Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review

Abstract

Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Currently, chemotherapy and radiotherapy are the standard treatments for cancers. However, these treatments cause a significant number of side effects, as they damage both the cancer cells and the actively dividing normal cells indiscriminately. Hence, a new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects. However, the progression of cell-based immunotherapy is hindered by the combined action of TME and TD-EVs, which render the cancer cells less immunogenic. Recently, there has been an increase in interest in using immune cell derivatives to treat cancers. One of the highly potential immune cell derivatives is the NK cell-derived EVs (NK-EVs). As an acellular product, NK-EVs are resistant to the influence of TME and TD-EVs, and can be designed for “off-the-shelf” use. In this systematic review, we examine the safety and efficacy of NK-EVs to treat various cancers in vitro and in vivo.

Extracellular vesicles derived from immortalized human natural killer cell line NK3.3 as a novel therapeutic for multiple myeloma

“…These drugs not only damage proliferating cancer cells, but also destroy normal dividing cells, causing severe decline in patients’ health. Because of adverse side-effects, there is a need to develop new treatments that are highly specific towards cancerous cells without harming healthy cells ( 34 ).…”

“…Tumor-derived EVs also suppress recruitment and function of immune effector cells. Together, the TME and tumor-derived EVs create an acidic, hypoxic environment that is inhibitory to NK cell activation and cytotoxic function ( 34 ). These factors contribute to tumor cell survival and drug-resistance.…”

“…8226/Luc cells were more sensitive to both NK cell- and NK EV-mediated killing than U266 cells. U266 cells may be more resistant to NK and NK EV killing mechanisms due to low expression of NK receptor ligands or by their ability to release tumor-derived EVs that block the signals that activate NK cells and NK EVs, diminishing cytotoxicity ( 34 ). The basis of the differences in sensitivity to NK EV-mediated killing is being explored.…”

“…This makes it difficult to compare the benefits of NK EV therapy among studies. NK EVs have been studied extensively in vitro as a cancer therapeutic, but there are limited in vivo studies that evaluate efficacy, biodistribution, stability and toxicity ( 34 , 35 ).…”

A clinically relevant large‐scale biomanufacturing workflow to produce natural killer cells and natural killer cell‐derived extracellular vesicles for cancer immunotherapy

“…While some progress has been made in the large‐scale production of NK cells, NK‐EVs currently lag, requiring additional research and development (Bröker et al., 2019; Childs & Berg, 2013; Granzin et al., 2015; Koehl et al., 2013; Lapteva et al., 2012; Luhm et al., 2002; Siegler et al., 2010; Spanholtz et al., 2011; Sutlu et al., 2010). This process should involve GMP‐compliant cell culture conditions, a bioreactor system and a scalable EV isolation process to consistently yield functional, high‐purity NK‐EVs (Chan et al., 2023; Estes et al., 2022; Gobin et al., 2021; Urzì et al., 2022; Visan et al., 2022; Watson et al., 2016). In addition, to maintain the batch‐to‐batch consistency of a qualified product, it is necessary to address specific challenges that may arise during the production of clinical‐grade NK‐EVs.…”