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Jul 28, 2016
 |  BC Innovations  |  Tools & Techniques

Innate harmony

Why NK cells are the next big thing in immuno-oncology

On the heels of cancer immunotherapy's clinical success, NK cells - a long-known but underappreciated component of the innate immune system - are emerging as the hottest new tool to fight cancer, with the potential to be safer and more broadly effective than their adaptive immune system counterparts.

The excitement centers on the potential of NK cells to solve some of the challenges of chimeric antigen receptor (CAR) T cells, allowing companies to bring together the immune system's innate and adaptive arms in a more comprehensive approach to creating tumor immunotherapies.

"People who aren't in the field would certainly know about T cell CARs, but few people know about natural killer cells and the important role they play in the immune response against tumors. If you're looking for the next big thing to come down the road in cancer immunology, NK cells are certainly it," said Daniel Kaufman, professor of medicine and director of the Cell Therapy Program at the University of California San Diego.

Unlike T cells, which recognize a specific antigen to elicit cytotoxic activity, NK cells can non-specifically find and destroy tumor cells and other abnormal cells. In addition, their mechanism avoids some of the key liabilities of T cell therapies.

Despite producing some dramatic clinical results in blood cancers, CAR T cells are still on shaky ground because their potential to overstimulate the immune system can lead to severe, possibly fatal, toxicities.

That vulnerability was underscored earlier this month when FDA placed a temporary clinical hold on Juno Therapeutics Inc.'s Phase II trial of its JCAR015 CAR T therapeutic after two patient deaths from cerebral edema were reported. The trial - which restarted after five days, in patients not taking fludarabine - is evaluating JCAR015 for relapsed or refractory acute lymphoblastic leukemia (ALL).

But NK cells don't carry cytokine-related dangers because they don't undergo in vivo clonal expansion like T cells. That expansion leads to a rapid increase in release of cytokines that can overwhelm the immune system.

"T cells can secrete cytokines that cause cytokine release syndrome and neurotoxicities, which haven't been associated with NK cell fusions," said Nicolai Wagtmann, CSO of Innate Pharma S.A., a company developing bispecific antibodies to increase NK cell activity. He added that early clinical studies on NK cells showed no cytokine-related side effects.

The cells also have a manufacturing advantage over CAR T cells. They can be produced as an off-the-shelf product because they don't cause graft-versus-host disease (GvHD), and donor-sourced cells are actually more effective at killing tumors than patient-derived cells.

"A lot of people have hit upon NK cells as the next big thing because they can be done on a bigger scale without having to go through the individual patient collection required for CAR T cells," said Kaufman.

At least seven companies have NK cell therapies in clinical and preclinical development (see Figure: Natural death). The most advanced product, CNDO-109-Activated NK cells, are donor NK cells primed with a cancer cell line cell lysate to activate the cells prior to delivery. Fortress Biotech Inc. has the cells in a Phase I/II trial for acute myelogenous leukemia (AML).

Killing them softly

NK cells were discovered more than 40 years ago, but interest in them has undergone a resurgence in the last 10 years in oncology following the discovery that patients with impaired or...

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