The prospect of genetically engineering natural killer cells for cancer immunotherapy

Abstract

The use of natural killer (NK) cells in cancer immunotherapy demonstrates promising potential, yet its efficacy is often limited due to the loss of tumor-killing capacity and lack of specificity in vivo. Here, we review current approaches to confer enhanced tumor-killing capacity and specificity by genetic engineering. Increasing sensitivity to cytokines and protecting NK cells from the immune checkpoint endowed sustainability of NK cells in the tumor microenvironment. Transducing chimeric antigen receptor (CAR) in NK cells successfully targeted both hematologic and solid tumors in preclinical models. The use of human pluripotent stem cells as an expandable and genetically amenable platform offers a stable source of engineered NK cells for cancer immunotherapy. We highlight that CAR-NK cells from human pluripotent stem cells are a promising approach for cancer immunotherapy.

Integrating single-cell genomics for specific guidance of iPSCs fate commitment in adoptive cell therapy

“…Currently, several protocols have been established to induce the target immune cells. First, iPSCs are directed towards the definitive cell lineage with feeder cells or without feeder cells, although it costs less time when induce of iPSCs without feeder cells [3], the composition and function of differentiated lineage in the following immune cell products is still unknown. To produce iPSCs-derived products for therapeutic purposes, it is crucial to establish robust and reproducible differentiation protocols that consistently yield high efficiency and maintain consistency across different batches.…”

“…Clinical trials using NK cells have been available and recently involve treatment for hematologic malignancies and solid tumors, the interest in NK cells as a candidate for immunotherapy has grown exponentially. As a member of innate immune cells, macrophages play a crucial role in specific immunity by presenting antigens to T cells and secreting inflammatory factors [3]. CAR-macrophages are characterized by high tumor accumulation rate and efficiently penetrate the dense stromal tissue surrounding tumors.…”

“…Another approach being explored is the use of modified oncogenic immune cell lines, which can be easily expanded to large doses. Nevertheless, it is imperative to highlight that this specific cell line has inherent limitations associated with its tumorigenic and cytogenetic dysregulations, requiring irradiation for clinical use, which limits its long-term activity of proliferating and killing tumor cells in vivo [3]. After long journey of exploration, iPSCs differentiated immune cells have developed to circumvent these challenges, as they provided an outstanding strategy for generating clinical-scale immune cells by enabling genetic modifications and unrestricted expansion to occur during the pluripotent cell phase.…”