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Targeted Immunotherapy Treats Patient's Recurrent Glioblastoma

ARTICLE IN BRIEF

In a proof-of-concept study, researchers reported that a patient with recurrent multifocal glioblastoma of the brain and spine, who received autologous chimeric antigen receptor (CAR)-engineered T-cells targeting a brain tumor-associated antigen, had complete remission of tumors without serious toxicity.

For the first time researchers have safely eliminated recurrent glioblastoma, without significant toxicity, using a patient's own genetically-modified T-cells.

Glioblastoma, a rare but deadly cancer affecting fewer than 200,000 people each year in the United States, has a median survival just over 14 months. Fewer than 3 to 5 percent of patients survive for five years or longer.

In a proof-of-concept case study, published in the December 29 New England Journal of Medicine, investigators at the City of Hope Comprehensive Cancer Center in Duarte, CA, reported that a patient with recurrent multifocal glioblastoma of the brain and spine, who received autologous chimeric antigen receptor (CAR)-engineered T-cells targeting a brain tumor-associated antigen, had complete remission of tumors without serious toxicity.

The 50-year-old patient was enrolled in a phase I clinical trial and had failed to respond to resection, radiation, and the oral chemotherapy drug temozolomide. His T-cells were genetically enhanced in the laboratory to target the tumor-associated interleukin receptor IL13Rα2 antigen, and then grown in quantity before being reinfused into the cavity where the tumor had been excised. IL13Rα2 is over-expressed on the surface of most glioblastoma cells as well on several other types of tumors, but infrequently in healthy human brains.

Although no tumors reappeared at the primary site, several new lesions appeared in the brain and one large tumor in his spinal cord. When secondary tumors appeared in another area well-supplied with blood, they delivered the CAR T-cells by intraventricular infusion.

Reasoning that additional infusions into the ventricular system to cerebrospinal fluid (CSF) would better deliver the cells to these sites, a second catheter device was placed in the right lateral ventricle, allowing for 10 additional treatment cycles at 1- to 3-week intervals.

The regimen for both delivery routes lasted for a total of 220 days, and no high-grade (above grade 3) toxic effects were observed. Treatment resulted in regression of all intracranial and spinal tumors, as well as increases in cytokines and immune cells in the CSF.

Regression of both brain and spinal tumors occurred, as well as increased numbers of immune cells in the CSF. Clinical responsiveness continued for 7.5 months, when the study was submitted, and the patient is still alive, lead researcher Behnam Badie, MD, told Neurology Today.

“This study provides proof-of-principle data that IL13Rα2 is a useful immunotherapeutic target in glioblastoma. It also demonstrates that CAR T-cells can mediate profound antitumor activity against a difficult-to-treat solid tumor,” he said, adding that a second patient is now undergoing similar treatment.

“Other research has demonstrated the effectiveness of CAR T-cells against blood cancers, but this is the first time this has been shown to work in solid tumors,” he told Neurology Today. “I believe the results show we have a potential breakthrough treatment.”

Seven other patients in the trial have received infusions solely in tumor cavity site(s), but based on the positive findings in this single patient the researchers have expanded their study to evaluate intraventricular administration in a larger group of subjects, Dr. Badie said.

He noted that the absence of systemic toxic effects is especially significant given the severe cytokine release syndrome and neurotoxicity often seen in patients with high tumor burden given CD19-targeted CAR T-cell therapy.

CAR T-cell targeted immunotherapy is currently either approved or is being tested in clinical trials against a number of refractory B-cell blood cancers, including leukemia, lymphoma and multiple myeloma.

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DR. BEHNAM BODIE: “This study provides proof-of-principle data that IL13Rα2 is a useful immunotherapeutic target in glioblastoma. It also demonstrates that CAR T-cells can mediate profound antitumor activity against a difficult-to-treat solid tumor.”

Although not yet approved by the U.S. Food and Drug Administration (FDA) for glioblastoma, the agency is expected to approve CARs against CD19-specific cancers as soon as this year. Last July the agency halted a leading phase 2 trial of CD19-specific CAR T-cell therapy against B-cell acute lymphoblastic leukemia after three patients died from brain swelling, which researchers attributed to the addition of a chemotherapy drug shortly before the CAR cells were infused. However, just three days later, the FDA agreed with the scientists and gave the go-ahead to restart the trial.

EXPERTS COMMENT

Intraventricular administration moves CAR T-cell therapy from a local therapy aimed at one or a few tumors to one that can potentially treat tumors throughout the CNS, said neuro-oncologist Nimish A. Mohile, MD, associate professor at the University of Rochester Wilmot Cancer Center.

“Although this was just one subject, the patient had a very poor prognosis – second recurrence, multifocal, unmethylated, IDH1 wildtype, and leptomeningeal involvement,” he told Neurology Today.

“I don't think we have enough data from ongoing immunotherapy trials to make a comparison with other immunotherapies, some of which have shown transient inflammatory issues.”

He noted that toxicity is the major concern with CAR T-cell therapies; however, the approach used by the researchers in the study appears to have a much better safety profile than CAR T-cell therapies in lymphoma.

“Even so, the intracavitary approach is limited because it only provided local control. It is unclear if intraventricular administration would be effective in parenchymal tumors that are not associated with leptomeningeal metastases,” he said.

“If the technique continues to show similar benefits in other patients, it might be beneficial in primary brain tumors with extensive leptomeningeal involvement, if the appropriate antigens can be identified.”

John M. Maris, MD, D'Angio Chair of Neuroblastoma Research at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said: “This is an important single case, proof-of-concept report demonstrating that engineered immune cells from a patient can be trained to attack very resistant brain tumors.”

“It is important because it is one of the first examples of this approach working in solid tumors. Most of the success to date has been in leukemias,” he noted.

“Compared to other therapies, such as checkpoint blockades, this single case shows a more profound response, but this will need to be extended to other such patients. Also, in this patient the disease ultimately recurred. I think the major take-home message is that this type of CAR therapy has now been ‘credentialed,’” Dr. Maris told Neurology Today.

“I have no significant concerns with the approach, but this is a very aggressive disease. It is incumbent on us to understand both the short- and long-term side effects of this therapy if indeed it moves forward.”

The major limitation with the report aside from involving a single patient is tumor heterogeneity, according to Dr. Maris. “Glioblastomas are complex ecosystems, and IL13Ra2 typically is not expressed on every glioblastoma cell. For this type of approach to ultimately have sustained effectiveness, CARs targeting two or three cell surface molecules need to be created.”

Should the technique continue to show similar benefits in other subjects, it might theoretically also work against other brain/CNS tumors as well solid tumors outside the brain, he said, adding that studies in children with glioblastoma and other brain tumors are ongoing and/or in the planning stages.

EXPERTS: ON AN ANTIGEN-TARGETED THERAPY FOR GLIOBLASTOMA

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DR. NIMISH MOHILE noted that toxicity is the major concern with CAR T-cell therapies; however, the approach used by the researchers in the study appears to have a much better safety profile than CAR T-cell therapies in lymphoma. “Even so, the intracavitary approach is limited because it only provided local control. It is unclear if intraventricular administration would be effective in parenchymal tumors that are not associated with leptomeningeal metastases.”

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DR. JOHN M. MARIS: “Compared to other therapies, such as checkpoint blockades, this single case shows a more profound response, but this will need to be extended to other such patients. Also, in this patient the disease ultimately recurred. I think the major take-home message is that this type of CAR therapy has now been ‘credentialed.’”

LINK UP FOR MORE INFORMATION:

•. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-Cell therapy http://www.nejm.org/doi/full/10.1056/NEJMoa1610497. N Engl J Med 2016;375:2561–2569.
•. Brown CE, Badie B, Barish ME, et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma https://www.omicsonline.org/references/bioactivity-and-safety-of-il13r2redirected-chimeric-antigen-receptor-cd8-t-cells-in-patients-with-recurrent-glioblastoma-495400.html. Clin Cancer Res 2015;21: 4062–4072.