Cancer-killing T cells have been programmed to have two levels of specificity. First, the T cells have been equipped with a receptor sensitive to a protein that is found only in central nervous system (CNS) tissue. Second, once the receptor is engaged, the T cells locally induce a set of genetically encoded payloads directed toward different CNS diseases.
In mouse studies, the programmed T cells attacked glioblastoma and treated the inflammation of multiple sclerosis. These findings were reported by the UCSF scientists who developed the technology behind the programmed T cells. According to these scientists—who were led by Scott S. Zamvil, MD, PhD, Hideho Okada, MD, PhD, and Wendell A. Lim—the technology will soon be tested in a clinical trial for people with glioblastoma.
Detailed results from the mouse studies recently appeared in Science, in an article titled, “Programming tissue-sensing T cells that deliver therapies to the brain.”
“To engineer cells that can specifically target the CNS, we identified extracellular CNS-specific antigens, including components of the CNS extracellular matrix and surface molecules expressed on neurons or glial cells,” the article’s authors wrote. “Synthetic Notch receptors engineered to detect these antigens were used to program T cells to induce the expression of diverse payloads only in the brain.”
“CNS-targeted T cells that induced chimeric antigen receptor expression efficiently cleared primary and secondary brain tumors without harming cross-reactive cells outside of the brain,” the authors continued. “Conversely, CNS-targeted cells that locally delivered the immunosuppressive cytokine interleukin-10 ameliorated symptoms in a mouse model of neuroinflammation.”
In this work, the UCSF team enhanced the homing ability of T cells so that they could be more effectively deployed for therapeutic purposes, particularly for brain cancer, which is among the hardest cancers to treat. Surgery and chemotherapy are risky, and drugs can’t always get into the brain.
“Living cells, especially immune cells, are adapted to move around the body, sense where they are, and find their targets,” said Lim, a professor of cellular and molecular pharmacology at UCSF.
Essentially, the UCSF team developed a “molecular GPS” that gave T cells a “zip code” for the brain and a “street address” for the tumor. They found the ideal molecular zip code in a protein called brevican, which helps to form the jelly-like structure of the brain, and only appears there. For the street address, they used two proteins that are found in most brain cancers.
The scientists programmed the immune cells to attack only if they first detected brevican and then detected one or the other of the brain cancer proteins.
Once in the bloodstream, they easily navigated themselves to the mouse’s brain and eliminated a growing tumor. Immune cells that remained in the bloodstream stayed dormant. This prevented tissues elsewhere in the body that happened to have the same protein “address” from being attacked.
One hundred days later, the scientists introduced new tumor cells into the brain, and enough immune cells were left to find and kill them, a good indication that they may be able to prevent any remaining cancer cells from growing back.
“The brain-primed CAR T cells were very, very effective at clearing glioblastoma in our mouse models, the most effective intervention we’ve seen yet in the lab,” said Simic, the Valhalla Foundation Cell Design Fellow. “It shows just how well the GPS ensured that they would only work in the brain. The same strategy even worked to clear brain metastases of breast cancer.”
In another experiment, the researchers used the brain GPS system to engineer cells that deliver anti-inflammatory molecules to the brain in a mouse model of multiple sclerosis. The engineered cells reached their target, and the inflammation faded.
The scientists hope this approach will soon be ready for patients with other debilitating nervous system diseases.
“Glioblastoma is one of the deadliest cancers, and this approach is poised to give patients a fighting chance,” said Okada, a UCSF oncologist. “Between cancer, brain metastases, immune disease, and neurodegeneration, millions of patients could someday benefit from targeted brain therapies like the one we’ve developed.”
