January 2016, Vol. 3, No. 1
Using Natural Killer Cells in Immunotherapy: What Is Known, and Where to NextNatural Killer Cells
In their review article, Carin I. M. Dahlberg, PhD, from the Cell Therapies Institute, Nova Southeastern University, Fort Lauderdale, FL, and the Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, NOVUM, Stockholm, Sweden, and colleagues evaluated natural killer (NK)-cell–based therapies targeting cancer. In particular, they discussed current data on the use of NK-cells, as well as novel therapies, including genetic modification and complementary therapies seeking to improve the clinical outcomes of NK-cell–based immunotherapies.
“Even though NK-cell–based therapies represent one of the most promising strategies to combat cancer, to our knowledge, no clinical trial has clearly demonstrated a significant benefit in patients with malignancies,” the study authors explained. “Nevertheless, there is a lot of promise in early clinical and preclinical data that cannot be omitted. In the near future, different NK-cell–based products will reach multicenter clinical trial stage, and we will start to see efficacy data.”
Using NK-Cells in Cancer Care
Dahlberg and colleagues began their review by discussing the role of NK-cells in cancer. These types of cells recognize tumor cells by certain activating receptors, including natural cytotoxicity receptors that detect altered expression of their ligands on the tumor cell surface. Other mechanisms to trigger NK-cells include downregulation or lack of major histocompatibility complex (MHC) class I molecules on the cell surface of tumor cells, as well as mechanisms of action after these cells have been triggered, including upregulation of Fas ligand on the NK-cell surface, which can lead to apoptosis of the tumor cells.
However, tumors, including acute myeloid leukemia (AML), have gained the ability to evade NK-cells, according to the authors. The evasion of those cells in cancer has been associated with several mechanisms, including reduced natural cytotoxicity receptor surface expression, and upregulation of nonclassical MHC class I molecule human leukocyte antigen (HLA)-G. Furthermore, research in patients with cancer has indicated that NK-cells themselves may develop abnormalities. These include defective expression of activating receptors, which has been observed in several cancers, including hepatocellular carcinoma, metastatic melanoma, AML, chronic lymphocytic leukemia, and multiple myeloma. Defective NK-cell proliferation also has been observed in patients with metastatic renal-cell carcinoma and chronic myelogenous leukemia, whereas decreased NK-cell activity has been seen in patients with renal-cell carcinoma.
Furthermore, the authors discussed clinical-grade NK-cell products, as well as various sources of NK-cells. Most NK-cell–based products originate from peripheral blood mononuclear cells. Other sources include umbilical cord blood, cell lines, and human embryonic stem cells, as well as induced pluripotent stem cells.
In addition, Dahlberg and colleagues emphasize the important role of cytokines in ex vivo manufacturing of NK-cell–based products. In this setting, cytokines stimulate, differentiate, activate, and expand NK-cells. Interleukin (IL)-2 is one of the most popular cytokines used for this purpose. IL-15 is another important cytokine, because it is required for NK-cell maturation and survival. Other factors to consider when achieving clinically relevant NK-cell numbers, viability, and tumor cytotoxicity include the expansion platform, cell culture media, and serum supplementation.
NK-cell–based anticancer products have been used in the clinical studies of a wide range of patients with cancer, the authors continued. Adoptive autologous NK-cells have been studied in patients with breast cancer, lymphoma, glioma renal-cell carcinoma, non–small-cell lung cancer, and adenocarcinoma. Data show that these cells are safe and have no toxic side effects. Some clinical trials have shown that these types of cells only have partial effects on certain tumors, or do not lead to an improvement in patients with metastatic carcinoma or relapsed lymphoma.
Another NK-cell–based anticancer product is allogeneic NK-cell products, which have been used to treat patients with leukemia, renal-cell carcinoma, leukemia, colorectal cancer, hepatocellular cancer, lymphoma, and melanoma. However, the authors noted that the risk associated with allogeneic NK-cell transplantation is graft-versus-host disease. Precautions should be taken to reduce this risk, including immunosuppression, infusion of CD3-depleted high-purity NK-cells, and selecting the donor that matches the host HLA.
Dahlberg and colleagues then discuss immune suppression of NK-cells in the tumor microenvironment, noting that the efficiency of NK-cells targeting solid tumors has not been fully seen in the clinical setting.
Novel Uses for NK-Cells
Taking a closer look at future therapies, Dahlberg and colleagues review the use of genetically modified NK-cells. In particular, they explain that the specificity of NK-cells can be enhanced to the target cells by modifying them to recognize antigens specifically expressed on tumor cells. In particular, studies have shown that NK-cells that have been genetically modified to produce IL-2 or IL-5 cytokines have increased survival and proliferation, and enhanced activation and antitumor activity in vivo. The study authors also mention using another approach to genetically modify NK-cells, where tumor specificity can be enhanced via antibody-dependent cellular cytotoxicity.
Monoclonal antibodies (mAbs), including anti-CD20 (rituximab), anti–human epidermal growth factor receptor 2 (trastuzumab), anti-CD52 (alemtuzumab), anti–epidermal growth factor receptor (cetixumab), and anti-CD38 (daratumumab), have been developed to target specific tumor antigens. Dahlberg and colleagues go into detail about the uses of these therapies in different populations of patients with cancer. For example, they reported mild, infusion-related reactivity, and complete or very good partial responses with reduced bone marrow plasma cell levels in patients with relapsed myeloma who were treated with daratumumab. Furthermore, research has shown that combination therapy with mAbs, along with existing treatments, may enhance NK-cell activity in antitumor therapy. Several clinical trials have evaluated the use of completely human IgG4 anti–killer cell immunoglobulin-like receptor antibody (IPH-2101) as a single treatment, or in a combination, among patients with hematologic diseases.
To enhance NK-cell tumor reactivity, bi- and tri-specific antibodies cross-linking CD16 with tumor-specific mAbs have also been engineered from chimeric antigen receptors (CARs). In addition, the authors discuss the use of CARs fused with intracellular lymphocyte stimulatory molecules to create high-affinity, specific recognition of tumor antigens and tumors. The use of CARs has been extensively studied and has led to several phase 1 and 2 clinical trials. Only 2 clinical trials looking at CAR NK-cells have been approved, they noted.
Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, are another area of future research. These drugs can simulate NK-cells and T-cells, and may be better able to target cancer cells.
Combining NK-cell products along with other drugs that directly target tumor cells or modulate the cytotoxic activity of NK-cells may be useful if further research indicates that NK-cell products cannot fully eliminate tumor cells as a result of the immunosuppressive effects of the tumor microenvironment, or in vivo expansion and cytotoxicity. mAbs and IMiDs may be used together with NK-cell products to enhance tumor targeting and elimination. In addition, combination therapy with NK-cell–stimulating cytokines (IL-2, IL-12, IL-15, and IL-21) could be used to enhance NK-cell–mediating killing. NK-cell infusions plus chemotherapy could also be used as an alternative combination to overcome tumor-induced dysfunctions.
“NK-cell–based therapies are, in theory, complementary to many different upfront, maintenance, and late-line therapies,” Dahlberg and colleagues concluded. “Further studies clarifying the complementary efficacies and synergies have to be initiated to conclusively state if there is any place for these intriguing cells in [the] search for an effective treatment of cancer.”
- Dahlberg CI, Sarhan D, Chrobok M, et al. Natural killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity. Front Immunol. 2015;6:605.
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