Targeting Glioblastoma with CAR T Cells

To date, chimeric antigen receptor (CAR) T-cell therapy's considerable potential has mostly been documented in hematologic malignancies. However, a case report from City of Hope Comprehensive Cancer Center in Duarte, CA, suggests that this immunotherapeutic approach may also be effective against glioblastoma (N Engl J Med 2016;375:2561–9).

The 50-year-old patient had recurrent multifocal leptomeningeal glioblastoma—lesions in both cerebral hemispheres, as well as spinal metastases—which is “exceedingly difficult to treat, with survival being 8 weeks on average,” says Behnam Badie, MD, chief of neurosurgery and the study's co–senior author. Badie and his team resected several of the patient's brain tumors before giving him multiple infusions of CAR T cells engineered to target IL13Rα2, which is frequently overexpressed in glioblastoma.

“In a previous trial, we generated IL13Rα2-targeting CARs on cytotoxic CD8+ T cells, but the antitumor efficacy achieved wasn't long-lasting,” says first author Christine Brown, PhD. “This time, we used central memory T cells and optimized our CAR design along with the manufacturing process. Preclinical studies indicated that these improvements resulted in more potent, persistent therapeutic cells.”

Rather than the standard route of intravenous infusion, the researchers used a catheter device to deliver the patient's CAR T cells directly into his largest resected tumor cavity. After six treatment cycles, however, they observed that although there were no signs of local recurrence, his nonresected tumors were progressing, and additional lesions had developed, including new spinal metastases that caused leg numbness.

As such, the delivery route was tweaked: CAR T cells were injected directly into the patient's cerebrospinal fluid instead. “We hypothesized that the fluid would carry the cells to different regions of the brain, improving control of tumor growth at distant sites,” Badie explains. Even so, the team was surprised to see complete elimination of the patient's brain and spinal tumors. His robust response lasted 7.5 months, during which he returned to his normal activities.

Notably, the side effects were mild—low-grade headaches, fever, and fatigue—and cytokine release syndrome, which is potentially deadly, did not occur. Although the patient's disease eventually recurred, the tumors were found in new locations, not at or near the initial sites. Preliminary research suggests the development of resistance through decreased IL13Rα2 expression on the tumor cells, Badie says.

To Michael Lim, MD, director of the Johns Hopkins Brain Tumor Immunotherapy program in Baltimore, MD, “the fact that this patient had a 7.5-month response is pretty impressive,” given the nature of his cancer. He is encouraged by the unconventional delivery method, noting that “this is such a difficult disease to tackle, it's great to see people thinking out of the box.”

Overall, “we should be cautiously optimistic that CAR T-cell therapy will have a role in glioblastoma,” Lim says, “but it's just one modality. Sustained antitumor responses will require incorporating multiple components of the immune system.”

Badie agrees; he and his team would like to evaluate their therapy alongside checkpoint inhibition for this patient, who is still alive. They also plan to see if simultaneous infusions into resected tumor cavities and cerebrospinal fluid improve efficacy. Developing multitargeted CAR T cells against other glioblastoma antigens, including HER2 and EGFRvIII, may be another option. –Alissa Poh

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.