CAR-T cells directly administered to the brain demonstrate safety in a phase 1 clinical trial for recurrent glioblastoma
Background
Addressing the challenges of treating brain tumors due to the blood-brain barrier Glioblastoma is the most common and aggressive type of brain cancer. Despite surgery, radiation therapy, and chemotherapy, the 5-year survival rate remains below 5%. This is largely due to the blood-brain barrier (BBB), which prevents drugs from reaching the tumor. Furthermore, the tumor's genetic heterogeneity and the immunosuppressive microenvironment surrounding the tumor hinder immune cell attacks.
Emerging new target proteins for brain tumor treatment The reason why chimeric antigen receptor T-cell (CAR-T) therapy, which has been successful in treating blood cancers, has not been effective in glioblastoma is due to the BBB. Systemically administered CAR-T cells cannot cross the BBB, and increasing the dose only increases the risk of systemic side effects. Researchers have identified the B7-H3 immune checkpoint protein, which is commonly found on glioblastoma cells, as a new target. This protein is expressed at very low levels in normal brain tissue, making it a suitable therapeutic target.
Key Findings
Bypassing the barrier through direct injection into the ventricles The researchers conducted a phase 1 dose-escalation study in patients with recurrent glioblastoma, directly injecting B7-H3 CAR-T cells into the brain. By administering the drug into the ventricles, where the patient's cerebrospinal fluid circulates, they designed a route that bypasses the BBB. The analysis revealed that no serious adverse events or dose-limiting toxicity (DLT) signals were observed in association with the treatment.
Minimizing side effects and observing tumor suppression Only mild cytokine release syndrome (CRS) and transient headaches occurred, and no severe immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. In the process of verifying safety, some patients showed significant tumor shrinkage, indicating promising therapeutic responses. This study clinically demonstrated that directly delivering therapeutic cells to the tumor site inhibits systemic toxicity while increasing the rate of cancer cell death. Patients maintained a stable condition for an average of several months.
Significance and Prospects
A milestone in overcoming the barriers to treating solid tumors This study provides a key to overcoming the chronic challenges of drug delivery limitations and immune suppression in solid tumor treatment. It demonstrates a new direction for solid tumor treatment by changing the route of drug delivery to directly reach the brain. In addition to demonstrating safety, further clinical trials with more patients are needed to determine the long-term survival benefits.
The need for multi-target and combination therapies Considering the severe genetic heterogeneity of glioblastoma, targeting only the B7-H3 protein may not completely prevent cancer cells from escaping. The scientific community is exploring solutions in the development of multi-target CAR-T therapies that target two or more antigens simultaneously, or in combination therapies with immune checkpoint inhibitors. Another challenge is to develop technologies that maintain the long-term killing activity of CAR-T cells by removing immunosuppressive substances in the tumor microenvironment. Subsequent discussions for phase 2 clinical trials are expected to accelerate.
Nature Medicine, Published online: 06 August 2026; doi:10.1038/s41591-026-04557-6In this phase 1 dose-escalation trial, intracranial delivery of B7-H3-targeting chimeric antigen receptor T cell therapy in patients with glioblastoma showed no dose-limiting toxicity signals and encouraging signals of clinical benefit.
In clinical practice, this technology is expected to be a cornerstone in establishing a personalized precision treatment model for patients with recurrent glioblastoma. A scenario in which a small drug delivery device, called an Ommaya reservoir, is implanted in the patient's head, and CAR-T cells are regularly injected into the ventricles as an outpatient treatment, may become a reality. Unlike systemic intravenous administration, this approach offers the advantage of maintaining a high therapeutic concentration with only a small amount of cells injected into the target site. It is also expected to provide economic benefits by reducing the large-scale manufacturing costs and production burden associated with mass-producing patient-specific cells. The frequency of unnecessary hospitalizations, where patients have to be isolated in the intensive care unit and receive intensive care due to severe systemic side effects, will also be reduced. This is likely to lead to significant improvements in the quality of life for both patients and their families by shortening the hospital stay and reducing the financial burden of medical expenses.