Patient Achieves Remission With CAR-T Cell Therapy for Aggressive Brain Tumors

Results may be “game changer” in how brain malignancies are treated, study reports

City of Hope researchers in Duarte, California, have successfully treated a patient with recurrent multifocal glioblastoma using MB-101 (Fortress Biotech), a chimeric antigen receptor T-cell (CAR-T) therapy, to attack cells with the interleukin-13 receptor α2 (IL13Rα2) antigen, which is common in brain cancer. City of Hope is an independent research and treatment center for cancer, diabetes, and other life-threatening diseases.

A case study published in the December 29 issue of the New England Journal of Medicine outlines the results of a patient treated with his own genetically modified CAR-T cells, using central memory T cells, a stem-cell-like subset of immune cells.

In CAR-T therapy, T cells are engineered by adding chimeric antigen receptors (CARs), which help the immune cells target tumors. Unlike other T cells, which attack and then die, memory cells remain in the patient’s system for a longer period—possibly a decade or more—and grow a reservoir of cancer-killing cells that can attack and destroy future glioma tumor cells.

According to Fortress Biotech, IL13Rα2 is an attractive target for CAR-T therapy because it has limited expression in normal tissue but is overexpressed on the surface of most glioblastoma cells. CAR-T cells are designed to express a membrane‐tethered IL‐13 receptor ligand incorporating a single‐point mutation that provides high affinity for IL13Rα2 and reduces binding to IL13Rα1 to reduce the targeting of healthy tissue.

The 50-year-old man reported in the case study presented with recurrent multifocal glioblastoma and was enrolled in a phase 1 clinical trial after failing standard-of-care therapy consisting of resection, radiation, and treatment with temozolomide. The patient developed multifocal disease, with tumors involving both the brain and the spinal cord.

As part of the clinical trial to test the safety of CAR-T cell therapy delivered directly to brain tumors, the patient received multiple infusions of MB-101, which were well tolerated. Regression was observed in both brain and spinal tumors, as well as increased numbers of immune cells in the cerebrospinal fluid. This clinical response was sustained for 7.5 months after the initiation of CAR-T cell therapy, according to the article.

“By injecting the re-engineered CAR-T cells directly into the tumor site and the ventricles, where the spinal fluid is made, the treatment could be delivered throughout the patient’s brain and also to the spinal cord where this particular patient had a large metastatic tumor,” said co-senior author Behnam Badie, MD. “I believe these recent results show we have a potential breakthrough treatment that may have a remarkable impact on patients with malignant brain tumors.”

Dr. Badie said the results of this case study demonstrate that, even at the lowest dosage, CAR-T therapy is a “game changer” in how brain tumors may be treated in the future.

“The most exciting thing about our study is that it proves a better treatment may be attainable,” said lead author Christine Brown, MD. “We can take a patient who has actively growing, advanced, metastatic multifocal glioblastoma, and we can see regression of all lesions, including in the spine. To date, that’s unheard of.”

Glioblastomas are tumors that arise from astrocyte cells, which make up the supportive tissue of the brain. These tumors are usually highly malignant because the cells reproduce quickly and are supported by a large network of blood vessels. Glioblastoma is the most common brain and central nervous system malignancy, accounting for 15% of all primary brain tumors and 55% of all gliomas. Approximately 27,000 new cases of glioblastoma occurred worldwide in 2015.

While glioblastoma is a rare disease (two or three cases per 100,000 life-years in the United States), it is very lethal, with five‐year survival rates of less than 10%. Chemotherapy with temozolomide and radiation treatment have been shown to extend median survival from approximately 12 months to 15 months, while surgery remains the standard of care.

Glioblastoma remains difficult to treat because of the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage; by the difficulty of the brain repairing itself; and by the limitations of drugs in crossing the blood–brain barrier.

Sources: City of Hope; December 28, 2016; and Fortress Biotech; December 28, 2016.