Photo by Robert Hood / Fred Hutch
Many patients with non-Hodgkin lymphoma participating in an early-phase immunotherapy trial had their advanced tumors disappear completely after their immune cells were genetically engineered into cancer fighters, despite having previously exhausted multiple conventional cancer treatments, a new study found.
These short-term results, the latest from this closely watched study in blood cancer of these modified cells, called CAR T cells, were released Wednesday in the journal Science Translational Medicine.
Thirty-two participants in the trial received an infusion of CAR T cells following chemotherapy (called lymphodepletion) that was given to make space in the patient’s body for the infused CAR T cells. The team found that the CAR T cells most effectively knocked out the cancer in a group of 11 patients who received a two-drug combination chemo followed by an intermediate dose of the engineered T cells. Seven of these participants, or 64 percent, went into complete remission ― “which is very high” given the advanced stage of these patients' cancers, said Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutchinson Cancer Research Center and one of the study leaders.
These data demonstrate how dialing in the treatment parameters can make these cells more effective cancer-fighters in patients with this particular type of cancer, Turtle said.
“The main message is that you can treat patients with non-Hodgkin lymphoma with CAR T cells and get very good response rates with optimization of the CAR T-cell dose and lymphodepletion,” Turtle said.
The addition of a chemo drug called fludarabine in the lymphodepletion step helped the CAR T cells multiply more and survive longer in these patients than in those who had just been prepped with a chemo regimen without fludarabine, the researchers found. Among the 20 patients who received the chemo regimen with fludarabine, half of them achieved a complete remission, regardless of T-cell dose. (Of the remaining 12 patients who received a different lymphodepletion regimen, only one of them went into complete remission after CAR T-cell infusion.)
“Strategies like modifying the lymphodepletion in conjunction with suitable CAR T-cell dosing can have a big impact on clinical outcome,” Turtle said.
One of several ongoing trials of CAR T cells around the nation, this study’s hallmark is its use of a 1-to-1 ratio of helper and killer CAR T cells, which join forces to kill CD19-positive tumor cells. By controlling the mixture of T cells that patients receive, the researchers can see relationships between cell doses and patient outcomes that were previously elusive.
“The idea … is that by doing that, we would get more reproducible data around the effects of the cells ― both beneficial effects against the cancer and also any side effects they might cause the patient,” said the Hutch’s Dr. Stan Riddell, one of the senior authors on the paper, along with Hutch colleague Dr. David Maloney. “And then by adjusting the dose, we could improve what we call the therapeutic index: the benefit against the tumor, without too much toxicity.”
On average, patients on the trial had undergone five previous rounds of cancer treatments, and half of them had even had blood stem transplants. Despite this, their cancers had still come back by the time they joined the trial.
“They really had very few treatment options at the time they enrolled in our study,” Riddell said.
The study team extracted disease-fighting T cells from patients’ bloodstreams and sent them to a specialized lab at Fred Hutch to be reengineered. There, technicians inserted DNA instructions for making a synthetic, cancer-targeting chimeric antigen receptor, or CAR, into the cell’s genomes. The CARs used in the study, which were developed in Riddell’s lab at Fred Hutch, target a molecule called CD19 that is found on the surface of certain white blood cells, including some types of lymphoma cells.
After reengineering, the cells were multiplied in the lab using a process unique to Fred Hutch, in which cells undergo an extra growth-stimulating step. The team found that they were able to successfully generate CAR T-cell products even for patients who naturally had very few T cells.
After chemo, the study team transferred the freshly engineered T cells back into the patients through an IV. There, the cells encountered their CD19 targets, began to multiply, and went to work.
Some patients experienced serious toxicities due to CAR T-cell infusion. The researchers found that reducing the dose of T cells helped to reduce the occurrence of severe side effects.
Currently, there is no reliable way to predict which patients are most likely to be hit by these serious side effects, which limits doctors’ options for preventing or managing them. In this study, the researchers found that high levels of certain immune-signaling chemicals, or cytokines, in patients’ bloodstreams the day after CAR T-cell infusion were linked to the subsequent development of serious toxicities.
It’s not yet clear what an early intervention for CAR T-cell–related toxicity might look like, the investigators said. “But at least we now have the first bit of information that allows us to design those types of studies,” said Riddell.
Improving a promising strategy
The complete remission rates seen so far in this study do not reach the astoundingly high 93 percent rate the team published earlier this year on CD19-targeted CAR T cells in acute lymphoblastic leukemia patients. Turtle suspects that the fact that leukemia flows as a liquid in the blood and marrow makes it easier for the CAR T-cells to attack that cancer.
“In non-Hodgkin lymphoma, we still have very good complete remission rates, but they’re lower than those seen in acute lymphoblastic leukemia,” Turtle said. “And that may relate to the fact that lymphoma often grows as lumps, so it may be a more complex tumor microenvironment.”
The factors in lymphoma tumors that may impede T-cell activity ― and ways to circumvent them ― still need to be pinpointed, Turtle said.
In addition to Fred Hutch researchers, the study team also included scientists from the University of Washington and Juno Therapeutics. Juno provided one of the trial’s sources of funding, along with the National Institutes of Health, a Washington state research fund and private philanthropists.
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Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at email@example.com or follow her on Twitter at @sejkeown.
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