University of California, Los Angeles Background
Natural killer (NK) cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells provide rapid responses to viral infection and are also crucial to inhibiting tumor formation. They are uniquely able to directly recognize and kill infected and cancerous cells. As such, there has been great interest in exploiting NK cell activity for cancer immunotherapy. A major hurdle in applying NK cells to the clinic is the unique immunosuppressive microenvironment found in tumors. Successful NK cell-mediated clearance and targeting of tumor cells is dependent on NK cells’ ability to effectively infiltrate tumors, reach high levels of activity, and differentiate fully into their mature cytotoxic form. A method for ex vivo expansion of NK cells that are less susceptible to these immunosuppressive effects (coined ‘supercharged’ NK cells has previously been demonstrated by researchers; however, immunotherapy with NK cells has been limited due to inability to obtain sufficient numbers of highly functional NK cells, and an effective means to activate patient NK cells in vivo. Thus, there is a great need to develop a method to efficiently increase NK cell activity in vivo. Here, researchers in the Jewett laboratory demonstrate a novel mechanism for producing large quantities of these super-charged NK cells in vivo.
UCLA Researchers in the Department of Dentistry have developed a method to stimulate NK cells proliferation and activation using gene knockdown. Genes crucial for cell differentiation were knocked down in human monocytes which were differentiated into osteoclasts. NK cells expanded and proliferated using these monocytes/osteoclasts were found to be more prolific and active. This approach is demonstrated to activate and expand large numbers of NK cells in vivo, in vitro, or ex vivo for use in immunotherapeutic strategies. The gene targeted in this approach can be targeted in immunotherapy strategies seeking to encourage activation of NK cells in vivo.
Stage of Development
The procedure has been tested in animal models and human cell lines.
Tseng, H-.; Arasteh, A,; Kaur, K.; Kozlowska, A.; Topchyan, P.; Jewett, A., “Differential cytotoxicity but augmented IFN- γsecretion by NK cells after interaction with monocytes from humans, and those from wild type and myeloid-specific COX 2knockout mice,” Front. Immunol., 2015, 6, 259. doi: 10.3389/fimmu.2015.00259
.Kozlowska, A. K.; Kaur, K.; Topchyan, P.; Jewett, A., “Adoptive transfer of osteoclast-expanded natural killer cells forimmunotherapy targeting cancer stem-like cells in humanized mice,” Cancer Immunol Immunother, 2016, 65(7),835-45.doi: 10.1007/s00262-016-1822-9.
Increased immune responses to tumors by super‑charging patient NK cells in vivo.
Allows activation of NK cell population in vivo (avoids ex vivo expansion).
NK cell immunotherapy in cancer patients.
Combination cancer immunotherapies.