The Role of CAR NK Cells: Competition or Complement to CAR T-Cell Therapy?

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for some hematological malignancies, and there are hundreds of trials investigating CAR T-cell therapies in hematology and oncology. However, these therapies are complex to produce.

CAR-engineered natural killer (CAR NK) cells may be an alternative that compete with and complement CAR T-cell therapy, explained Ulrike Köhl, PhD, MD, professor of immune oncology and director of the Institute for Clinical Immunology at the University of Leipzig and director of the Fraunhofer Institute for Cellular Therapeutics and Immunology in Leipzig, Germany, during a plenary session at the European Hematology Association 2021 Virtual Congress.

For both CAR T cells and CAR NK cells, effector cells cannot recognize cancer cells to start killing, but transduction of the respective effector cells results in a new receptor that is upregulated on the surface and binds to the cancer cell. The benefits of CAR T-cell therapies in diseases like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) has become well known. There are approximately 800 trials worldwide, Köhl said.

“But we are also aware that manufacturing of these autologous personalized CAR T cells is very complex,” she said. The process includes stimulation, transduction, expansion, and formulation. The average duration to manufacture CAR T cells is about 12 days, but it can take as long as 22 days.

Quality control is also challenging, and the CAR T-cell product can fail. Studies have shown that between 1% and 12% of patients, and possibly even up to 17% of patients, the product fails.

“What's the reason for that? These are heavily pretreated patients with a limited bone marrow function [and] less functional and exhausted T cells,” Köhl explained.

With NK cells, there is experience with allogeneic NK cell trials that show a good graft versus leukemia effect without graft-versus-host disease (GVHD), she said. A study of NK cell trials found that interleukin (IL)-2 stimulation led to improved NK cell cytotoxicity, but there was the disadvantage of tumor immune escape.

Köhl gave the example of a child with acute myeloid leukemia (AML) in an early relapse state, who reached complete remission 1 month after NK cell application. “Unfortunately, this did not last very long,” she said. “And this is due to tumor immune escape mechanism.”

Trials that redirected NK cells showed improved results. For instance, in ALL, donor NK cells activated with cytokines against ALL cells killed 70% of the leukemic cells, and when the NK cells were redirected, they could completely eliminate all of the ALL cells, according to Köhl.

Similar results were seen in AML, where activate NK cells had good activity against AML cells, but redirected CAR NK cells “killed much better.”

There is a growing interest in CAR NK cells. Worldwide, there were 20 trials in 2019: half were redirected against CD19 and the other half against different cancer epitopes. A year and a half later, there were 35 trials.

The first in-human trial in the United States led by Katy Rezvani, MD, PhD, at the University of Texas MD Anderson Cancer Center, tested CAR NK cells in patients with relapsed refractory B lymphoid malignancies redirected against CD19 and encoded with IL-15 for long-term persistence.¹ In the 11 patients, there were good clinical outcomes: of the 8 patients who had a response, 7 had a complete remission.

Rezvani and her colleagues postulated that a single cord-blood unit could produce more than 100 doses of CAR NK cells with which to treat patients. In addition to the good response, there was no cytokine release syndrome, no neurotoxicity, and no GVHD.

Given the results seen with CAR NK cells, could they compete with CAR T-cell therapy? Köhl doesn’t think it’s that simple.

“We need both,” she said. “They clearly have also different roles,” with CAR NK cells possibly being used as a bridge to transplantation.

Reference

1. Liu E, Marin D, Banarjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545-553. doi:10.1056/NEJMoa1910607