Natural killer cells derived from donated umbilical cords could be modified to seek and destroy some types of leukemia and lymphoma.
Donated cord blood may provide an attractive, allogeneic, off-the-shelf source of natural killer cells for immunotherapy. Researchers at the University of Texas MD Anderson Cancer Center report in the journal Leukemia that this approach should greatly improve the logistics of delivering chimeric antigen receptor (CAR) T-cell therapy to large numbers of patients, which is a major limitation for current CAR T-cell therapies.
“We can basically come up with an off-the-shelf product. You can make accessibility easier and potentially cheaper,” said Katy Rezvani, MD, PhD, a professor of stem cell transplantation and cellular therapy at MD Anderson Cancer Center in Houston.
The team’s preclinical research showed that natural killer cells derived from donated umbilical cords could be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering was also able to boost their persistence and embed a suicide gene that allowed the modified cells to be shut down if they caused a severe inflammatory response.
A first-in-human phase I/II clinical trial of these cord blood–derived, CAR–equipped natural killer cells is now underway at MD Anderson for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or non-Hodgkin lymphoma. “The first patient has been treated and the trial is up and running,” said Rezvani in an interview with OncoTherapy Network. “If it is as successful in humans as it was in our animals, it could overcome the availability problem of CAR T cells.”
Natural killer cells are the immune system’s most potent killers, but they are short-lived and cancers manage to evade a patient’s own natural killer cells to progress. However, cord blood–derived natural killer cells are genetically equipped with a receptor that focuses on B-cell malignancies; interleukin-15 (IL-15) improves the function of these cells. Rezvani noted that IL-15 could help natural killer cells potentially persist for months instead of 2 or 3 weeks.
Using a retroviral vector, the researchers transduced natural killer cells taken from cord blood with the CD19-targeted CAR, IL-15, and an inducible caspase-9–based suicide gene. Cell line tests found the engineered natural killer cells to be more efficient killers of lymphoma and CLL cells, compared with unmodified natural killer cells.
Another experiment showed that the engineered cord blood–derived natural killer cells killed CLL cells much more efficiently than natural killer cells taken from CLL patients. Mouse model lymphoma experiments using a single infusion of low-dose natural killer cells resulted in prolongation of survival. At a double dose, none of the mice treated with the natural killer cells expressing IL-15 and CD19-targeted CAR died of lymphoma, with half surviving for 100 days and beyond. All mice treated with other types of natural killer cells died by day 41.
The researchers are also developing cord blood–derived natural killer cells for other targets in a variety of blood cancers and solid tumors. “We are testing our strategy against lung and breast cancer in vitro and in animal studies. If they prove to be successful, we will move to the clinic, but we are at least 2 years away,” said Rezvani.