A drawback of NK cells is they are short-lived and don’t proliferate inside the body. To overcome that, Dr Rezvani engineered the cells to produce a growth factor, IL-15, prolonging the cells’ persistence. As a precaution against uncontrolled growth, the researchers also included a “safety switch” by which they could shut down the cells by administering a small-molecule drug for reversal, if need be. “We never had to use that safety switch in any of our patients,” said Dr Rezvani. “None of the patients developed any toxicity, and none developed any uncontrollable growth of these NK cells.”

According to the paper, the engineered NK cells persisted in the patients for at least 12 months, an observation that Dr Campana called “puzzling,” because allogeneic cells typically are rejected within 2 weeks of infusion.

“That is a surprising finding, and we need to really go to the bottom of it,” Dr Campana said. It may be that cord blood cells stimulate less rejection than adult cells, or there may be something else at work. In any event, he said, while CAR-T cells have been shown to persist for up to 2 years, that longevity may not be necessary for NK cells to be effective, because they are also so cytotoxic.

“I think it’s important evidence that these cells are clinically effective,” said Veronika Bachanova, MD, PhD, associate professor of medicine at the University of Minnesota in Minneapolis, on the recent findings. However, she cautioned that it’s difficult to assess how much of the remission seen was due to the CAR-NK therapy alone. “Many of these patients received subsequent therapy,” she said. “That’s the biggest uncertainty of this paper.”

Of the 8 patients who showed a response to the NK cell therapy, 5 received additional treatments. Two patients received chemotherapy for minimal residual disease, and 2 others received hematopoietic stem cell transplantation without evidence of minimal residual disease. The fifth patient had started with CLL with Richter transformation, and after treatment with CAR-NK cells, the high-grade lymphoma went into remission, but the CLL persisted, and the patient was treated with chemotherapy.

The researchers are working on cryopreservation of NK cells in hopes of creating a truly off-the-shelf product. A larger, multicenter study is planned for next year in conjunction with Takeda. “Hopefully then we’ll be able to confirm the results that we’ve observed at MD Anderson to a larger group of patients,” Dr Rezvani said.

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“I think that allogeneic products are ultimately where we should be going,” said Dr Campana. In an academic setting, he noted, it’s no problem to make cells for each patient, but scaling that up poses a significant logistical challenge. Ultimately, CAR-T and CAR-NK cells could provide a powerful combination therapy. “I personally think the cells are complementary, and we’ll end up using both in the future,” Dr Campana said. “That’s how the immune system works.”

“The field is moving very fast,” added Dr Bachanova. “This is very nice; to see the safety of this particular genetically modified product. It opens a door for the field of NK cell therapeutics.”

References

  1. Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382:545-53.
  2. Marin V, Kakuda H, Dander E, et al. Enhancement of the anti-leukemic activity of cytokine induced killer cells with an anti-CD19 chimeric receptor delivering a 4-1BB-ζ activating signal Exp Hematology. 2007;35(9):1388-1397.