Categories
Glycine Receptors

Recent evidence suggests non-expanded and expanded NK cells have different migration patterns when infused into animal models (61)

Recent evidence suggests non-expanded and expanded NK cells have different migration patterns when infused into animal models (61). available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors persistence, and doubts regarding their ability to migrate to tumor tissues following adoptive infusions. Although recent data have shown CMV reactivation reduces the risk for AML relapse following HSCT (11) potentially caused by CMV-induced NK cells cross-reacting with AML cells, NK cells, unlike T-cells, lack antigen specificity, further tempering enthusiasm for their use as immune effectors in cellular therapy. Genetic manipulation of NK cells to (+)-CBI-CDPI2 improve their persistence, cytotoxicity, tumor targeting capacity, and ability to home to disease sites holds potential to advance the efficacy of NK cell-based cancer immunotherapy. However, until relatively recently, (+)-CBI-CDPI2 the genetic manipulation of NK cells has proven to be challenging. Viral transduction, successfully used for T cells, has been associated with (+)-CBI-CDPI2 low levels of transgene expression and unfavorable effects on cell viability when used with NK (+)-CBI-CDPI2 cells. Recent optimization of viral transduction and the establishment of electroporation technologies for efficient gene transfection have revived the enthusiasm for studies evaluating genetic modification of NK cells. Investigators around the world (+)-CBI-CDPI2 are now exploring the potential of multiple different NK cell modalities to genetically reprogram with the overall aim of further improving upon their capacity to kill tumors in cancer patients. One example of how this technique can be utilized is to introduce genes into NK cells coding for gamma-cytokines (IL-2 Rabbit polyclonal to MAP1LC3A and IL-15) to induce independence from the obligate need of exogenous cytokines for proper persistence and expansion post infusion. This and similar strategies may further improve the efficacy of NK cell-based immunotherapy, as tumor regression following adoptive NK cell infusions in AML patients has been reported to be dependent on their ability to expand (6), while being limited by regulatory T cells also mobilized following exogenous cytokine administration (12, 13). The introduction of chimeric antigen receptors (CARs) and the down-regulation of inhibitory NK cell receptors such as NKG2A are additional examples of specific genetic manipulations that can be utilized to improve the outcome of adoptive NK cell immunotherapy. Given their rapid and efficient method of recognizing tumor cells, NK cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. This review focuses on methods for introducing transgenes into NK cells and the advantages and limitations of such strategies. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these specific strategies may be best utilized in clinic to maximize the anti-tumor potential of NK-cell based immunotherapy. Methods and Challenges with Genetic Manipulation of NK Cells: Viral Transduction Versus Transfection Genetic manipulation of T cells has successfully been used in both preclinical and clinical research (14). In contrast, studies on genetically engineered NK cells have historically been limited by poor efficacy of transgene delivery and substantial procedure-associated NK cell apoptosis. In this section, we discuss available approaches for gene delivery into NK cells, characterizing how each approach developed over time while highlighting the positive and negative aspects of each method (Box 1). Box 1 Pros and Cons for Methods of Genetic Modification of NK Cells. (Table ?(Table1).1). In contrast, viral transduction of primary resting human NK cells typically results in substantially lower transduction efficiencies. Most studies on viral transduction of NK cells have utilized retro- and lentiviral vectors. Although adenoviral- and vaccinia virus vectors have been utilized for transduction of NK cells, their use has been limited and they will not be discussed further in this review. Table 1 Overview of techniques used to genetically modify NK cells with reported gene delivery efficacies and effect on cell viability.a were the first viral vectors used to genetically modify NK cells. The first report on retroviral transduction of NK cells was published in the late 1990s and focused on genetic manipulation of the NK cell line NK-92 (16)..