Could Infections Teach Us How to Make Treatments for Pediatric ALL Even Better?
The 3rd article in a 3-part series on recent developments and ongoing research in immunotherapy for childhood cancers.
Alix Seif, MD, MPH, knows the pros and cons of the new immunotherapy treatment Kymriah (tisagenlecleucel). It’s the first FDA-approved gene therapy available in the United States. It’s also known as CAR T-cell treatment.
Pediatric oncologist, Alix Seif, MD, MPH, explains how children respond differently to immunotherapy than adults.
Seif is a pediatric oncologist and researcher at the Children’s Hospital of Philadelphia (CHOP) where Kymriah was studied. She wasn’t one of the researchers who helped develop it. She does, though, work in the same lab as Kymriah’s lead investigator, Steve Grupp, MD. And Grupp’s one of her mentors. Plus, some of the children Seif treats have the type of cancer that Kymriah is for, B-cell acute lymphocytic leukemia (ALL).
“Kymriah is a game changer,” Seif says. “I have patients who wouldn’t be alive today without it.”
Kymriah is made by genetically modifying T cells – a white blood cell involved in immunity. A doctor removes a patient’s own T cells and sends them to a lab. There, the T cells are altered with a CAR (chimeric antigen receptor) so they can find and kill any cell with a certain marker on it, called CD19. These modified cells are infused back into the patient.
“CD19 is a golden target,” Seif says. “Most children with B-cell ALL have CD19 markers on their cancer cells so the drug’s incredibly effective.”
Seif says the side effects are usually short term and doctors are good at managing them. More than 80% of the children who have gotten Kymriah went into remission, she says. “These are children who have failed many treatments. So, it’s really quite exciting.”
CAR T-Cells May Not Continue to Circulate and Attack Cancer Cells
As ground-breaking as they are, though, Seif says, immunotherapy treatments using CAR T-cells have room to improve. The aspect that relates to her research is “immune memory.” That’s when the immune system learns to recognize something dangerous, like leukemia, and can remember to attack leukemia cells that return.
“CAR T-cells may persist in the body for a long time, Seif says. “But if they go away (and they do in some patients), then no one is around policing the cancer.”
That’s why persistence is one of the main aspects of CAR T-cell therapy still being studied.
If CAR T-cells don’t persist, then the immune system doesn’t create any immune memory to recognize and kill leukemia cells. And that means leukemia can return.
That’s the focus of Seif’s research—creating a treatment that kills leukemia cells that also teaches the immune system to recognize and kill any new leukemia cells in the future. ?
The drug she’s been testing in mice, with the support of a grant from the American Cancer Society, is CpG ODN. It is an immunotherapy but works differently from CAR T-cell treatments. “This type of immunotherapy activates, or stimulates, the immune system in the same way infections from viruses or bacteria do,” Seif explains. “That stimulation allows the immune system to be on high alert for leukemia cells that would otherwise hide from the immune system.”
“The chicken pox vaccine can stimulate the immune system to recognize and remember the chicken pox virus for life,” she says. “In the same way, when the immune system finds leukemia cells in the presence of this activating drug, it may act like a vaccine. That means it creates long-term immune memory for ALL. And that means, the drug could potentially prevent relapse for the child’s lifetime.”?
Down the road, after we’ve done a lot more testing, maybe treatment for ALL could start with CAR T-cell treatment to knock down the leukemia burden. Then we could follow that treatment with CpG to get a memory immune response.
Testing How the New Drug Will Work with Chemotherapy
The standard treatment for ALL is still chemotherapy. In Seif’s studies, CpG ODN worked well to kill leukemia cells in mice, as long as there wasn’t a lot of cancer to start with. The drug works best with residual disease, which is the smaller number of cancer cells that remain after chemotherapy.
So, learning how to combine the new drug with chemotherapy is an important step toward getting this drug to patients. That’s why Seif’s team experimented with different types of chemotherapies. They wanted to see if CpG ODN worked better with a certain type.
They tried some chemotherapies, for instance, that killed leukemia cells in a way that could make the leukemia cells more visible to the immune system. They expected that CpG would work better with these chemos. As it turned out, CpG worked well with all the chemotherapy combinations.
“Our experiments are still a bit early,” Seif says, “and we are adjusting our methods. So eventually we might find a stronger pairing of the new drug with a specific chemotherapy. For now, even though we didn't find the answer we expected, we’re happy that it prolonged the mice’s survival with every chemo we tried. Because that suggests our drug can work in combination with any of these drugs.”
Unlike CpG ODN, CAR T-cell treatment works well with a high number of leukemia cells. “Down the road, maybe treatment could start with CAR T-cell treatment to knock down the leukemia burden, then follow that treatment with CpG to get a memory immune response,” Seif says. Of course, she notes, researchers have a lot of questions to answer, probably over several years, before that treatment plan could be in place.
Learning How the New Drug Could Work in 13,000 Children with
B-cell ALL
All Seif’s research is both preclinical—in the lab and in animals—and translational, thinking through the issues involved in applying successful preclinical studies to patient care.
For the translational part of Seif’s American Cancer Society-supported research, she wanted to predict how well CpG ODN’s effect on the immune system would work in children with leukemia. To figure this out, she developed a method to use information already collected about thousands of children with leukemia.
Her method was to use the Pediatric Health Information System Database (PHIS). This database includes billing information from 45 children’s hospitals about medical care and use of medicines and other health supplies.
She used the PHIS data to learn about those children’s reaction to an infection without having to put even a single child on a clinical trial. “The beauty of the database,” Seif says, “is that we can identify a patient at diagnosis and follow children over time, any and every time they are in the hospital.”
PHIS had information for 13,000 children with ALL for Seif’s team to review. Her team was looking for children who had had a severe infection to see if they were less likely to have a relapse and have leukemia return after remission. If children who had an infection are less likely to relapse, then there’s a good chance that Seif’s drug, CpG ODN, which stimulates the immune system in the same way an infection does, will protect children with ALL from relapsing.
Next, she’ll continue studying ALL using information already collected by the Children’s Oncology Group (COG) to see if infection has a stronger effect in children with high risk ALL. She will also use the COG and PHIS databases to predict CpG ODN’s effect on acute myelogenous leukemia (AML).
READ PART 1: The Current and Future Promise of Immunotherapy for Childhood Cancers
READ PART 2: Adapting CAR T-Cell Therapy to Treat Neuroblastoma
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