Chimeric Antigen Receptor-Natural Killer Cells Shows Promise in CLL, Non-Hodgkin Lymphoma

Patients with relapsed or refractory CD19-positive cancers who were treated with cord blood-derived chimeric antigen receptor (CAR) natural killer (NK)-cell therapy experienced responses without the development of major toxic effects, according to a phase 1/2 trial published in The New England Journal of Medicine.

CAR NK cells are taken from a non-related healthy donor and can be manufactured in advance and stored for “off-the-shelf” use. The reason this treatment option is appealing is that it is ready for immediate use, compared with other CAR therapies that require the use of a patient’s own genetically modified T cells, which are then created through a multi-week manufacturing process, according to a press release issues by The University of Texas MD Anderson Cancer Center (MD Anderson).

“We have shown that it is possible to produce more than 100 doses of CAR-NK cells from a single cord-blood unit,” the researchers wrote. “This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR-NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients.”

At the university, the NK cells are isolated from donated umbilical cord blood. The researchers genetically engineered the cells to recognize CD19, a cancer-specific target, and are reinforced with an immune signaling molecule, IL-15, that enhances the multiplication and survival of the NK cells.

In this study, the researchers administered a single dose of the CAR NK-cell therapy at one of three dose levels to 11 patients — five of whom had chronic lymphocytic leukemia (CLL) and six who were diagnosed with non-Hodgkin lymphoma.

At a median follow-up of 13.8 months, eight patients (73%) responded to therapy and seven of those achieved a complete response, meaning they no longer showed evidence of disease. One patient had remission of the Richter’s transformation component but had persistent CLL.

“Responses were rapid and seen within 30 days after infusion at all dose levels,” the researchers wrote. “The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.”

Post-remission therapy was administered to five of the responding patients.

“We are encouraged by the results of the clinical trial, which will launch further clinical studies to investigate allogeneic cord blood-derived CAR NK cells as a potential treatment option for patients in need,” corresponding author Dr. Katy Rezvani, professor of stem cell transplantation and cellular therapy at MD Anderson, said in a press release.

No patients experienced cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. Side effects experienced by participants were primarily related to the conditioning chemotherapy given before cell infusion and were resolved within one to two weeks, Rezvani said in the release. Moreover, no patient required admission to an intensive care unit for management of treatment side effects.

Lastly, the maximum tolerated dose was not reached.

“Due to the nature of the therapy, we’ve actually been able to administer it in an outpatient setting,” said Rezvani. “We look forward to building upon these results in larger multi-center trials as we work with Takeda to make this therapy available more broadly.”