The blood cells of cancer patients, reprogrammed by doctors to attack their leukemia and re-infused back into the patients’ veins, led to complete remissions in 27 of 30 people. That’s especially exciting because those patients had failed all conventional treatments.
Today’s report, in the New England Journal of Medicine, is an extension of data presented last year at the American Society of Hematology’s annual meeting. Not all of the remissions lasted, the report showed. Nineteen patients in the study remain in remission 2 to 24 months later, and 15 of them didn’t need any additional treatment. Seven patients relapsed between 6 months and 9 months after their infusion; those included three people whose cancers spread beyond the blood cells the new treatment targets. Five patients left the study for alternative therapy.
The numbers are remarkable because these patients had cancer return as many as four times before they joined the study, including some whose cancer had returned after stem cell transplants, said Carl June, the leader of the research team and an immunotherapist at the University of Pennsylvania. In other words, these people were the sickest of the sick.
"Initially, we didn’t know if we were just lucky with the first patients," June says. The group’s first patient, a 9-year-old named Emily Whitehead was treated when she was 6. Shehas remained cancer-free without any further intervention for more than 2 years and was at a fundraising bike ride with June last weekend, where $1.9 million was raised to continue the research. "She’s become sort of a legend," June says.
Living without B cells isn't perfect, but it's better than dying of cancer
The best comparison to the group's results are those for Novartis's Gleevec, which aided 90 to 98 percent of patients in early trials, June says. It is now approved for 10 kinds of cancer. Unlike this method, however, patients must take the Gleevec pill every day. June's treatment regimen requires just one dose.
For this method, the researchers harvest a patient’s T cells using a process like blood transfusion. Then the lab at the University of Pennsylvania’s Clinical Cell and Vaccine Production Facility does a gene transfer, to teach the T cells to target a protein found on the surface of B cells, another type of blood cell that’s affected in leukemia. The T cells are then transplanted back into the patient, where they hunt and kill anything with the protein attached to it.
That means all B cells, not just the cancerous ones, are killed. Tests of all treated patients showed that their normal B cells had been killed along with the tumors. Because B cells are responsible for creating antibodies, which hunt any viruses or bacteria circulating in the blood stream, the solution isn’t ideal; patients usually receive immunoglobulin replacement to help boost their immune systems to healthy levels.
"It's striking how similar their response rate is to ours."
Living without B cells isn’t perfect, but it’s better than dying of cancer, says Michel Sadelain, an immunologist at Memorial Sloan-Kettering who wasn’t involved in today’s study. He’s also doing research on the designer T cells, using a different technique for programming and growing the modified cells. His group’s response rate was 88 percent in a group of adults with a different type of leukemia, chronic lymphocytic leukemia. Most of today’s patients were between 5 and 22 years old, and they all had acute lymphoblastic leukemia.
"It’s striking how similar their response rate is to ours," Sadelain says. "Those numbers are almost the same, but coming from different hands, at different centers, in different patient populations. It probably speaks to the power of the approach."
Because the numbers are so similar between the two centers, it means that it’s less important to focus on manufacturing differences, Sadelain says. More important are the side-effects, seen in all groups of patients who’ve been treated by this method. Twenty-two of the 30 patients experienced cytokine release syndrome, where their immune systems went into overdrive while hunting down the cancer. The cytokine release syndrome creates flu-like symptoms, such as a fever, nausea and muscle pain; 8 patients also experienced breathing difficulties. Those responses can be severe; Whitehead nearly died. The syndrome dies down on its own with time. Figuring out how to manage the response is the next big challenge, Sadelain says.
Designer T cells could become an outpatient treatment
Unlike with most cancer therapies, the genetically-modified cells need to be given only once, June says. He hopes to treat patients in less dire straits eventually. For those patients, designer T cells could become an outpatient treatment, since the cytokine release syndrome seems to be related to how many tumors the people being treated have.
Today’s trial took into account all patients who were treated. The National Cancer Institute has done work with modified T cells also, using a so-called "intent-to-treat" study, a kind of analysis that includes every patient who initially enrolled, even if that patient later drops out of the trial or doesn't take the right dose of drug. The NCI research found that some patients weren’t able to grow full doses of the T cells. Taking into account patients who researchers wanted to treat but couldn’t reach in time or couldn’t grow cells for would probably drop the response rate by about a third, says Crystal Mackall, the chief of pediatric oncology at the National Cancer Institute.
The field has undergone a boom
The NCI data, published in the Lancet on Monday, showed that of the 21 patients enrolled, 19 received the prescribed dose; the other two patients had blood cells that didn’t grow to the assigned dose concentration. Unlike in today’s experiment, all surviving patients went on to bone marrow transplant as part of the study design.
The most exciting part of the method, which uses what the scientists call chimeric antigen receptor T cells, is that it can be used to target any sugar or protein expressed on the surface of a cancer, June says. His group is looking to begin trials in glioblastoma, pancreatic and ovarian cancer. Sadelain’s group will open studies in breast and lung cancer patients next year. The field has undergone a boom as more researchers and drug companies have become interested.
"We're gratified to see industry stepping in."Besides Memorial Sloan Kettering Cancer Center, the University of Pennsylvania and the National Cancer Institute, two other major academic facilities are doing similar work, Baylor College of Medicine and the Seattle Cancer Care Alliance. Meanwhile, Novartis is partnering with the UPenn researchers; Pfizer signed a deal with Cellectis to develop their own technology; GlaxoSmithKline is working with Juno Therapeutics to work on treatments as well; and so too are Celgene and Bluebird Bio, which have rights to the Baylor work. Kite Pharma, another company developing similar technology, had a $128 million IPO in June.
"We’re all gratified to see industry stepping in," Mackall said. "Ten years ago, five years ago, if you’d asked me if biotech and big pharma would jump in, I’d say no way. But it’s absolutely happening."
That’s explosive growth since the first case report from June’s lab in 2011, when two of three patients with chronic lymphocytic leukemia experienced remission, according to reports in NEJM and Science Translational Medicine. Those patients remain in remission, June says.
"We pinch ourselves."
June’s group received a breakthrough therapy designation from the US Food and Drug Administration in July, for treating acute lymphoblastic leukemia in adults and children. The designation, created in 2012, is meant to speed new drugs that treat life-threatening illnesses. The designer T cells were the fifth therapy to receive the designation.
"This is unlike almost all cell and gene therapies in that it’s actually ahead of the schedule we set for ourselves when we first started treating patients," June said. "We pinch ourselves because, you know, until recently we didn’t know if we got lucky or if it would last. Our initial patients are still in remission, so we know it’s durable and reproducible. That’s something that makes us excited every day."