Adoptive cell therapy has emerged as a novel and promising treatment option for relapsed and refractory malignancies. This therapy, which commonly uses T cells extracted from the patient, has shown effective results, especially in many hematological malignancies. However, there have been concerns about the safety of T cell therapy, as CAR-T cell therapy is associated with potentially life-threatening toxicities. Different patients show different tolerances to CAR-T therapy, with some patients experience varying levels of neurotoxicity and cytokine storms.
Recently, natural killer (NK) cells have become an alternative cell type for clinical utility given the low propensity for graft-versus-host disease. NK cells are also known to have anticancer effects with few side effects, making them an option in the application of adoptive cell therapy.
NK cells play a key role in host immunity by detecting cells that down-regulate MHC class I presentation and upregulate stress ligands in tumors. However, current NK therapies using primary NK cells are prone to manufacturing problems related to expansion and storage. In contrast, NK cells differentiated from induced pluripotent stem cells (iPSCs) provide an alternative that can address these problems.
iPSCs are capable of providing a universal cell source for all types of cell therapy, including immunotherapy with NK cells for cancer. Unlike primary NK cells, NK cells prepared from iPSCs have uniform quality and can be easily modified to produce the desired response to tumor cells. In addition, there are many benefits of using iPSC-derived NK cells to treat cancer. In particular, several effective approaches have been used to increase the therapeutic potential of iPSC-derived NK cell therapy, such as genetic modifications targeting NK-mediated antibody-dependent cellular cytotoxicity (ADCC) capabilities, and cytotoxicity.
One of the roles of NK cells is their indirect cytotoxicity in cancer immunotherapy. NK cells can activate several other immune cells, such as B cells, T cells, macrophages, dendritic cells and neutrophils. The study showed that iPSC-derived NK cells perform the same function. iPSC-derived NK cells can recruit T cells to the tumor site, where both cell types exert cytotoxicity especially when combined with an anti-PD-1 antibody.
Recent studies have shown that the addition of iPSC-derived NK cells to immunotherapy regimens can maintain high cytotoxicity and enhances in vivo tumor control. These manufactured NK cells produce inflammatory cytokines that kill tumor cells and effectively cooperate with anti-tumor T cells in mouse models, making them a potential anticancer anti-cancer treatment.
A research team at the University of Minnesota found that harnessing the features of adaptive NK cells to generate iPSC-derived NK cells can enhance the efficacy of immunotherapy. In immunotherapy, specific subsets of immune effector cells are most likely to mediate anti-tumor responses. However, it is difficult to obtain these subsets because cell-based immunotherapy is hampered by limited effector cell persistence and lack of availability on demand. The researchers created a triple-gene-edited iPSC with a high-affinity, non-clearable version of the Fc receptor, which effectively addresses these limitations. This finding suggests that a unique subset of the immune system can be modeled by iPSC technology to effectively treat patients with advanced cancer.
NK cell-based immunotherapies already provide a promising method to treat several types of cancer. iPSC technology offers new solutions for obstacles associated with conventional NK cell therapies regarding manufacturing, banking, and improving anti-tumor activity. The combination of NK cells and iPSC technology holds great promise and clearly has a disruptive clinical potential. However, it is essential to further examine the therapeutic potential of iPSC-NK cell immunotherapies in both preclinical and clinical studies. It is believed that iPSC-NK cell therapy will bring new treatment options for more patients with diseases in the future.
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