Next‐generation chimeric antigen receptors for T‐ and natural killer‐cell therapies against cancer

Abstract

SummaryAdoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor‐specific antigens that can be targeted without cross‐reactivity against normal tissues. This may lead to unwanted on‐target off‐tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on‐target off‐tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.

Contemporary Approaches to Immunotherapy of Solid Tumors

“…An important extratumoral effect of CAR-T-cell therapy is trogocytosis, which consists of receptor-mediated transfer of cognate antigen from tumor cells to immune cells expressing the receptor [ 158 ]. This results in loss of antigen and promotes tumor escape from CAR-T cell therapy [ 134 ]. Tumor antigen escape is the main reason of developing resistance to CAR-T cell therapy [ 134 , 158 , 159 ].…”

“…This results in loss of antigen and promotes tumor escape from CAR-T cell therapy [ 134 ]. Tumor antigen escape is the main reason of developing resistance to CAR-T cell therapy [ 134 , 158 , 159 ].…”

Golden age of immunoengineering

“…Interestingly, the foundational CAR design also works in NK cells. In the review by Rezvani and colleagues, 11 they highlight advances and understanding in CAR T and NK cells. Recent clinical trials with CAR NK cells have demonstrated exciting clinical efficacy with fewer side effects than CAR T cells.…”

Harnessing natural killer cell effector function against cancer

“…However, these come at a high treatment cost and can be associated with severe toxicities. NK cells are under clinical assessment for solid and haematological malignancies in multiple phases 1 and 2 trials as an alternative cellular source for CAR-based therapies ( Table 2 ) [ 45 , 62 ]. Importantly, CAR-NK cells have the potential for off-the-shelf utility (allowing for reduced product cost and time) and reduced toxicities compared to CAR-T therapy (reviewed in [ 45 , 63 , 64 ]).…”