Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer

Abstract

Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are bone marrow-derived innate lymphocytes that can eliminate tumors directly, with their activity governed by the integration of signals from activating and inhibitory receptors and from cytokines including IL-15, IL-12, and IL-18. NK cells do not cause GVHD or other alloimmune or autoimmune toxicities and thus, can provide a potential source of allogeneic “off-the-shelf” cellular therapy, mediating major anti-tumor effects without inducing potentially lethal alloreactivity such as GVHD. Given the multiple unique advantages of NK cells, researchers are now exploring the use of CAR-engineered NK cells for the treatment of various hematological and non-hematological malignancies. Herein, we review preclinical data on the development of CAR-NK cells, advantages, disadvantages, and current obstacles to their clinical use.

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

“…Another approach is to specifically block CD16A cleavage by expressing a non‐cleavable version of the receptor, such as CD16A‐S197P, in engineered NK cells. Various autologous and allogeneic NK cell platforms could be utilized, including expanded cord blood or peripheral blood NK cells, NK cell lines, and stem cell‐derived NK cells, which offer different advantages . A potential limitation of this approach is that NK cells expressing non‐cleavable CD16A might be less efficient at serial killing of Ab‐coated tumor cells in vivo.…”

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…In preclinical and clinical trials, CAR-engineered NK cells targeting several different antigens, such as CD19, CD20, CD33, CD138, CD319 (also known as signalling lymphocytic activation molecule family member 7, SLAMF7), CD3, CD5, and CD123, were investigated for their anti-tumour activity in vitro and in vivo [reviewed in 16]. Due to the tremendous therapeutic efficiency of CD19-directed CAR-modified T cells and their clinical use, data regarding the side effects and toxicity of CAR-T cell therapy are routinely obtained.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Because of their cytotoxic capacity, a few studies have also examined the potential of NK lymphocytes to serve as a cellular platform for CARs (reviewed in [336]). This was done for example using primary NK cells [337] and the NK92 cell line with the intent of using it as a "off the shelf"/universal donor cell [338,339].…”

“…Incorporation of IL15 into the CAR construct increases NK cell persistence in vivo [340], whereas the addition of C-X-X motif chemokine receptor 4 (CXCR4) increased their mobility to the tumor site [341]. Clinical studies evaluating the efficacy of CAR-NK are scarce (half a dozen taking place mainly in China and one in the US [336]) and they mainly target CD19 for B cell malignancies, CD33 for CD33+ AML [147] or MUC1.…”