A new way to treat childhood cancer

Children’s Wisconsin's MACC Fund Center for Cancer and Blood disorders is now certified to offer cutting-edge CAR T-cell therapy

New therapies that harness a patient’s own immune system to fight cancer have emerged as the “fifth pillar” of cancer treatment, joining surgery, radiation, chemotherapy and molecularly targeted biologics. Now, Children’s is part of the fifth pillar, becoming one of only about 40 pediatric hospitals in the country authorized to provide the CAR T-cell immunotherapy Kymriah™ (tisagenlecleucel) to patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). 

Kymriah and similar drugs under investigation mark “the beginning of a new way to treat childhood cancer,” according to Julie An M. Talano, MD, a pediatric hematologist-oncologist at Children’s and associate professor at the Medical College of Wisconsin, who leads the bone marrow transplant clinical research team at Children’s.

Kymriah uses CD19-directed genetically modified autologous T-cell immunotherapy to treat patients up to 25 years old with ALL. It is also approved for use in patients 18 and older with non-Hodgkin lymphoma.

Getting approval to offer the therapy at Children’s required a rigorous process that took nearly a year. Novartis, the drug’s manufacturer, and the U.S. Food and Drug Administration require that centers be certified before providing the therapy because the treatment regimen is complex and potential for life-threatening side effects is high.

But the treatment also has great potential. In a clinical trial with 63 pediatric patients with ALL, the one-time treatment demonstrated an 83 percent overall remission rate within three months of infusion. “We knew we wanted to offer this therapy to our patients close to home,” Dr. Talano said.

Expanding access to therapy

Dr. Talano estimates that at least five patients a year seen at Children's will be eligible for the treatment. In addition, given that fewer than 30 hospitals in the country are approved to offer it, more patients may be referred from other areas.

Children who might qualify for CAR T-cell therapy should be referred as early as possible. “The CAR T-cell protocol requires that patients are stable enough to have a central line implanted to collect the cells,” Dr. Talano explained. “It also takes several weeks to manufacture the cells (at Novartis) and these children are fragile and often quite ill. So there’s a very small window of opportunity.” 

In addition, just as with a bone marrow or stem cell transplant, children receiving Kymriah require chemotherapy before the modified cells are re-infused, and they must be infection-free prior to transfusion.

“If a child has too many complications, they might not be eligible for the treatment,” Dr. Talano said.

Managing CAR T-cell challenges

One of the greatest risks with Kymriah is cytokine release syndrome (CRS), in which the large, rapid release of cytokines into the blood from the modified immune cells leads to  fever, nausea, headache, rash, rapid heartbeat, low blood pressure and respiratory problems. The condition occurred in 20 percent or more of patients enrolled in the clinical trial for the drug and can be fatal. Neurologic side effects may also occur, including encephalopathy.

Thus, Dr. Talano said, “We mandate that the patients be monitored very closely for 30 days after the cells are infused.” That requires remaining close to the hospital for quick access to care.

Dr. Talano and her team also worked closely with the emergency room and intensive care unit staff to educate them about the treatment and the early signs of CRS and other complications. Because steroids can render the re-engineered cells ineffective, each patient’s electronic health record warns that the child has a steroid allergy and to avoid using that category of immunosuppressants.

The hematology team also created standard order sets if patients are admitted with CRS so treatment with tocilizumab, an anti-IL-6 receptor biologic typically used to treat rheumatoid arthritis, can begin immediately.

Taking CAR T-cell therapy to the next level

Clinicians and researchers at Children’s and The Medical College of Wisconsin are now working to develop their own CAR T-cell product. The novel CAR T-cell targets both the CD20 and CD19 antigens instead of CD19 alone, Dr. Talano said. “The thought is that with two targets there is, hopefully, less chance of cancer cells escaping the therapy and returning,” she said. The cells are manufactured in the lymphocyte propagation laboratory at the Medical College under the direction of Bryan Johnson, PhD, and Fenlu Zhu, PhD, of the pediatric hematology and oncology department.