In a groundbreaking development, a chimeric antigen receptor T-cell (CAR-T) therapy for recurrent glioblastoma, developed by Mustang Bio and City of Hope, has shown promising results in a phase 1 clinical trial. The trial, which is the largest reported so far on a CAR-T therapy in glioblastoma, demonstrated stable disease or better in half of the subjects, including one patient who has remained cancer-free for over five years.

Published on March 7 in Nature Medicine, the study not only highlights the potential of CAR-T therapy injected directly into a brain tumor and the cerebrospinal fluid but also challenges the existing treatment paradigm of glioblastoma. Dr. Christine Brown, the deputy director of the T Cell Therapeutics Research Laboratories at City of Hope and creator of the therapy, believes that these findings are reshaping the field and have the potential to revolutionize how brain tumors are treated.

Glioblastoma, the most common and aggressive primary brain tumor, has a low median survival rate without treatment, which increases slightly with therapy but remains challenging due to tumor regrowth resistance. In the phase 1 study, all 58 patients enrolled had experienced at least one recurrence of the disease and had exhausted other treatment options.

Each participant received weekly doses of CAR-T cells targeting the interleukin-13 receptor alpha 2 (IL13Rα2), a well-established glioblastoma target that has undergone preclinical and clinical exploration for CAR-T therapy. The trial administered increasingly higher CAR-T cell doses through various methods, including direct tumor injections, infusion into the cerebrospinal fluid, or a combination of both.

Notably, the study observed no neurotoxicity in any of the patients, despite initial concerns about the safety of injecting CAR-T cells directly into the brain. Side effects were limited to headaches and fevers for a few days following the treatment. The researchers attribute the absence of adverse effects to the specific expression of the IL13Rα2 receptor on the tumor cells and certain populations of inflammatory cells, distinguishing it from other CAR-T therapies that may impact healthy brain tissue.

The trial's overall median survival duration was eight months, with 29 patients experiencing stable disease for at least two months post-treatment. Notably, patients who received CAR-T cells both in the tumors and the cerebrospinal fluid showed a median survival of 10.2 months, surpassing the usual six-month rate for recurrent glioblastoma patients.

Mustang Bio has obtained the licensing rights for the CAR-T therapy developed by City of Hope, and further optimization of the manufacturing process has been implemented to enhance its effectiveness. The research team plans to investigate why some patients responded better to treatment, focusing on the interaction between host immunity and CAR-T cell therapy.

The study also sets the stage for future trials, including the development of bispecific CARs targeting multiple antigens and the exploration of combinations of different CARs in a single treatment approach. By leveraging these innovative techniques, the team aims to make a significant impact on the treatment of glioblastoma and improve the outcomes for patients.

While much remains to be explored, the success of this phase 1 clinical trial provides a glimmer of hope for patients combating recurrent glioblastoma. The potential of CAR-T therapy in directly targeting brain tumors opens new avenues for treatment and offers a potential shift in the current treatment landscape for glioblastoma.