RARE Daily

CAR T Cell Therapy Shows Clinical Activity in Patients with Aggressive Brain Tumors in Phase 1 Trial

March 7, 2024

Rare Daily Staff

A pioneering phase 1 CAR T cell therapy trial for the treatment of glioblastoma at City of Hope demonstrated promising clinical activity against incurable brain tumors, according to research published today in Nature Medicine.

The study, which is the largest reported trial to date of CAR T therapy for solid tumors, evaluated CAR T cells engineered to target the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2), a product invented at City of Hope, one of the largest cancer treatment and research centers, and exclusively licensed by Mustang Bio.

One of the main challenges for treating brain cancer is that medications have difficulty crossing the blood-brain barrier. To overcome that barrier, the trial delivered CAR T cells directly into the brain tumor and the cerebrospinal fluid, the fluid that protects and surrounds the brain and spinal cord.

Some 29 of the 58 patients with recurrent high-grade glioma brain tumors, mostly glioblastoma, achieved stable disease after treatment with CAR T cells for at least two months. There were two partial responses, one complete response and a second complete response after additional CAR T cell therapy cycles were delivered under compassionate use.

“Glioblastomas are extremely aggressive tumors that leave patients with very limited treatment options, especially after they have relapsed, but this study shows the potential of CAR T cell therapy in treating brain cancer,” said Christine Brown, professor in immunotherapy and deputy director of the T Cell Therapeutics Research Laboratories at City of Hope, who developed IL13Rα2-targeting CAR T cell therapy. “This study is also the most extensive evaluation of delivering CAR T cells directly to a brain tumor, which we pioneered at City of Hope, and sets the foundation for other studies to utilize this approach.”

Participants, all of whom had relapsed after prior treatment for GBM with surgery, chemotherapy, or radiation, or all of these therapies, received intracranial injections of CAR T cells that target IL13Rα2, which is overexpressed in most glioblastomas.

Doses of the therapy were escalated as the trial progressed and all doses tested were well-tolerated. Three routes of administration were evaluated: direct injection to the tumor site, infusion into the cerebrospinal fluid, or injection into both areas.

The median overall survival for all patients was eight months. The trial culminated in treating a patient cohort that used an optimized manufacturing process and injected CAR T cells at both the tumor site and into the cerebrospinal fluid. For this final patient cohort, researchers were able to establish a maximal feasible dose and found that these patients had the best median overall survival of 10.2 months, which was higher than the expected survival rate of six months in patients with recurrent glioblastoma.

“These were heavily pretreated patients so we were not sure how they would do with CAR T cell therapy,” said Behnam Badie, Heritage Provider Network professor in gene therapy, chief of neurosurgery at City of Hope and the study’s senior author. “But some of them even did better than how they initially responded to standard of care treatments.”

Next, the team says that future randomized studies in larger patient cohorts will be needed to confirm and expand their findings related to the critical parameters for successful CAR T therapy.

Brown says they are also excited to start a trial to engineer CAR T cells to be resistant to transforming growth factor-beta, a dominant tumor suppressor, as well as a study to combine different CARs that can target multiple antigens and build new bispecific CARs that could engage two disease targets instead of just one.

“Between the positive outcomes we saw in our phase 1 study and the new avenues we are exploring, we hope our work can have a dramatic impact on the field of immunotherapy and the lives of cancers patients around the world,” she said.

Photo: Christine Brown, professor in immunotherapy and deputy director of the T Cell Therapeutics Research Laboratories at City of Hope

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