Results published today from the longest-running clinical trial of chimeric antigen receptor (CAR) T cell therapy for cancer offer key insights into factors affecting the safety and effectiveness of this groundbreaking immunotherapy treatment.
Memorial Sloan Kettering scientists report in the New England Journal of Medicine that adults with acute lymphoblastic leukemia (ALL) who received CAR therapy responded better if they had a small amount of disease at the time of treatment. Compared with patients who had a greater amount of disease, those in the low-disease category lived significantly longer and experienced fewer life-threatening side effects.
The eagerly awaited findings are based on an analysis of data from 53 adults with ALL who were treated with CAR therapy at MSK. The maximum follow-up time was five and a half years, with a median of 29 months. The overall median survival was 12.9 months. For those in the low-disease category (defined as less than 5% leukemia cells in the bone marrow), the median survival was 20.1 months.
Strikingly, about 50% of people in the low-disease category were still alive and well after five years. Doctors speculate that they may be cured.
“This is the longest follow-up study of people with ALL treated with CAR therapy,” says Jae Park, a medical oncologist at MSK and the principal investigator of the phase I trial. “It confirms the power of CAR T cells as an effective cancer therapy in adults with ALL. With the long follow-up, we were able to demonstrate for the first time that people with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”
Previous studies of CAR therapy in children and adults with ALL had shown impressive initial response rates, ranging from 70% to 90%. The follow-up data on these groups, however, is limited. Whether people treated with CAR T cells would continue to do well over time has been an open question.
The new results provide the first strong evidence that some people with an otherwise incurable cancer can experience lasting benefits extending to five years or more after receiving a single infusion of CAR T cells. The results also point to specific factors that may influence how well people do on the treatment.
“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr. Park says. “Our data suggest that we should give CAR therapy when the disease volume is small to achieve the greatest long-term efficacy and lowest toxicity.”
Ultimately, he says, it may make sense for people to receive CAR T cell therapy as a frontline treatment, rather than after other options have failed.
A Powerful Treatment with Serious Potential Side Effects
Doctors and patients alike are excited about CAR therapy because it has proven to be a lifesaving option for very sick people who otherwise would have died from their disease. More than a thousand people in the United States alone have received the immune-based treatment, despite the sometimes severe side effects that can come from supercharging immune cells and releasing them into the body.
The main potential complication of CAR therapy is cytokine release syndrome (CRS). This powerful surge of immune activity can overwhelm the body’s organs and lead to death. Caring for people with CRS requires enormous skill and clinical expertise.
Another potential complication is neurotoxicity, including a dangerous swelling of the brain called cerebral edema. Some CAR trials have been stopped early because there were deaths from cerebral edema. None of these deaths occurred at MSK.
The results of this study provide important lessons for limiting and managing these side effects. They further show that CAR therapy provides a potential cure for a group of people — adults with relapsed ALL — for whom no FDA-approved CAR T cell treatment exists.
“This study represents the culmination of 20 years of research at MSK,” says Michel Sadelain, Director of the Center for Cell Engineering at MSK and lead author of the study. “These data strongly support the use of this CAR therapy for adults with relapsed ALL, and predict better outcomes when used earlier in the course of the disease.”
Patients enrolled on this trial received a single infusion of 19-28z CAR T cells manufactured at MSK. Each person’s T cells were isolated from their blood and exposed to a harmless viral vector that inserted the 19-28z CAR gene. The engineered CAR T cells were grown and multiplied in the lab and then infused back into the patient.
Everyone on the study had received multiple previous chemotherapy treatments and either had relapsed or was resistant to further chemotherapy. The rate of complete remission — meaning a leukemia-free state — was 83% (44 people). The overall rate of severe CRS was 26% (14 people), including one death. The rate of severe neurotoxicity was 42% (22 people). There were no cases of fatal neurotoxicity or cerebral edema on the trial.
Some people on the study went on to have a stem cell transplant. Receiving this additional treatment did not correlate with a better outcome.
The analysis of factors affecting the outcome of treatment was retrospective in nature and needs to be confirmed in a prospective trial. MSK investigators hope to open such a trial soon.
About CAR T Cell Therapy
The CAR T cells used in this study are built to target a molecule called CD19. This marker is found on the surface of normal and cancerous B cells. MSK scientists were the first to show that CD19 is an optimal target for CAR therapy and played a pioneering role in developing CAR therapy. MSK’s CD19 CAR T therapy received a Breakthrough Therapy Designation from the FDA in 2014.
Two commercial CAR T cell therapies are currently approved for use in people: tisagenlecleucel (Kymriah®) for children and young adults with ALL and axicabtagene ciloleucel (Yescarta®) for adults with non-Hodgkin lymphoma.
There is no FDA-approved CAR T cell therapy for adults with ALL.
This work was supported by the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, the William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at MSK, Juno Therapeutics, and the Lake Road Foundation.