It may be unsettling to contemplate, but the human body is constantly fighting cancer caused by genetic damage to its cells from chemicals, UV rays and biochemical mistakes. Fortunately, the immune system mops up the vast majority of those cells turning rogue — thanks in large part to early foot soldiers called natural killer cells, which are born with multiple ways to detect and destroy abnormal cells.

Scientists have long hoped to harness these vigilant natural killers for cancer therapies in the clinic. But until recently, they’ve been disappointed, as trials using transplanted natural killer cells to fight blood cancers have shown safety but little effect in slowing or stopping tumors.

In the last few years, though — following dramatic progress in immunology and genetic engineering — a wave of early clinical trials is at last giving encouraging signs.

In February, one of the first published findings in this new generation of natural killer cell trials appeared in the New England Journal of Medicine: It reported a high response rate and surprisingly low side effects among 11 patients with two forms of blood cancer when they were treated with natural killers genetically engineered to boost the targeting and destruction of cancer cells.

And natural killer cells also are starting to take on solid tumors. In December, at a cancer symposium in San Antonio, researchers reported encouraging preliminary findings in patients with metastatic triple-negative breast cancer, which is especially difficult to treat. When nine patients were given off-the-shelf natural killer cells in combination with other treatments, five of them saw their tumors shrink or become undetectable during the study period.

Immunity in action

Our immune system holds two main armies: the innate immune system and the adaptive immune system. Each includes many types of protective cells, and the two work together in complex ways to take out foreign invaders or body cells turned traitor.

The innate immune system is made up of cells already armed for all battles, such as natural killer cells, discovered and named in the 1970s. In contrast, the adaptive immune system includes the more familiar components — antibodies, T cells and B cells — that are highly specialized in their targets. Among these guardians, T cells are exquisitely tuned to defend against cells gone wrong by latching onto specific proteins on their surface.

Graphic describing key cells in the two main branches of the immune system. Cartoon versions of natural killer cells, T cells and B cells are depicted, along with some of their properties.

The immune system has two main parts. The innate immune system, which includes natural killer cells, responds to generic threats, such as cells that are missing molecules that identify them as normal body cells. In the adaptive immune system, T and B cells tailor their attacks to particular molecules, or antigens, of tumors or invading pathogens.

Harnessing T cells in immunotherapies — treatments that unleash the immune system against disease — has been the greatest recent success story in cancer, with several therapies approved by the Food and Drug Administration against blood cancers. In one breakthrough treatment called CAR T cell therapy, a patient’s own T cells are withdrawn and genetically modified so that they generate proteins called chimeric antigen receptors. These CAR proteins sit in the membranes of the T cells and grab onto specific proteins on the surface of cancer cells, triggering heightened attack.

But CAR T cell therapies are not cure-alls. Many patients don’t respond. The treatments need to be managed expertly to avoid dangerous side effects. The individualized manufacturing process, done to avoid an attack by the patient’s own immune cells, is slow and extremely expensive and doesn’t always produce usable cells.

Scientists believe that natural killer cell therapies may offer major advantages in safety, cost and feasibility over CAR T treatments. For one thing, infusing natural killer cells doesn’t provoke dangerous immune overreactions or attacks against the recipient’s healthy cells, so they can be transplanted from person to person without serious side effects.

“NK cells could be universally applied to many patients as an off-the-shelf product that’s processed in a few centralized high-throughput facilities, frozen and shipped around the country quite easily, then hung up and infused from a bag just like a bag of saline,” says Clint Allen, an ear, nose and throat surgeon and cancer researcher at the National Institute on Deafness and Other Communication Disorders.

The cells are also ready from the get-go to attack every incoming threat, be it a cancerous cell or a cell that’s been infected by, say, a virus or a fungus. “The beauty of NK cells is that they can be applied to all comers,” says George Ansstas, an oncologist at Washington University School of Medicine in Saint Louis.

Moreover, natural killer cell therapies can be repeated. That may turn out to be a requirement in treating many advanced cancers, since mature natural killer cells tend not to persist in the body for as long as T cells do — typically only a couple of weeks, which may not be long enough to truly stomp out the cancer threat. The plus side is that the treatment can be repeated and any toxic side effects should be temporary.

A killing machine

Natural killer cells have two main routes for recognizing abnormal cells. In one, they directly recognize that a cell is abnormal, usually because the rogue cell is not properly producing a set of proteins that should sit on its surface and signal to the immune system that it’s human. In the other route, natural killers attach to an antibody that has been placed on the abnormal cell to mark it for destruction.

In both cases, the natural killer cell releases a flood of molecules that can kill dangerous cells and enlist the help of T cells and other immune watchdogs.

Graphic showing how the activity of natural killer cells is regulated

Natural killer cells look for two kinds of signals that determine whether to attack another cell, as depicted in this simplified illustration. Top: If the NK cells see only “self” markers, such as major histocompatibility complex (MHC) proteins, they leave the other cell alone. Middle: If the NK cells don’t find “self” markers, the other cell must be foreign, and they attack. Bottom: If the NK cells see both “self” markers and unexpected molecules, such as certain markers carried by tumor cells, the other cell must be infected or abnormal, and they attack even more strongly.

The natural killer cell therapies under study also come in an array of flavors. As they have for decades, researchers are looking for drugs that might beef up the anticancer activity of NK cells already in the body.

More dramatically, there are also dozens of early transplant trials underway, targeting blood cancers and solid tumors. The studies employ a spectrum of approaches that infuse natural killer cells as one ingredient of many in a complicated therapeutic regimen.

The sources of the cells are varied: blood donated by family members or harvested from umbilical cords, natural killer cell-derived cell lines, and induced pluripotent stem cells — adult cells that were genetically returned to an uncommitted, plastic state and then reprogrammed to behave like natural killer cells.

In a trial that began in 2014 for patients with various advanced solid tumors, for example, the natural killer cells are healthy cells donated by family members, says Monica Thakar, a pediatric hematologist-oncologist at the Fred Hutchinson Cancer Research Center in Seattle. In preliminary findings Thakar plans to present at the 2020 meeting of the American Society of Clinical Oncology (held virtually because of the Covid-19 pandemic), results in the first 15 patients were encouraging, she says, and the therapy’s toxicity low.

A variety of clinical studies are built around cells created from a cell line called NK92 that was derived decades ago from malignant natural killer cells. NantKwest of Culver City, California, has set up 20 clinical trials and administered more than 700 doses of various forms of NK92 cells, according to the company. In the latest trials, the NK92 cells have been genetically modified for greater potency and staying power.

Allen is collaborating with NantKwest to launch a trial for head and neck cancer that he had hoped to start this summer before the Covid-19 pandemic. In this study, NK92 cells have been engineered to make two proteins. One, which sits on the surface of the natural killer cell, has been tailored to attach to antibodies on the surface of cancer cells. The second protein is a molecule known as IL-2, which helps the natural killer cells survive and expand.

The trial published in the New England Journal of Medicine, meanwhile, uses natural killer cells that are derived from cord blood and engineered to make a CAR protein. The therapy is analogous to the best-performing types of CAR T cell therapies, which target blood cancers that display a protein called CD-19 on their surfaces.

This therapy, given as a single dose, performed roughly as well as the CAR T therapies, scientists at the University of Texas’s MD Anderson Cancer Center in Houston reported. Among 11 patients with advanced blood cancers, eight showed a complete remission of their disease, with none of the dangerous side effects often seen with CAR T treatments. “We were very happy and very encouraged with these results,” says MD Anderson hematologist-oncologist Katy Rezvani, who led the trial. It is now being expanded to 60 patients and Rezvani is working with Takeda Pharmaceuticals, which licensed this product, for a phase 2 clinical study.

Other clinical trials are underway, such as one started in 2019 at UC San Diego that uses natural killer cells created from induced pluripotent cells against several types of solid tumors. The trial, which is sponsored by Fate Therapeutics of San Diego and builds on research by hematologist Dan Kaufman of UC San Diego and hematologist-oncologist Jeffrey Miller of the University of Minnesota Medical School, will be followed with trials of cells that are engineered to produce a CAR protein.

Combining for the kill

Scientists also are examining ways to combine NK cell therapies with various other cancer treatments — especially other immunotherapies. There’s plenty of evidence that this could be fruitful, says Miller, who co-authored a 2019 overview of natural killer cell therapies in the Annual Review of Cancer Biology.

Miller and many other researchers see particular promise in exploiting natural killer cells with an emerging class of immunotherapies called immune engagers. These therapies take the same basic targeting strategies of CAR cells, but without reengineering the natural killer cells themselves.

Graphic showing how chimeric antigen receptors and immune engagers work

Natural killer cells can’t always recognize key molecules, or markers, on the surface of tumor cells, which reduces their ability to attack. Here are two ways to enhance that recognition and thus make a better killer. Left: Biologists genetically modify the natural killer (NK) cells so that they have a new receptor on their surfaces. The engineered receptor contains the activation region of an ordinary NK cell receptor and a piece from an antibody that recognizes the tumor marker. This “chimeric antigen receptor” (CAR) allows the NK cell to recognize and attack tumor cells. Right: Instead of genetically modifying the NK cells themselves, biologists create “linker molecules” that bind to both an existing NK cell receptor and a marker on the surface of a tumor cell. This enables the NK cells to attack. These “immune engagers” sometimes also contain a third binding region that, additionally, triggers NK cells to proliferate, thus strengthening the immune response.

Instead, scientists manufacture, and then infuse into patients, molecules that are designed to attach tumor cells on one end and natural killer cells on the other — thereby stimulating the natural killer cells. The FDA has already approved one immune engager that links T cells to a type of leukemia cell. Miller and his colleagues hope to launch a similar trial for a natural killer cell engager as soon as recovery from the Covid-19 pandemic makes it feasible.

There’s no lack of ambition in natural killer cell research. Tapping into tricks developed for T cells, the efforts may soon surpass the T cell strategies in treating some diseases, particularly many solid tumors, where CAR T cells have struggled to achieve much. That’s partly because solid tumors have a huge bag of defensive tricks that make it hard for immune cells to attack, thus posing far more formidable obstacles than blood cancers for any immunotherapy.

Natural killer immunotherapy is in its infancy, Rezvani says. “We really don’t know what’s the best source for the cells. What’s the best way to expand the cells? What’s the best way to engineer the cells? What’s the best signaling molecule? There’s still so much that we need to learn.”