IL-13Rα2-Targeting CAR T-Cell Therapy Improves Brain Cancer
Researchers were able to deliver the CAR-T cells directly into the tumor site and the cerebrospinal fluid
LOS ANGELES, CA — A pioneering Phase 1 CAR-T-cell therapy trial for treating glioblastoma at the City of Hope demonstrates promising clinical activity against incurable brain tumors, according to research published recently 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 (IL-13Rα2).
One of the main challenges in treating brain cancer is that medications have difficulty crossing the blood–brain barrier. To overcome it, the trial delivered CAR-T cells directly into the brain tumor and the cerebrospinal fluid (CSF).
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. The case was reported in The New England Journal of Medicine in 2016.
“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, PhD, The Heritage Provider Network Professor in immunotherapy and deputy director of the T Cell Therapeutics Research Laboratories at the City of Hope. “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.”
Response to IL-13Rα2-targeted CAR-T-cell therapy
Participants—all of whom had relapsed after prior treatment for GBM with surgery, chemotherapy, radiation, or all of these therapies—received intracranial injections of CAR-T cells that target IL-13Rα2, 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 CSF, 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 CSF. 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, MD, The 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.”
Delivering therapy and sampling the environment
In addition to evaluating the safety and feasibility of IL13Rα2 CAR T cells delivered locally for this trial, Brown, Badie, and the team also wanted to learn more about which patients might respond best to the therapy. By sampling tumors and CSF at the delivery sites, they found certain markers that were positively associated with survival and CAR-T cell administration and bioactivity, respectively.
“The idea that you can deliver a therapy and sample the environment at the same time to analyze changes in the brain is very unique and could have a huge impact on the field,” said Badie. “I think people will be adopting these technologies that can help us recognize potential mechanisms of resistance to or failure of therapy.”
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. “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 cancer patients around the world,” said Badie.
- This press release was originally published on the City of Hope website