Natural born killers: harnessing innate immunity to fight severe infections

Our immune systems are composed of many types of blood cells that protect us from viruses, bacteria and even cancer. These diverse cell types each perform distinct functions and must synergize to effectively fight infections or cancer development. Some of these cells, like B or T cells, are trained up against specific molecules presented on infected cells or cancer cells. These molecules function like “Wanted” posters. When the B or T cells see the bandits presented on the posters running amok in the body, they attack them to neutralize the threat in the body. While the approach from these cells is highly specific and effective, it takes much longer because the cells must wait until they see a suspect on the “Wanted” poster.

Other immune cells take a more vigilante approach to infections or cancer. Instead of waiting until they see a poster, they constantly patrol the other cells around them in search of suspects. When these immune cells find a suspicious-looking cell, they instantly attack and sound the alarm to start the response from the slower immune cells. These patrolling immune cells are called Natural Killer (NK) cells, and they are one of the body’s frontline defenders against infections and cancer.

Because of the broad specificity of NK cells against other sick cells, they are a promising candidate for therapeutics in many different contexts. The idea is relatively simple: If you infuse NK cells into patients having a hard time fighting infections, the new NK cells will scan for and eliminate any invaders or cancer cells in the individual’s body. This NK boost would be especially useful in people whose own immune systems are compromised, like the elderly or cancer patients, and could potentially shorten the duration of an infection or extend patient survival.

Because NK cells also target cancer cells, they also hold therapeutic potential for cancer patients in the absence of infection. Dr. Colleen Delaney, a founder of Deverra Therapeutics and former faculty member at Fred Hutch, has been developing this alternate form of cell therapy for decades. She and her colleagues have created methods to derive NK cells from healthy donor blood. Once the NK cells are produced, the team freezes vials of them until they are ready for use in patients. When a patient is selected as a candidate for infusion, the team can grab a vial from the freezer, thaw the cells out, and inject them into the patient. Delaney and her colleagues are actively developing this system to fight blood cancers like AML. Still, they knew that their NK cells held the potential to treat other things.

With the onset of the COVID-19 pandemic, Delaney teamed up with Dr. Joshua Hill in the Vaccines and Infectious Disease Division to test the potential of NK cells to treat severe COVID-19 cases. “The pandemic hit, and we felt obligated to investigate whether NK cells could provide an anti-viral effect,” said Delaney. To do this, they conducted a phase 1 clinical trial testing the safety of NK cells in patients with severe cases of COVID-19. For their trial, the group identified nine hospitalized COVID-19 patients whose immune systems could benefit from a boost. Three of these patients had some type of blood cancer, and eight of them had comorbidities like hypertension or type 2 diabetes that made it more difficult for them to fight the COVID infection. The participants were divided into three groups that received an infusion of 100 million, 300 million, or 900 million NK cells.

Because this was a phase I trial, the primary goal is to evaluate the safety of NK cell infusion in COVID patients. Throughout the trial, no adverse side effects were reported from any of the patients that received the NK cell infusion, highlighting the safety of this tool for infections. The researchers were especially concerned about recipients developing cytokine release syndrome, a life-threatening condition that is caused by the recipient immune system overreacting to cell therapy. To this end, they analyzed the concentration of different inflammatory cytokines in each recipient’s blood. There was no spike in any inflammatory cytokine immediately after infusion, but there were subtle increases that eventually resolved after four weeks. Given the limited number of patients in the study, much more work needs to be done to fully assess the safety of NK cells for infections.

Though conclusions about efficacy are limited based on the results of this trial, seven of the nine patients were discharged without complications after receiving the NK cell infusions, highlighting their potential to effectively treat COVID. In the future, Hill hopes to conduct “more studies, and better studies with controls, of NK cell therapy for infection prevention and treatment in highly immunocompromised patients,” and to analyze the effectiveness of these cells in other types of infections.

Delaney is very hopeful for the future of her product. Because NK cells do not cause severe reactions due to host incompatibility like other types of blood cell therapies, researchers can pool NK cells from several donors into the same product. Their potential for targeting many types of ailments and promising safety profile could make them a cost-effective, accessible tools in hospitals that cannot access more expensive and complicated cell therapies. “We need these types of products,” says Delaney, “to make [cell therapy] affordable and easily delivered.”

This work was supported by a grant from Deverra Therapeutics.

Liu WL, Kampouri E, Bui JK, Sekhon MK, Tercero A, Finlay D, Asghedom LH, Romasanta GR, Rice NT, Ranjbaran F, Stoltzman C, Cook J, Blake J, Delaney CS, Hill JA. 2024. Off-the-shelf allogeneic natural killer cells for the treatment of COVID-19. Mol Ther Methods Clin Dev. 32(4):101361.