CAR-T Treatment in Glioblastoma: Will the Effect Be Sustained?

A significantly powerful form of immunotherapy, the chimeric antigen receptor (CAR)-T—cell treatment has so far been developed in patients with hematological cancers. However, a new single-patient case study, published in the New England Journal of Medicine, has raised the possibility of using CAR-T cells in the treatment of glioblastoma, an aggressive form of brain tumor.

The treatment was provided at City of Hope to a 50-year-old man who presented with glioblastoma in the right temporal lobe. Following standard treatment of tumor resection, radiation, and temozolomide, the patient relapsed. At that point, the patient was enrolled in a study evaluating the safety and efficacy of IL13Rα2-targeted CAR-T cells. IL13Rα2 is a glioma-associated antigen linked to a reduced rate of survival. The authors wrote that based on their previous study, they improved the antitumor potency and T cell persistence of the IL13Rα2-targeted CAR-T cells by including a 4-1BB (CD137) costimulation domain and a mutated IgG4-Fc linker.

By the time the patient was administered the IL13BBζ—CAR-T cells, the tumor had progressed to a multifocal leptomeningeal glioblastoma in both cerebral hemispheres. The patient underwent surgical resection of 3 of the 5 developing tumors. An initial single infusion of 2×10⁶ IL13BBζ—CAR-T cells was followed by 5 infusions of 10×10⁶ cells, along with 6 weekly intracavitary infusions of IL13BBζ—CAR-T cells in the resected cavity of tumor 1. Safety and tumor response were assessed after the third and sixth infusions.

The authors report that while the tumor that received local treatment remained stable for 45 days after surgery, the remaining 4 tumors (2 resected and 2 non-resected) continued to progress. Additionally, 2 new lesions developed near the previously resected tumors. The patient also had metastasis to the spine.

Since the infusions could successfully prevent local tumor recurrence, without any effect on tumor development or progression at distant sites, the patient was administered 10 intraventricular infusions of IL13BBζ—CAR-T cells without any other treatment. Following the first 3 infusions (day 133), a significant reduction in the size of all intracranial and spinal tumors was observed. By the 5th infusion (day 190) all tumors had shrunk by 77% to 100%. Following the last 5 intraventricular infusions, the tumors remained undetectable by positron emission tomography and could not be measured by magnetic resonance imaging. While the response was sustained for 7.5 months following the first CAR-T treatment, tumors developed at 4 new locations. Preliminary evidence suggests a decrease in expression of the IL13Rα2 receptor as a cause of the recurrence.

In terms of safety, no grade 3 or higher toxicity was observed during the study period, but grade 1 or 2 events (such as headaches, generalized fatigue, myalgia, and olfactory auras) were noted within 72 hours following the T-cell infusions.

Reacting to these results, Jae Park, MD, a hematologist-oncologist who specializes in CAR-T therapy at Memorial Sloan Kettering Cancer Center told STAT news, “I can’t say this paper’s solved the problem of solid tumors, or this is the way to treat them. But it’s the first trial to show an objective response in glioblastoma, and suggests this is one way to get around the limitations of CAR T.”

Reference

Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016 Dec 29;375(26):2561-9. doi: 10.1056/NEJMoa1610497.