Natural Killer Cell–Based Immunotherapy: A Less Toxic Treatment for Leukemia?

Although chemotherapy and radiation have long been standard treatments for leukemia, immunotherapies have been increasingly researched and are considered promising options. A recent review assessed current research on natural killer (NK) cells, which serve as the first line of defense against cancer and play a key role in mitigating abnormal cell population growth.

Leukemia is a bone marrow and blood cancer characterized by irregular hematopoietic stem cell differentiation, with main subtypes including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia CML, and chronic lymphocytic leukemia (CLL). NK cells play a key role in the recognition and cytolysis of abnormal and rapidly proliferating cell populations.

The review, published in Cancers, explores current research on NK cells and their potential uses in leukemia treatment.

Compared with traditional chemotherapy and radiation, which cause non-specific cell destruction and increase patients’ susceptibility to infection, adverse side effects, and immune cell inactivation, immunotherapies such as NK cell-based therapy are targeted and antigen-specific, using the patient’s own immune system to fight cancer cell growth.

NK cells typically make up approximately 10% of lymphocytes circulating in the body, moving in a latent state until receptor-ligand interactions stimulate them. NK cells do not have cytotoxic properties when in contact with healthy host tissues or cells, but they release lytic granules or produce cytokine to destroy any virally infected or cancerous cells they encounter. Research has shown that leukemia results in a decrease in the number of active NK cells as well as in their cytotoxic and degranulation abilities.

Thus, NK cell-based immunotherapy aims to increase NK cell activation by blocking the inhibitory interactions that occur when NK cells encounter healthy cells under normal conditions. This type of treatment also expands NK cell populations and enhances their overall function.

NK cell-based immunotherapies being studied for leukemia treatment include:

• adoptive transfer
• monoclonal antibodies (mAbs)
• chimeric antigen receptor-NK Cells (CAR-NKs)
• bi-specific/tri-specific killer engagers (BiKEs/TriKEs)

Current research on these therapies aims to induce complete remission in patients and minimize the adverse side effects often associated with them.

Monoclonal antibodies. One of the most common forms of NK cell-based therapy are mAbs, which block specific biomarkers and increase antibody-dependent cellular cytotoxicity to boost NK cell function. Combination therapy with different types of cytokines is one potential method of increasing NK cell populations. A small phase 1 trial of NK cells combined with the mAb rituximab after chemotherapy produced complete response in 7 of 9 patients.

Adoptive transfer. This method involves isolating NK cells from peripheral blood, bone marrow or umbilical cord from the patient (autologous) or a healthy donor (allogeneic) and purifying or genetically modifying the cells with cytokines before infusing them back into the patient. When the NK cells encounter incompatible ligands, graft-versus-leukemia can occur and increase their activity to kill leukemic cells. This has been found effective in AML especially, although relapse is common and post-transplant pharmacological intervention is a key aspect of success.

CAR-NK cell therapy. This treatment is in experimental phases, but it may be capable of killing cancer with minimal risk of toxicity or graft versus host disease (GvHD). This makes CAR-NK a potentially less toxic option than CAR-T cell therapies, which have shown success in refractory and relapsed B-ALL cancers but often cause neurotoxicity, cytokine release syndrome (CRS), and come with a higher risk of GvHD. CAR-NK also has the potential to be more accessible, because it does not have to be individualized to each patient and can come in an off-the-shelf form.

BiKEs and TriKEs. These are engineered mAbs, created by fusing together single-chain variable fragments to make them bi- and tri-specific for certain tumor antigens. NK cells can recognize the BiKEs or TriKEs, then induce apoptosis of their target. The study authors note that while BiKEs have shown some success in inducing antibody-dependent cellular cytotoxicity on target cells, TriKEs have shown superiority in inducing cytotoxicity, degranulation, and cytokine production.

Leukemia cells have been shown capable of manipulating expression of NK cell receptors to go unrecognized by NK cells, and targeting the biomarkers involved in this process could also be an avenue of treatment as these therapies are explored. Specifically, NK cell receptors 2B4, CS1, and LLT1 might be effective targets.

Continued research and clinical trials are needed to determine the effectiveness of NK cell-based treatments, with some already ongoing. Researching the specific receptor-ligand interactions that make NK cells cytotoxic in the presence of cancer cells may also aid in the understanding of these treatments, the authors noted.

Overall, study authors see great potential in NK cells as future leukemia treatments are developed. “In addition to providing an alternative therapy for patients who may not respond to conventional treatment, NK cell immunotherapy focuses on harnessing a patient’s own immune system to fight cancer proliferation, minimizing off-target effects,” they wrote.

Reference

Allison M, Mathews J, Gilliland T, Mathew SO. Natural killer cell-mediated immunotherapy for leukemia. Cancers (Basel). Published online February 8, 2022. doi:10.3390/cancers14030843