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.

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

“…Trogocytosis is an event involving the transfer of cancer antigens from cancer cells to NK cells, thus leading to antigen loss in cancer cells. NK cells which receive cancer antigens are targeted by CAR-NK cells ( 61 ). As a result, fratricide of NK cells occurs due to the NK cells present trogocytic antigen mediated by trogocytosis ( 61 ).…”

“…NK cells which receive cancer antigens are targeted by CAR-NK cells ( 61 ). As a result, fratricide of NK cells occurs due to the NK cells present trogocytic antigen mediated by trogocytosis ( 61 ).…”

Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside

“…The knock out of target antigens in effector cells can overcome fratricide, but this method is unsuitable for antigens transferred to effector cells during trogocytosis. Low affinity of CAR to antigen or optimized CAR signaling transduction may serve as alternative approaches [ 114 ].…”

Immune-Cell-Mediated Cancer Treatment: Advantages, Drawbacks And Future Direction

“…CAR-NK therapy could be improved by investigating the significance of optimizing the immunochemical characteristics of the CAR model, comprehending variables that contribute to cell product persistence, improving transporting of transferred cells to the tumour, facilitating metabolic wellness of the newly delivered product category, and finding ways for minimizing tumour escape via antigen destruction as well as trogocytosis (Kilgour et al 2023;Raftery et al 2023). NK cell therapy can be improved further by implementing different approaches, as shown in Figure 5.…”