Viruses, infectious microbes, and cancers might invoke fear in healthy humans, but the foreign invaders and mutants have a boogeyman of their own: natural killer (NK) cells. These immune cells certainly live up to their ominous name. 

NK cells lurk in your tissues and bloodstream, are the first to respond to molecular signals from damaged or stressed tissues, and mobilize the rest of your immune system -- including T cells, B cells, and the like -- to get to work. Researchers have shown that NK cells can still wreak havoc on cancer when other immune cells are disabled, they're the tumor-busting force behind the health benefits of exercise, and long-term survival rates for some of the deadliest cancers appear to be influenced by the activity of NK cells and the genes that control them.

That's led to a healthy amount of research into NK immunotherapies, which could boast significant advantages over first-generation immunotherapies based on chimeric antigen receptor T-cells (CAR-T). Unfortunately, biopharma companies have been largely unable to replicate the inherent seek-and-destroy capability of NK cells in early stage clinical trials. Can they ever live up to the hype?

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Why develop NK immunotherapies? 

NK cells were first explored as immunotherapy candidates in the 1980s, but human understanding of biology and biomanufacturing kept a tight lid on the potential. Decades later, the field is finally catching up. That's important because, on paper at least, immunotherapies based on NK cells boast several noteworthy advantages over CAR-T therapeutics.

For instance, NK cells and CAR-NK therapeutics can be produced from inherently allogeneic ("off-the-shelf") cell lines, which means a single cell line or donor could produce an infinite number of therapeutic doses. CAR-T medicines have to be strictly matched from donor to patient, or engineered with gene editing platforms such as CRISPR, which increases manufacturing steps and drives drug prices higher.

Allogeneicity also means engineered NK cells don't trigger negative immune responses in patients, such as cytokine release syndrome, which has led to multiple clinical holds and patient deaths for trials involving CAR-T therapies. That should allow each dose to drive a more durable response, and could allow patients to receive multiple doses of NK therapies, which could significantly improve clinical outcomes and survival rates compared to CAR-T therapies. 

Perhaps most important, NK cells can identify and target cancer cells with or without CARs. That should significantly lessen the risk that cancers develop resistance to treatment and reemerge in patients stronger than before, which is possible with molecular antibodies, checkpoint blockade (CPB) drugs, and CAR-T medicines. It could also create the opportunity to combine immunotherapies to create a one-two punch that sends cancer cells to their death. 

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What companies are working on NK cells?

Established companies have largely remained spectators when it comes to NK immunotherapy development, but that was also true for CAR-T, gene therapies, and liquid biopsies until concrete clinical evidence demonstrated the business potential of each approach. Fate Therapeutics (NASDAQ:FATE) is one of the more reputable companies working on the opportunity, and it sports a market cap of a relatively lowly $1 billion. Most other pure play NK stocks are embroiled in controversy, valued at a few hundred million dollars or less, or still early stage start-ups out of reach of individual investors.

Fate Therapeutics is developing six unique drug candidates that rely on NK cells to target a range of solid tumor and blood cancers. Some are derived from universal cell lines, while others come from donors. Some are monotherapies, while others are combined with checkpoint inhibitors. Its lead drug candidate, FT500, was cleared to begin clinical trials in November 2018, and the first patient was dosed in April 2019. The NK immunotherapy is being combined with separate monoclonal antibody CPB drugs with the aim of avoiding or overcoming the development of tumor resistance to treatment.

The business ended March with $183 million in cash on hand, and reported an operating loss of $20 million in Q1 2019. Expenses will creep up as Fate Therapeutics advances more drug candidates in the clinic, but promising results could help it snag a deep-pocketed partner. Considering it remains one of the only reputable pure plays in NK immunotherapies and is exploring multiple approaches, investors might keep it on their watch lists.

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Investors can also explore companies harnessing the power of NK cells a bit more indirectly. For instance, Affimed Therapeutics (NASDAQ:AFMD) is developing a pipeline of drug candidates that allow your body's NK cells to recognize cancer cells that have disguised themselves. The company is exploring three experimental therapies aimed at Hodgkin's lymphoma, other lymphomas, multiple myeloma, and various solid tumor cancers. Promising preclinical results have resulted in a partnership with Merck to explore a combination therapy involving Affimed's innate cell engager technology (which mobilizes NK cells) and Keytruda (a checkpoint-inhibiting monoclonal antibody).

There's also Nektar Therapeutics (NASDAQ:NKTR), which has struggled to communicate its strategy but dazzled investors with pipeline updates recently nonetheless. The company is developing NKTR-255 to invoke long-term immune responses, primarily by mobilizing your body's NK cells to recognize stealthy cancer cells. It's currently being explored as a combination therapy with CAR-T medicines in blood cancers and with antiviral therapeutics in a collaboration with Gilead Sciences.

A long way to go, but the promise is undeniable

The enormous potential of NK cells has largely remained out of reach of biopharma companies to date, but recent successes in CAR-T immunotherapies and biologic drug manufacturing have injected more confidence into the fledgling field of NK immunotherapies. It's reasonable for investors to consider successful development a matter of "when", not "if", but the opportunity is still wide open.