Dual-target CAR-T allows researcher to ‘dream big’ about a cure for high-risk leukemia
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Key takeaways:
- A phase 1 trial is testing a novel CAR-T that targets both ADGRE2 and CLL-1 in adults with AML.
- The CAR-T is optimized to spare normal hematopoietic stem cells and eliminate leukemia cells.
Jae Park, MD, compared the moment to a baby being born.
The first infusion of a phase 1 study using a novel chimeric antigen receptor T-cell therapy for patients with relapsed or refractory acute myeloid leukemia is about to happen and Park could feel his anticipation building.
“It’s mixed feelings. It’s certainly the excitement, obviously — kind of nervous, too,” Park, chief of the cellular therapy service and a hematologist/oncologist specializing in leukemia at Memorial Sloan Kettering Cancer Center, told Healio that morning. “It’s finally happening and it’s time for us to put out our best efforts and dream big.”
The CAR-T — developed in the lab of Michel Sadelain, MD, PhD, Stephen and Barbara Friedman chair and director of the Center for Cell Engineering at Memorial Sloan Kettering — targets cells expressing both ADGRE2 and CLL-1 antigens.
Previous efforts to develop immunotherapy for the treatment of AML have yielded limited success because many potential targets are also expressed on either hematopoietic stem cells or normal myeloid cells. By targeting the two antigens — ADGRE2 and CLL-1 — this study is hoping to spare normal hematopoietic stem cells and more selectively target AML cells.
“Any CAR-T cell therapy in AML we’re very excited about, but particularly this one,” Park said. “We usually have no curative option for these patients.”
Background
If Park sees a patient with AML without knowing anything about the individual or the disease, he estimates that person has about a 60% chance of complete response to therapy.
However, he said the difference between low- and high-risk patients can be staggering. Park estimates individuals with favorable risk have about an 80% response rate, whereas high-risk people have between 20% to 30%.
“If you don’t respond to the initial chemotherapy, your chance of survival is unfortunately dismal,” Park said. “Your chance of being alive within 1 year is approximately 20% to 30% or lower.”
Standard care for high-risk patients starts with chemotherapy. If a patient achieves remission, the goal is then getting them to a hematopoietic stem cell transplant for a potential cure. Those who are refractory to standard chemotherapy or relapse thereafter — including relapse after transplant — are difficult to treat, Park said, and salvage chemotherapy only works in 10% to 20% of individuals.
“Several advances have been made in AML, but only for those patients who have targetable mutations — FLT3, IDH1, IDH2 or fusion genes involving MLL1. These are some of the genetic abnormalities for which we have a targeted oral drug options,” Park said. “They have made significant improvement. However, none of the medications are curative, so [patients] still need to go to transplant even if they were lucky enough to achieve response. And there are still many more patients who do not carry these mutations for whom we have no effective treatment options currently. That’s where the immunotherapy hopefully will come in.”
Immunotherapies have not been successful in this patient population to date.
“There is no single target that’s only expressed in leukemia cells and not expressed in normal myeloid cells,” Park said.
Attacking a target that can be found on a hematopoietic stem cell can prevent a patient from recovering normal blood counts and require a rescue bone marrow transplant, and going after those on myeloid cells could lead to neutropenia or infection, he added.
Dual-target CAR-T trial
Park believes this new trial could address this gap.
ADGRE2 is expressed more uniformly on leukemic stem cells but at very low level in hematopoietic stem cells, according to Park. “CAR binder used for this study is designed to ignore and spare normal hematopoietic stem cells expressing ADGRE2 at very low level but engage only with leukemic cells,” he said.
CLL-1, on the other hand, has high expression on many leukemia and myeloid cells. In the investigational CAR-T product used by Park and colleagues, CLL-1 is used not as a primary target but directs CAR T cells to eliminate leukemic cells more completely with low ADGRE2 expression and provide an additional activation signal to the CAR.
“This approach significantly increases specificity, eliminates leukemia cells more completely and limits damage to other cells,” Park said. “If successful, this can be a stand-alone therapy and not require rescue bone marrow transplant.”
The phase 1 trial is slated to have six patients with relapsed or refractory AML — those with at least one prior line of chemotherapy and who have residual disease. Individuals who have relapsed after bone marrow transplant are also eligible.
Study participants will receive lymphodepletion with fludarabine plus cyclophosphamide, and then a single infusion of the CAR T cells.
“After that, we want to expand the study,” Park said. “We want to identify the right dose for these patients first in the dose-escalation portion of the study and then treat more patients to validate the efficacy and safety findings.”
The first six patients will receive a bone marrow biopsy at weeks 2 and 4.
“If I don’t see any leukemia cells in 2 weeks, I'll be ecstatic,” Park said.
“If I don’t see any in 4 weeks and begin to see normal myeloid cells recover, then I’d be even more ecstatic because that means these CAR T cells are working exactly how we predicted them to be,” he added. “Even a response in one patient would be very exciting in this field where no immunotherapy has shown to be successful, and no standard therapy exists.”
Potential adverse events include cytokine release syndrome and infection, although Park said immune effector cell-associated neurotoxicity syndrome is less of a concern in patients with AML based on experience to date.
“These patients are very sick; some don’t even make it.”
Future of AML therapy
Researchers at Memorial Sloan Kettering are also investigating CLL-1 armored with interleukin-18 for patients with AML, Park said.
“That is the other CAR that we are also excited about,” he added.
Allogeneic CAR-T are also being researched in industry-sponsored studies, which increases the number of potential treatments this patient population may be able to choose from.
“I’m excited about this era right now,” Park said. “If not our product, hopefully one of these other products will not only help us learn more but get into that first real activity that all of us will be excited about and finally offer hope of a cure for our patients.”
Park hopes to have preliminary data on the new trial by the end of the year or early 2025.
“It’s kind of like a baby being born,” he said. “Now, I have to see how they grow. It’s that feeling of the delivery room that finally is happening now. I can’t wait to see what it’s going to bring us.”
For more information:
Jae Park, MD, can be reached at parkj6@mskcc.org.
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