Next-generation cell therapies: the emerging role of CAR-NK cells

Abstract

T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.

Realizing Innate Potential: CAR-NK Cell Therapies for Acute Myeloid Leukemia

“…CAR-NK continues to represent a small segment of a landscape of CAR therapies dominated by T-cells [ 14 ]. Active and completed clinical trials investigating CAR-NK cell therapies are summarized in Table 2 , and have also been compiled in detail in recent articles [ 127 , 128 ]. The pioneering phase I clinical trial at MD Anderson Cancer Center of cord blood derived CD19 CAR-NK cells represents the most advanced clinical data available and provides important insights for AML CAR-NK development [ 17 ].…”

Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies

“…Importantly, a majority of the patients receiving CAR NK therapy had a positive response to the treatment, and CAR NK cells were not associated with any toxicity such as cytokine release syndrome, neurotoxicity, or graft-versus-host disease. Therefore, CAR NK cell immunotherapy presents an allogenic therapy that can be readily available for instant use [ 93 , 94 ]. Moreover, CAR NK cells are able to exert anti-tumor effects in addition to the CAR function since they also obtain their native receptors, therefore averting any relapse or resistance associated with antigen loss and CAR therapy [ 93 , 95 , 96 ].…”

“…Moreover, CAR NK cells are able to exert anti-tumor effects in addition to the CAR function since they also obtain their native receptors, therefore averting any relapse or resistance associated with antigen loss and CAR therapy [ 93 , 95 , 96 ]. Additionally, unlike CAR T cells, CAR NK cells can target tumor cells without the requirement of specific TAA recognition and despite the down-regulation of MHC class I on tumor cells [ 94 , 97 ]. This demonstrates the potential of CAR NK cells as universal CAR cells [ 93 , 98 ].…”

“…Although CAR NKs have shown some success in recent clinical trials, there are still challenges associated with this treatment option. For example, CAR NK cells have low ex vivo expansion as well as low transduction efficiency and lifespan, which limits their use and warrants further research [ 94 , 109 ]. However, electroporation pulse codes and buffer optimization for protein uptake can improve NK transduction rates [ 103 ].…”

Targeted Treatment of Follicular Lymphoma

“…Importantly, because NK-cells are human leukocyte antigen (HLA) agnostic, graft-versus-host-disease is not induced. This opens up the option of manufacturing using “off the shelf”, allogenic, umbilical cord blood derived NK-cells ( Table 2 ) [ 100 ]. The first-in-human phase 1/2 clinical trial of allogenic CAR NK-cell therapy in B-cell malignancies encoded a CAR against the CD19 B-cell antigen and IL-15 to enhance transduced NK-cell persistence and function [ 101 ].…”