Cord blood stem cells have long been used in the treatment of over 80 diseases and are being explored in the clinical setting to treat several degenerative diseases. Among the different types of stem cells that cord blood contains, natural killer (NK) cells exhibit unique properties capable of targeting cancer cells and virus-infected cells. With the sudden outbreak of viruses such as COVID-19, otherwise known as coronavirus, there becomes an even greater need to seek “off-the-shelf” treatments that are quickly accessible to patients. Recently, NK cells have been the target of study at MD Anderson Cancer Center in which researchers are isolating these cells from cord blood and using them “as is” in addition to developing them into a CAR-NK cell product to treat certain types of cancers. The expected advancements of NK cell therapy continue to stress the unknown potential of stored cord blood. Let’s take a further look at cord blood-derived NK cells and see how they may play a role in innovative treatment therapies for some of today’s prevalent conditions.
NK Cells Deliver Safe and Feasible Results for Certain Cancers
Numerous clinical trials have shown that allogeneic NK cells alone can target
different types of cancers such as acute myeloid leukemia (AML), melanoma, renal cell carcinoma, Hodgkin lymphoma, breast and ovarian cancer, and refractory lymphoma. Compared to other types of stem cells such as Treg (T) cells, NK cells are considered "ready to go" because they have the ability to fight anything they recognize as foreign and do not require a previous encounter with the malignant cells in order to respond. In addition, while T-cell therapies such as anti-CD19 chimeric antigen receptor (CAR) T-cell therapy have shown substantial clinical efficacy in B-cell cancers, the CAR T cells can have toxic effects and manufacturing these types of cells present complex limitations.
Kathy Rezvani, M.D., Ph.D. and professor of Stem Cell Transplantation and Cellular Therapy at
MD Anderson is optimistic about the future of CAR-NK cell therapies stating, “Our vision is to improve upon existing treatments by developing armored CAR NKs that could be administered off-the-shelf in an outpatient setting—enabling more patients to be treated effectively, quickly and with minimal toxicities.”
Results from the phase I and phase II study published in the New England Journal of Medicine revealed, “The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.”
What makes cord blood-derived NK cells of more importance is the fact that there is a more rapid recovery of NK cells reported after umbilical cord blood transplants (UCBT) than peripheral blood hematopoietic stem cell transplantation (PB-HSCT). A
study demonstrated that faster recovery could be attributed to the fact that UCB contains different NK cell progenitor populations that have the capacity to differentiate into NK cells that are typically absent in peripheral blood. Further
research supports the idea that, “The expansion of NK cells derived from both fresh and frozen UCB [umbilical cord blood] CD34
+ cells using a cocktail of cytokines in a culture system has also been described as an efficient system to generate large numbers of NK cells.”
NK Cells Serve as Treatment for Viruses in Clinical Trials
NK cells are also being studied for their use in certain viruses. The state of a person’s immune system dramatically impacts one’s ability to fight off infectious diseases. Therefore, there is an emerging interest in finding new methods to address immunocompromised patients through adoptive cellular therapies. These types of patients and recent stem cell transplant recipients face a higher risk of developing complications due to viral,
fungal, or
bacterial pathogens.
Research shows that NK cells are able to directly kill their target by cytotoxic molecules and mediated apoptosis (programmed cell death). Likewise, these types of cells are able to change a patient’s immune response by secreting different chemokines to aid in the battle against foreign pathogens.
One publication elaborates on this point by suggesting, “a number of studies have demonstrated that genetic mutations may lead to reduced NK cell numbers or functional NK cell impairment such as mutations affecting genes
IL2RG,
JAK3, and
ADA which cause severe combined immunodeficiency syndromes.” Even more interesting, is the proposed evidence that different mechanisms trigger NK cells during influenza infection; and that these mechanisms listed as influenza nucleoprotein (NP) matrix 1 (M1) antibodies and CD16 impact the early activation of NK cells following the flu vaccine. After infection with the influenza virus,
functional NK cells act as innate effectors responsible for orchestrating antiviral responses. Ongoing animal and human clinical studies continue to illustrate NK cells as active key players in antimicrobial immunotherapy.
Thus, in light of the COVID-19 (coronavirus) cases, many have begun to link the idea of NK cells in the above-mentioned host-directed therapies to the potential to combat other types of viruses. Currently, there is a Phase II study taking place at MD Anderson Cancer Center to determine the safety and efficacy of mesenchymal stem cells (MSCs), which can be found in cord blood, to treat patients suffering from acute respiratory distress syndrome (ARDS) in combination with drugs. Cord blood-derived MSCs exhibit many beneficiary functions that have been explained in
past articles and numerous research studies. In particular,
cord blood MSCs from allogeneic donors are being evaluated to explore their role in the reduction of non-productive inflammation and how these cells affect tissue regeneration.
As pointed out in a most
recent article on the matter, “The isolation and short-term expansion of anti-viral directed T cells has been proven to be a life-saving procedure in patients after autologous hematopoietic stem-cell transplantation with cytomegalovirus infection. Expansion of anti-2019-nCoV-specific T cells, as cellular drugs, could aid to prepare T-cell products for the adjunct treatment of patients with severe 2019-nCoV infection.” However, animal studies conducted in mice hint at the potential of NK cells to target infectious diseases. Moreover, as studies continue to develop, and these cells are explored more, we may see NK cells as a desirable cell product. Given all that is known about NK cells and the fact that they don’t possess detectable graft vs. host disease, it makes them a safer and faster alternative to their other cell product counterparts.
In addition, umbilical cord-derived mesenchymal stem cells (UC-MSCs) could also show promise for the emerging treatment of COVID-19. Currently, there are three
clinical trials taking place to inspect the safety and efficiency of human umbilical cord mesenchymal stem cell therapy for severe pneumonia patients infected with 2019-nCoV. Likely, more umbilical cord clinical trials will evolve in light of one such particular
case concerning a 65-year-old Chinese woman who was reportedly treated with three shots of umbilical cord stem cells and showed a "startling recovery." More research is needed to determine the exact role that these stem cells play as the race to find an effective treatment progresses.
As research continues to bridge the gap between the unknown and the proven, we may see the popularity in NK and other umbilical cell products rise. The possibility to manufacture NK cells with coronavirus antibodies would be an innovative concept and could serve as a treatment option to advance in the upcoming years. The logistics surrounding engineered cord blood NK cells may deliver a nearly immediate solution in response to the limitations associated with current cell therapies.