David Avigan doesn’t like to use the word “miracle” to describe CAR T-cell therapy, but he knows what people mean when they do.
“As a field, we’re always a little cautious — our patients are on a roller coaster,” said Avigan, the Harvard Medical School Theodore W. and Evelyn G. Berenson Professor of Medicine for the Study of Oncology at Beth Israel Deaconess Medical Center and director of the Beth Israel Deaconess Cancer Center. “But frankly, we’ve seen very dramatic responses in patients with advanced disease.”
First approved by the FDA in 2017, CAR T-cell therapy enlists the body’s immune system in the fight against cancer. It has triggered rapid improvement in some of the sickest patients, those whose hopes had faded with the failure of one treatment after another. Physicians report astonishing results: tumors melting away over weeks or even just days, and people who appeared to be on death’s door getting up and reclaiming their lives.
“They had received every other known therapy and experimental therapy — nothing worked — and after CAR T therapy they would go into remission and just a week later be walking around like they were totally normal, even if they got really sick during the therapy,” said Robbie Majzner, HMS associate professor of pediatrics Dana-Farber Cancer Institute and director of the Pediatric and Young Adult Cancer Cell Therapy Program at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “We had one patient who almost died during the therapy, and two weeks later he was leukemia-free and snowboarding. It was just unbelievable.”
For all its promise, however, CAR T-cell therapy works for only some patients and some cancer types. Remission rates are currently between 50 and 90 percent, depending on the condition, and cancer is still the largest single cause of mortality for those undergoing the treatment. The therapy can also cause serious side effects and is expensive.
HMS researchers are hard at work to change that — investigating ways to reduce risk; expand CAR T-cell therapies from blood cancers to solid tumors and to noncancerous conditions such as type 1 diabetes, other autoimmune disorders, and chronic infection; and make the technology accessible to more patients.
For example:
- Eric Smith, HMS assistant professor of medicine at Dana-Farber, and others engineered a CAR T-cell therapy originally effective against leukemia and lymphoma into a weapon against a third blood cancer, multiple myeloma.
“The platform is just so amenable to further engineering,” said Smith, who is also director of translational medicine immune effector cell therapies at Dana-Farber. “We’ll be curing a higher percentage of patients with the next iteration.”
- Marcela Maus, HMS professor of medicine at Massachusetts General Hospital and director of the hospital’s Cellular Immunotherapy Program, and Bryan Choi, HMS associate professor of neurosurgery at Mass General, have trialed a two-pronged CAR T-cell therapy against glioblastoma, a devastating brain tumor that kills more than 90 percent of patients within five years. The first three participants in the study saw dramatic improvements in their cancer, though the effects were durable in only one. Follow-up data on 10 patients was presented at the American Society of Clinical Oncology this month.
“There’s been a lot of hope for the technology to be able to dramatically improve the lives of patients with other diseases for a long time,” said Maus. “That part is a little bit early and it’s been less straightforward to achieve.” Nonetheless, she’s seen enough to feel confident in significant promise for advances that bolster attacks against a wider range of cancers.
- Mohammad Rashidian, HMS associate progress of radiology at Dana-Farber, has developed a so-called enhancer protein designed to address two of CAR T’s shortcomings: T-cell exhaustion that leads to a weak initial response, and responses that fade over time, as can happen in myeloma cases. The advance has the potential to provide protection against cancer the way infection or vaccination might against infectious disease.
“I’m very optimistic,” Rashidian said. If the team’s early data is replicated in human trials, he said, “we would anticipate substantially better responses, and hopefully a lot of patients should be cured.”
- As a pediatric oncologist, Majzner is testing a CAR that targets a molecule found on cells in several cancer types. If it shows promise, it could spark more interest from industry by allowing drugmakers to create CAR T cells for pediatric patients with a range of cancers rather than just one or a few.
“We’ll have trials for that in solid tumors and in brain tumors,” Majzner said. “Perhaps it will leapfrog ahead for patients that now receive therapies for pediatric solid tumors that look like they did 40 years ago. Success would change the way we treat these cancers for sure.”
Read the full feature in the Harvard Gazette, including a timeline and an illustrated explainer about CAR T-cell therapy.
