LOS ANGELES—Researchers at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute recently developed a tool to track and kill malignant brain tumor cells—gliomas specifically—and provide long-term protection against their return.
The study reportedly provides the first documented evidence that marrow-derived stem cells possess the same tumor-tracking capability of other neural stem cells, says Dr. Keith L. Black, director of the Maxine Dunitz Neurosurgical Institute, director of Cedars-Sinai's Division of Neurosurgery, and co-director of the Comprehensive Brain Tumor Program. It also includes the first report on the use of the cytokine interleukin-23 as a potential gene-delivered therapy against gliomas.
"Most anti-tumor gene strategies attempt to deliver genes directly to tumor cells, but gliomas are especially challenging because of their highly invasive and migratory characteristics," Black explains. "By combining the tumor-tracking properties of bone marrow-derived neural stem cells with interleukin-23, we are able to initiate a very powerful anti-tumor response that tracks to migrating glioma islands and offers long-term protection—all of which would make this a very attractive therapeutic option."
That attractiveness would extend not only to achieving better patient outcomes but perhaps sharply reducing medical costs related to brain tumors. Gliomas are the most commonly diagnosed of both benign and malignant primary brain tumors, accounting for 45 percent to 50 percent of all primary brain tumors.
As a result of this work and "based on patented technology of generating bone marrow derived neural stem cells and the demonstrated efficacy of generating memory T cells with the intratumoral delivery of interleukin-23, we are planning a spin-off company called Regeneuron," says Dr. John S. Yu, a neurosurgeon and co-director of the Comprehensive Brain Tumor Program at Dunitz Neurosurgical Institute. "We are accruing angel funding and we are developing this company to enable advancement of this technology to take to Phase I trial for patients with glioblastoma within a year."
Researchers at the Institute had already documented several years ago that some neural stem cells have the ability to target and track glioma cells in the brain, even as they migrate. Now, however, the researchers have identified the mechanism that enables certain neural stem cells to develop this tracking ability and have genetically engineered neural stem cells to transport cytokines—proteins that regulate immune responses—to track down and destroy glioma cells.
"We were able to track to the tumor very efficiently and, like a heat-seeking missile, deliver a killer depot," says Yu, the senior author of an article published in Cancer Research on the discovery. "We obtained the stem cells from bone marrow, mirroring what we want to do clinically, which is to take bone marrow cells from a patient, make them into neural stem cells, put in the gene of interest and treat the patient."
Because the stem cells originate in the bone marrow instead of the brain, fetal or embryonic tissue, there is a potentially unlimited supply of cells that are theoretically free of ethical and tissue-rejection issues, Cedars-Sinai reports.
In the Cedars-Sinai animal studies, bone marrow-derived neural stem-like cells (BM-NSC) genetically engineered to produce interleukin-23 were injected into intracranial gliomas and other areas of the brain. Treated animals survived significantly longer than those in control groups, with 60 percent surviving tumor-free beyond day 120. Only 20 percent of those treated with interleukin-23 that was not attached to neural stem cells survived, and no animals survived if they received neural stem cells without interleukin-23.
The Cedars-Sinai researchers are now applying to regulatory agencies to translate their work into human clinical trials
