Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy

Abstract

Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable "off-the-shelf" treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.

Keywords: T cell; cancer; chimeric antigen receptor; immunotherapy; natural kill cell; trogocytosis.

Figure 1

Methods to overcome the barriers to the CAR-T and CAR-NK fields: cost, antigen loss, trogocytosis, trafficking, fitness, and persistence.

Figure 2

Trogocytosis-mediated antigen procurement leads to trogocytosis-mediated signaling, antigen loss leading to tumor escape, and fratricide. The tumor cell membrane (purple) and CAR antigen is transferred to the CAR-lymphocytes (green) via trogocytosis. (1) The transferred membrane acts as a target for CAR-mediated fratricide leading to lymphocyte cell death (grey). (2) The transferred membrane can also signal within the CAR-lymphocyte. (3) Finally, the transfer of the cell membrane results in antigen loss on the tumor cells themselves.