ASCO file photo
The 24 patients had undergone most standard therapies available to them and yet their chronic lymphocytic leukemia had come back strong. Almost all of them had been treated with a newly approved, targeted drug called ibrutinib; data from other studies show that most patients whose disease progresses after ibrutinib treatment do not survive long. The majority of the 24 had chromosomal markers in their leukemia cells that [DAE1] “predictors of a bad response to most standard therapies,” said Dr. Cameron Turtle of Fred Hutchinson Cancer Research Center.
But most of these patients, who were enrolled in a small, early-phase trial, saw their advanced tumors shrink or even disappear after an infusion of genetically engineered immune cells. Turtle, one of the study’s leaders, presented the results on Saturday at the 2016 annual meeting of the American Society of Hematology in San Diego.
In the trial, participants’ disease-fighting T cells were removed from their blood and genetically engineered in a lab at Fred Hutch to produce an artificial receptor, called a CAR, or chimeric antigen receptor, that empowered them to recognize and destroy cancer cells bearing a target molecule called CD19. After patients received chemotherapy, the CAR T cells were infused back into their bloodstream to kill their CD19-positive cancers.
While all 24 patients with chronic lymphocytic leukemia, or CLL, received the experimental therapy, Turtle focused in his presentation on the results in a subgroup of 19 patients who received particular chemotherapy regimens and doses of CAR T cells the researchers now prefer, based on recent data in other groups of patients on the trial.
Fourteen of 19 experienced a partial or complete regression of their disease in their lymph nodes. And of the 17 who had leukemia in their bone marrow when they enrolled on the trial, the marrow became cancer-free in 15 after they received CAR T cells. (In his presentation, Turtle presented new results not reflected in the abstract available online.)
“It’s very pleasing to see patients with refractory disease respond like this,” Turtle said. The research team “had seen very good responses [to the same CAR T-cell therapy] in acute lymphoblastic leukemia and non-Hodgkin lymphoma, so we hoped responses would be good in CLL too.”
Earlier this year, Turtle and colleagues published early results from this trial in patients with these other blood diseases. In the spring, the team’s paper showed that 93 percent of trial participants with B-cell ALL went into complete remission after their T cells were re-engineered with the CD19 CAR, even though multiple other treatments had already failed them. In September, the researchers published results showing complete remissions in seven of 11 non-Hodgkin lymphoma patients who received a particular preparative chemo regimen and CAR T-cell dosage.
Follow-up with CLL participants is ongoing. As per U.S. Food and Drug Administration requirements for experimental gene therapies, the research team will track patient outcomes for at least 15 years.
Turtle reported that the CLL patients with the highest number of CAR T cells in their blood after infusion were most often the patients who had had the greatest extent of cancer in their marrow, blood and lymph nodes at the time of infusion. Those with more CAR T cells were also most likely to have their disease disappear from the bone marrow after the cells entered their bodies.
Side effects included high fevers, due to activation of CAR T cells, and neurologic symptoms. Although one patient died from severe toxicity, the side effects experienced by other patients in the study were temporary, Turtle said.
In a separate poster presentation at the conference, Turtle and colleagues reported biomarkers they had identified in patients’ blood from the day after CAR T-cell infusion that were associated with the later development of the most severe toxicities. They hope these markers could eventually become the cornerstone of tests to predict and mitigate the most serious side effects of CAR T-cell infusion.
“If you can find biomarkers within a day of CAR T-cell infusion, which we have, you can then look at future cohorts of patients to work out whether early intervention can help prevent toxicity,” Turtle said.
The trial, which is ongoing and still enrolling participants, is co-led by Turtle and Hutch colleagues Dr. David Maloney and Dr. Stanley Riddell and supported by funding from Fred Hutch spinoff Juno Therapeutics, philanthropists, a Washington state research fund and the National Cancer Institute.
Several CD19 CAR T-cell trials in blood cancers are underway around the country. What makes this trial unique is its use of a one-to-one ratio of two functionally different subsets of T cells, which work together to fight off cancers. By giving patients a cell product with a defined composition of T-cell types, the researchers are able to better understand the link between CAR T-cell dose and patient outcomes.
The next steps are to determine why there was a lower response rate to CAR T-cell infusion in leukemia located in the lymph nodes than leukemia located in the marrow, Turtle said, and to figure out whether the addition of other treatments to the immunotherapy regimen could help to solve the problem.
These sorts of questions are broader than this particular trial, Turtle said, and he and his colleagues have already started working on them.
“We’re trying to identify the issues that are limiting [treatment] response and then fix them. We’re trying to define the best cell doses, chemotherapy regimens and interventional strategies to make CAR T-cell therapy safer and more effective,” Turtle said. “There’s obviously a lot of work to do.”
New immunotherapy clinic boon to future of this trial, others
Participants on this trial are seen at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. Trial co-leader Maloney is the medical director of a new immunotherapy clinic at SCCA, the first facility in the country dedicated to caring for patients on immunotherapy clinical trials. The Bezos Family Immunotherapy Clinic welcomed its first patients this fall and will be the center of care for future participants on the CD19 CAR T-cell trial.
The clinic’s specialized staff and facilities offer many advantages to this and similar trials, Turtle said.
“It’s a clinic full of people who are specifically tuned in to caring for patients receiving cutting-edge immunotherapies,” he said. “They know what the issues are, they know how to handle them and they know how to look after the patients. And all of this happens in a setting in which we have rapid access to on-site research laboratories to help us improve the results of immunotherapy treatments for our future patients.”