Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy

- Written by Ramya Ramaswami, M.B.B.S., M.R.C.P., M.P.H.

In the current era of cancer immunotherapy and with new insights into rare and aggressive cancers, patients with glioblastoma have new treatment options.  Glioblastoma is a lethal primary brain tumor as fewer than 10% of patients achieve 5-year overall survival. Treatment of glioblastoma involves multimodal treatment strategies (e.g., surgery, radiotherapy, and chemotherapy) that provide marginal benefit. Treatment failure is attributed to therapy-resistant invasive malignant cells.

Chimeric antigen receptor (CAR) T cells have been engineered to recognize distinct surface antigens for elimination, but can also be designed to address T-cell persistence, proliferation, and survival. This technology uses a patient’s own cells to direct treatment against cancer cells, thereby reducing the risk of graft-versus-host disease. CAR T cells directed at CD19, a B-lineage specific transmembrane glycoprotein expressed in more than 95% of B-cell malignancies, have been associated with clinical response in some patients. In a previously published report in NEJM, a heavily pretreated patient with chronic lymphocytic leukemia achieved a complete response following treatment with anti-CD19 CAR T-cell therapy. These cells and their effects persisted for 8 months after treatment. Despite promising results in hematological malignancies, similar effects have not been seen in solid tumors, possibly due to the heterogeneity in antigen expression in solid tumors.  One viable target is a receptor known as IL-13 receptor α2 (IL-13Rα2) that is overexpressed in over 50% of glioblastoma and is associated with poor survival.

In this week’s NEJM, Brown and colleagues report on the use of CAR T-cell infusions in a 50-year-old patient with recurrent multifocal glioblastoma. In a previous study, the authors saw transient responses to intracranial administration of CAR T cells targeting IL-13Rα2 in patients with glioblastoma. Therefore, in the current case, CAR-T cells against IL-13Rα2 included costimulation with a CD137 domain and the addition of a mutated IgG4-Fc (IL13BBζ-CAR T) linker, with the aim of improving antitumor potency and inducing T-cell persistence.

The patient initially presented with glioblastoma of the right temporal lobe with unfavorable features and was treated with surgical resection, radiation, and temozolamide. Six months later, he developed leptomeningeal disease and five new lesions. After the recurrence, the patient was enrolled in the clinical trial. Three of the five lesions were resected and IL13BBζ-CAR T-cell infusions were administered into the resected cavity of the tumor. Interval imaging after six infusions demonstrated stable tumor appearances at this site. However, there were new lesions near the previously resected area and in the spine causing leg weakness. A second catheter device was placed in the right lateral ventricle to improve delivery of IL13BBζ-CAR T cells to the cerebrospinal fluid, and another 10 infusions (every 1 to 3 weeks) were administered.

Following the first three intraventricular infusions, there was a dramatic response in all intracranial and spinal tumors and by the fifth intraventricular infusion, all tumors had decreased by 77% to 100%. The patient also reported symptomatic benefit for more than 5 months; he was able to wean off steroids, return to normal life, and assume his work activities. He experienced mild adverse events (headaches, fatigue, and myalgia) associated with the intraventricular infusion.

Cerebrospinal fluid analysis 1 to 2 days after intraventricular administration of IL13BBζ-CAR T cells demonstrated persistence of the T cells for up to 7 days after each infusion. An increase in inflammatory cytokines was also detected, suggesting stimulation of the host system. The report ends on a somber note, indicating that the patient presented with recurrence after 16 cycles of IL13BBζ-CAR T-cell therapy. The authors suggest that these recurrent cells may have decreased expression of IL-13Rα2.

Cases such as this provide insights into the safety, efficacy, and mechanism of new therapies. Trials of CD19 CAR T cells have been intermittently halted due to safety concerns and reported adverse effects.  We must proceed with caution to determine whether the benefits seen in this case apply to other patients.