Engineering CAR-NK cells: how to tune innate killer cells for cancer immunotherapy

Abstract

Cell therapy is an innovative approach that permits numerous possibilities in the field of cancer treatment. CAR-T cells have been successfully used in hematologic relapsed/refractory patients. However, the need for autologous sources for T cells is still a major drawback. CAR-NK cells have emerged as a promising resource using allogeneic cells that could be established as an off-the-shelf treatment. NK cells can be obtained from various sources, such as peripheral blood (PB), bone marrow, umbilical cord blood (CB), and induced pluripotent stem cells (iPSC), as well as cell lines. Genetic engineering of NK cells to express different CAR constructs for hematological cancers and solid tumors has shown promising preclinical results and they are currently being explored in multiple clinical trials. Several strategies have been employed to improve CAR-NK cell expansion and cytotoxicity efficiency. In this article, we review the latest achievements and progress made in the field of CAR-NK cell therapy.

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…ADAM17 is also a member of the metalloproteinase family that may have a similar function. Recently it was found that ADAM17 has the ability to hydrolyze MICA/B on the surface of tumor cells to generate soluble MICA/B (sMICA/B) (52), the latter of which alters the conformation of NKG2D on the surface of NK cells (234) and affects the recognition and binding of membranous MICA with NKG2D, thereby inhibiting NK activation signals and reducing the killing sensitivity of NK cells to tumor cells (235). Knockdown of ADAM17 prohibits MICA shedding and boosts MICA expression on the surface of hepatocellular carcinoma cells (131).…”

Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

“…Specifically, NK cells can be obtained either from autologous or allogenic peripheral blood. Nevertheless, the limited amount of autologous or allogenic NK cells obtained from peripheral blood not only impedes NK cell expansion, but also possesses heterogenous issues and is sensitive to freeze-thaw cycles which eventually reduces the efficiency of transduction ( 29 ). Therefore, another approach such as using NK cell lines is preferred to overcome the disadvantages of primary NK cells from peripheral blood.…”

“…showed that incorporation of activating receptors such as natural killer group 2 member D (NKG2D) in the transmembrane region of CAR structure and 2B4 as a co-stimulating domain was able to enhance the cytotoxicity of CAR-NK cells, thus demonstrating the highest efficacy to eradicate cancer cells compared to other CAR structures which did not use NKG2D ( 82 ). However, 2B4 cannot be used alone and should bind with CD3 for full CAR-NK cell activation ( 29 ). Parihar et al.…”

Toward the clinical development of synthetic immunity to cancer

“…Despite their promise for off-the-shelf therapy, there remain significant hurdles to implementing CAR-NK cells including technical challenges of efficient manufacturing, in-patient expansion and persistence, and optimizing their potency for maximum impact. 161 Because of their abundance in solid tumors and ability to infiltrate the TME, macrophages are another innate immune cell type highly sought after for engineering applications. Although broadly considered immunosuppressive in the TME context, macrophages can have potent antitumor capabilities and can be repolarized or activated in vivo with anti-CD47 or CD40 agonist for antitumor functions.…”

“…More recent studies focusing on solid tumors have demonstrated preclinically efficacy, 160 and there are now multiple phase I clinical trials assessing CAR‐NK cells in solid tumors; however, these have yet to report efficacy results. Despite their promise for off‐the‐shelf therapy, there remain significant hurdles to implementing CAR‐NK cells including technical challenges of efficient manufacturing, in‐patient expansion and persistence, and optimizing their potency for maximum impact 161 …”