first-in-human clinical trial for patients with recurrent glioblastoma. The trial is the first to combine City of Hope’s chimeric antigen receptor (CAR) T cells that target the IL13Rα2 antigen common on brain tumor cells in combination with nivolumab (commercial name: Opdivo), an anti-PD1 antibody, and ipilimumab (commercial name: Yervoy), also a checkpoint inhibitor that blocks the CTLA-4 protein.
To launch the randomized trial, the National Institutes of Health awarded $3.3 million over five years to Behnam Badie, M.D., The Heritage Provider Network Professor in Gene Therapy and chief of City of Hope’s Division of Neurosurgery, and Christine Brown, Ph.D., The Heritage Provider Network Professor in Immunotherapy and deputy director of City of Hope’s T Cell Therapeutics Research Laboratory. Brown and Badie also received $800,000 from Gateway for Cancer Research.
“Our hope is that by combining two powerful immunotherapies — CAR T cell therapy and checkpoint inhibitors — we can find additional treatments for patients with malignant glioma, who currently have few options,” Brown said. “In addition, the trial will allow us to conduct liquid biopsies of the cerebrospinal fluid throughout the treatment time to query the central nervous system, furthering our understanding of how checkpoint inhibitors alter the function and persistence of CAR T cells, as well as how it potentially promotes endogenous immune responses in the brain.”
Direct delivery to tumor site
The trial will deliver CAR T cells that target IL13Rα2 locally to the brain by direct injection to the tumor site and through infusion into the ventricular system. City of Hope was the first to use this type of delivery for glioblastoma patients receiving CAR T treatment, as well as the first to investigate CAR T cells targeting IL13Rα2. A 2016 case study in the New England Journal of Medicine outlined how a City of Hope patient’s brain cancer regressed for 7.5 months after receiving CAR T therapy to effectively attack cells with IL13Rα2.
With product provided by Bristol-Myers Squibb, patients will also receive nivolumab and ipilimumab. Nivolumab is an immune checkpoint inhibitor that can prevent the PD-1 protein from doing its job, which is to suppress the immune system from fighting cancer. By putting PD-1 in check, the body’s immune system can better fight cancerous cells. Ipilimumab blocks the CTLA-4 protein in a similar way.
For the trial, all patients will receive the IL13Rα2 CAR T cells weekly combined with nivolumab every other week. Patients on the experimental arm will additionally receive ipilimumab and nivolumab, each dosed once 14 days prior to the start of combination therapy with CAR T cells plus nivolumab.
The U.S. Food & Drug Administration (FDA) has approved the use of nivolumab for patients with various cancers including metastatic melanoma, nonsmall cell lung cancer, classical Hodgkin’s lymphoma, and head and neck cancer. Clinical trials are underway at City of Hope and other institutions to expand the use of nivolumab for other cancers or for use with other therapies. The FDA has approved the use of ipilimumab for metastatic melanoma or in combination with nivolumab for renal cell carcinoma and colorectal cancer.