CAR T-cell therapy ‘holds great promise’ for advanced chronic lymphocytic leukemia.
By: David L. Porter - healio.com/hematology-oncology/leukemia
There are new molecules and new therapies giving us tremendous response rates in CLL, but when these therapies stop working, patients by and large have a terrible prognosis," David L. Porter, MD, Jodi Fisher Horowitz professor of leukemia care excellence and director of blood and marrow transplantation at University of Pennsylvania Health System, said during his presentation. "Patients with multiply relapsed and refractory disease are incurable with anything but transplant, but the majority of these patients are not even candidates for transplant. We still need better therapies for patients with relapsed and refractory disease."
Use of targeted cellular therapy has the ability to overcome many of the limitations of conventional chemotherapy and other forms of adoptive immunotherapy, Porter said.
Genetically modified, autologous T cells with redirected specificity to tumor antigens combine the specificity of antibody therapy, the amplified response of cellular therapy and the memory activity of vaccine therapy.
Several years ago, researchers at University of Pennsylvania launched a pilot study of CTL019 - now known as tisagenlecleucel (Kymriah, Novartis) - to assess the therapy's safety, feasibility and immunogenicity for patients with CD19-positive leukemia and lymphoma. Researchers included patients with relapsed or refractory disease, and all patients had estimated prognosis of less than 2 years with other available therapies.
The first patient treated was a man aged 59 years with stage IV CLL who had undergone seven prior therapies, had become chemotherapy resistant and had no standard options available.
He underwent T-cell infusion in August 2010. Ten days after infusion, he developed high fevers, hypoxia and hypotension. He required ICU care for what is now understood to be a therapy-related toxicity known as cytokine release syndrome.
His symptoms lasted for approximately 2 weeks but spontaneously resolved. His blood counts quickly normalized for the first time in years, his bone marrow showed no sign of leukemia, and CT scans showed resolution of enlarged lymph nodes. By day 31, he achieved complete remission.
Investigators later learned the infused T cells had expanded in his body between 1,000- and 10,000-fold and remained detectable after more than 5 years, and he remains in complete remission more than 7 years after infusion.
More than 60 patients with highly relapsed and refractory CLL have been treated at Penn.
"When this works, it works dramatically. The problem is it doesn't work in everybody," Porter said.
Complete remissions happen in about one-quarter to one-third of patients, depending upon how they are selected. Overall response rates are approximately 50%.
The key question going forward will be how to get more patients to respond to therapy, Porter said.
"Ibrutinib seems to make the patient's T cells healthier and more reactive against CLL cells," Porter said. "It also seems to modify CLL to make it a better target for CAR T cells."
Researchers at Penn reasoned that patients on ibrutinib may have a better response if they continue taking the drug while they receive CAR T-cell therapy.
Investigators recently closed a trial in which 20 patients were treated with that approach.
Data from the first 11 patients, based on follow-up from 3 to 12 months, showed seven of 11 patients met strict criteria for complete remission. At 3 months, 10 of 11 patients (91%) had no detectable CLL in marrow.
"Although it is early, we have a suggestion that ibrutinib indeed may make CAR T cells more effective for CLL," Porter said. "In fact, when you look by next-generation sequencing, the majority of these bone marrow-negative patients have no CLL." - by Mark Leiser