinical data is very promising. Mice with DMG are being cured, and we are incredibly excited to bring this therapy to the children and young adults we care for. This is exactly the kind of innovative approach they deserve."
Authors: Other UCSF authors are Milos S. Simic, PhD, MS; Payal B. Watchmaker, PhD; Robert Zhu; Takahide Nejo, MD, PhD; Maggie Colton Cove; Jeffrey Haegelin; Haoyu Long; Aishi Zhao; Alejandra Bergquist; Wei Yu, PhD; Brianna Wong; Marco Gallus, MD, MS; Ricardo Almeida, PhD; and Joanna P. Phillips, MD, PhD.
Funding: This work was supported by the National Institutes of Health (R35NS142982, P50CA097257, P30CA082103); ARPA-H (D24AC00084-00); Botha-Chan Project Fund; Valhalla Foundation; UCSF Cell Design Institute; and the German Research Foundation.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health , which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at ucsf.edu or see our Fact Sheet .
