MRI scans of the brain of a patient who received experimental CAR T cell therapy and surgery for glioblastoma. | O’Rourke et al., Science Translational Medicine (2017)
In a pilot study in humans, 10 patients with highly malignant glioblastoma brain tumors received a treatment regimen called CAR T cell therapy that reengineers people's own immune cells to recognize cancer-specific proteins. The findings, published July 19 in Science Translational Medicine, could eventually expand the use of CAR T cell-based regimens beyond blood-based cancers like leukemia to solid tumors.
"I am firmly convinced that CAR T cells and other immunotherapies have a chance to be a major breakthrough for glioblastoma," said Donald O'Rourke, a professor of neurosurgery at the University of Pennsylvania Perelman School of Medicine and first author on the paper.
Glioblastoma is the most aggressive type of tumor that originates in the brain and with no curative treatments currently available, the average survival time for patients ranges from 15 to 18 months.
"This study is laying the foundation for a potentially powerful new therapeutic direction in a cancer that desperately needs new treatments," said O'Rourke. "CAR T cells are the ultimate in personalized precision medicine."
Of the 10 patients enrolled in the study — a clinical trial designed to evaluate safety and feasibility — none of the participants experienced any dangerous side effects and one patient's disease remained stable after 18 months.
Seven patients went on to require neurosurgery, which allowed the scientists to investigate in detail changes in the brain brought on by CAR T cell treatment.
The CARs that drive these treatments are custom-designed proteins called chimeric antigen receptors. CARs teach T cells to recognize specific cancer cell surface markers, or antigens, and then go on the attack against cells with those markers. To manufacture CAR T cells, scientists extract bone marrow from a patient, introduce genetic instructions for a CAR into the T cells, and then infuse those engineered immune cells back into the person's bloodstream.
For the new study, O'Rourke and his colleagues designed a CAR targeting an aberrant protein called EGFRvIII that is present in roughly 30% of glioblastomas and is thought to promote malignancy.
Well-engineered CARs are key, but successful therapy also requires close encounters between cancer and the modified T cells. For glioblastoma, some scientists were skeptical that CAR T cells would be able to cross the blood-brain barrier and penetrate solid tumors.
"We were all taught for decades that the brain is an 'immunoprivileged' site and that immunotherapy would not work in the brain," said O'Rourke. "That is clearly old dogma that is not accurate."
The researchers observed that CAR T cells were indeed able to infiltrate glioblastomas. Unexpectedly, however, tumors also began producing large amounts of immune-suppressing signals in response.
"I think that to mediate stronger anti-tumor effects, we're going to need to figure out how to attack the tumor on multiple fronts, either with combinations of drugs or therapeutics, or perhaps by more complex engineering of T cells," said Marcela Maus, a professor at Harvard Medical School, director of Cellular Immunotherapy at the Cancer Center at Massachusetts General Hospital and corresponding author on the paper.
"We have a great deal of work to do moving forward to resolve the many questions that arise from our early work," said O'Rourke. "But we now have rational, scientific hypotheses to test to improve upon clinical results observed with our first group of patients."
CAR T cell therapies have already shown tremendous promise for treating blood-based cancers, leading the Food and Drug Administration's Oncologic Drugs Advisory Committee to unanimously recommend a Novartis CAR T regimen named tisagenlecleucel for approval to treat pediatric B-cell acute lymphoblastic leukemia, in a landmark ruling in July 2017.
"It's rare to hear regulators refer to the data as 'the most exciting thing I've seen in my lifetime.' I feel exactly the same way," said Maus. Upon learning about the decision, Maus said, "our whole lab was skipping and almost in tears at the same time."
"Last week's vote represents 30 years' worth of work to find a new way to treat this devastating cancer and the start of a new era in using personalized immunotherapy to treat other types of cancers." said Carl June, a pioneering CAR T cell researcher and professor of immunotherapy at the University of Pennsylvania Perelman School of Medicine. "I'm happy, most of all, for the patients who will benefit."