Researchers at Memorial Sloan Kettering (MSK) report today in the New England Journal of Medicine that adult patients with acute lymphoblastic leukemia (ALL) who received chimeric antigen receptor (CAR) T cell therapy responded better if they had a small amount of disease at the time of the treatment. Compared with patients with a greater amount of disease, those in the low-disease category lived significantly longer and experienced fewer life-threatening side effects.
The findings are based on the final analysis of a phase I clinical study of 53 adult patients with ALL who were treated with CD19-targeted CAR therapy at MSK. The maximum follow-up time was five and a half years, with a median of 29 months. Among all patients, the median survival was 12.9 months. For those in the low-disease category (defined as less than 5 percent leukemia cells in the bone marrow), the median survival was 20.1 months. While previous studies of CAR therapy in children and adults with ALL had shown impressive initial response rates, the follow-up data from those groups is limited.
Patients enrolled on the trial (NCT01044069) 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.
All patients on the study had received multiple previous treatments, including bone marrow transplants, and either had relapsed or were resistant to chemotherapy. The rate of complete remission — meaning a leukemia-free state— was 83 percent (44 people). The overall rate of severe cytokine release syndrome was 26 percent (14 people), including one death. The rate of severe neurotoxicity was 42 percent (22 people). There were no cases of fatal neurotoxicity or cerebral edema on the trial.
Some of those on the study went on to have a stem cell transplant, but receiving this additional treatment did not correlate with having a better survival outcome.
“This is the longest follow-up study of people with ALL treated with CAR therapy,” says Jae Park, MD, 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 patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity. We are very encouraged by this progress and are eager to continue our work with these living therapies to provide new, better, and safer treatment options for patients.”
MSK researchers caution that the results of this study are suggestive and should be confirmed in a prospective trial.
Significant advances have been made in treating leukemia. These new MSK findings could lead to a change in the clinical practice of how people with ALL are treated. Current CAR T trials at other cancer centers require participants to have a significant amount of disease before they can enroll, but the MSK data suggest that these people are less likely to attain long-term benefits from the therapy.
“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 supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”
“This study has major implications for the future,” says Michel Sadelain, MD, PhD, Director of MSK’s Center for Cell Engineering and the study’s lead author. “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.”
The CAR T cells used in this study are built to target a molecule called CD19, which MSK researchers had previously identified as an optimal target for CAR therapy. This marker is found on the surface of normal and cancerous B cells. MSK scientists played a pioneering role in developing CAR therapy. In 2014, the Food and Drug Administration (FDA) granted MSK Breakthrough Therapy Designation for its CD19 CAR therapy for ALL.
In 2017, the FDA approved two commercial CAR T cell therapies: tisagenlecleucel (Kymriah®) for children and young adults with ALL and axicabtagene ciloleucel (Yescarta®) for adults with non-Hodgkin lymphoma. As of now, the FDA has not approved any CAR T cell therapy for adults with ALL.
“In recent years, we have witnessed many clinical studies that primarily focused on early response rates and toxicities in patients treated with CAR T cells. With the results of this study, we can begin to appreciate the long-term benefit and outcomes of this therapy,” said Dr. Sadelain.
Cancer immunotherapy was born at MSK over a century ago. Since then, MSK scientists have led the effort to develop immune-based treatments for cancer. MSK has been at the epicenter of discoveries in the field, and our work is bringing exciting new treatment options to people with cancer.
The roots of CAR T therapy stretch back nearly 30 years, to the work of Dr. Sadelain. In the early 1990s, the techniques to introduce genes into cells were just being developed.
In this personalized, cell-based immunotherapy approach, scientists genetically engineer a patient’s own T cells, a type of immune cell, to make a new protein that can latch on to cancer cells, turning the T cells into supercharged cancer fighters. The process involves removing T cells from a patient’s blood. The cells are then genetically engineered to contain a new gene that will better enable them to attack cancer. After being grown in a lab for a few days until there are billions of copies of them, these modified cells are reinfused into the patient’s blood.
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, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at MSK, Juno Therapeutics, and the Lake Road Foundation.