Advantages and applications of CAR-expressing natural killer cells

Abstract

In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

“…Chimeric antigen receptor (CAR)-redirected T cells have seen success in CD19 + hematological malignancies, leading to cure of acute lymphoid leukemia (ALL) and lymphoma of B-cell origin (1)(2)(3)(4)(5). The success of T-cell based CAR strategies depends on distinct T-cell subsets (6).…”

“…CAR-transfected NK cells showed cytotoxicity in vitro and in vivo (17). Many studies have used feeder-cell expanded NK cells or the NK-92 cell line as a template for CAR engineering (5,18). Thus, it remains unknown how repertoire diversity within the NK-cell compartment might influence the functional potential of CAR-redirected NK cells.…”

Immunotherapy in Pediatric Acute Leukemia: A Novel Magic Bullet or an Illusory Hope?

“…Further investigations led to multiple improvements of the method, like producing NK CAR cells as an alternative to T cells [42,43], enhancing cytotoxicity of CAR-T cells by the addition of costimulatory molecules (second and third generation) or by adding chemokine receptors to enable the effective infiltration to the tumor site. For example, the expression of CD40 ligand by genetically modified T cells leads to increased proliferation and secretion of proinflammatory TH1 cytokines, but also enhances the immunogenicity of tumor cells by upregulation of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70),…”

NK cell-based cancer immunotherapy: from basic biology to clinical application

“…[3,114]). Moreover, authorities have approved two clinical studies using CAR-expressing NK cells for the treatment of B-lineage ALL.…”

“…Unlike T cells, NK cells are always switched on and can recognize target cells independent of antigen specificity and MHC matching, which allows anti-tumor effects without eliciting strong graftversus-host disease (GvHD) responses. Moreover, NK cell based therapy will potentially be cheaper, more scalable and have a lower latency period from treatment decision to receipt of therapy compared to T-cell based competitors [3,4]. Therefore, approaches that utilize NK cells for cancer immunotherapy are gaining more and more attention worldwide.…”