In cancer immunotherapy, it’s all about the T cells and B cells. Could natural killer cells be the next rising star in fighting tumors?

At any given time, more than two billion natural killer (NK) cells circulate throughout the human body, cornering and identifying infected cells and binding to tumor cells.

NK cells got their name after scientists discovered, during mouse experiments in the 1970s, that the cells—part of the innate immune system—seemed to be able to kill a target tumor cell spontaneously and without prior activation.

Flash forward 40 years, and scientists are now engineering NK cells from human stem cells and transplanting them into cancer patients. Could this be the next big wave in cancer immunotherapy? At this week’s Molecular Medicine Tri-Conference in San Francisco scientists described some of the ongoing work in trying to harness these NK cells as cell-based therapy, and the hurdles that need to be overcome to make this strategy work in patients.

While NK cells are considered part of the innate immune system, Jeffrey Miller, a cell biologist and deputy director of the University of Minnesota’s Masonic Cancer Center, says some subgroups of NK cells also have adaptive qualities. They can exert immunological memory after contact with viruses and remember the inflammatory cytokines induced in response to tumors. This has made NK cells an important player in the development of immune-based therapies against cancer.

Miller, a pioneer in the research of NK-cell immunotherapy, has developed a number of different platforms that companies are now using to design NK-based therapeutics. One strategy, dubbed a tri-specific killer engager, takes a Y-shaped monoclonal antibody and binds one of the arms to an antigen on the surface of a tumor cell, the other to a receptor on an NK cell and then bridges them with a cross-linker of modified IL-15 cells to enhance proliferation of NK cells. A small phase 1 trial of patients with B-cell lymphoma and leukemia launched last year is testing this strategy.

The immunotherapy company NantKwest, meanwhile, just received Investigational New Drug approval from the US Food and Drug Administration to conduct a safety study of its genetically engineered, allogenic, off-the-shelf, natural killer cell therapy for the treatment of cancer.

But NK-cell based therapies have significant hurdles to overcome. It’s hard to predict the success of NK-based interventions, particularly those aimed at solid tumors, because the dominance of the tumor-induced microenvironment interferes with immune responses. And while animal and early clinical trials have found the use of NK cells to be safe, the cells don’t persist well after transplant and manufacturing enough of them to make the strategy effective is really hard to do.

Dean Lee, director of the Cellular Therapy and Cancer Immunotherapy Program at Nationwide Children’s Hospital in Columbus, Ohio, has resolved the weak NK expansion that occurs after the NK cells by engineering an artificial antigen presenting cell to express a protein that has a potent regulatory effect on NK cells.

Lee’s group has conducted seven different clinical trials, including one where NK cells were infused directly into the brain. The trials consisted of 200 infusions—120 intravenously and 80 through intraventricular injection—in 80 patients.

“NK cells are the hub around imuno-oncology,” says Lee.

Mouse Models in Immuno-Oncology

There are different immune-oncology strategies in play, including antibody drug conjugates, checkpoint inhibitors that target T-cell co-inhibitory receptors CTLA-4 and PD-1 and, more recently, chimeric antigen receptor (CAR) T cell therapy where immune cells are genetically modified to hunt down and destroy cancer cells. There are different mouse models that can be used to test the efficacy of drug responses using all these different strategies, including syngeneic mice that have a fully intact murine immune system, genetically engineered mice grafted with cancerous tissue from human patients—called the patient-derived xenograft—humanized mice that have some components of a human immune system and even humanized versions of PDX models.

All have their limitations, though, says Winfried Elias, a project manager of Charles River’s Cancer Discovery group. “There is no such thing as a mighty mouse,” says Elias.