NK cell-based immunotherapy for malignant diseases

Abstract

Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells

“…These findings highlight the role of the tumor microenvironment in host immune response impairment and NK lytic function, and may explain the poor efficacy of adoptive transfer of autologous NK cells frequently observed in cancer patients with melanoma, lymphoma, and breast cancer due to NK-cell dysfunction [30][31][32]. Immunohistochemical analysis of CD56 + infiltrating-NK cells in biopsy specimens of BC patients revealed a poor tumor infiltration, independently of tumor stage and grade, reflecting an inefficient homing of NK cells in BC, unlikely to control tumor progression.…”

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…NK cells with therapeutic potential can be obtained from peripheral or cord blood cells or other sources, and a variety of protocols can be applied for their large-scale production, such as Abs, immobilized molecules or soluble growth factors, and/or other cellular activators. 48 …”

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

“…3,48 However, possible side effects of immunoligand-associated NK cell activation in patients such as autoimmune reactions toward healthy B cells should be considered. Limitations of autologous and allogeneic NK cell infusions have been discussed elsewhere 49 and must be pointed out in the context of adoptive transfer of NK cells with immunoligand. Inherent NKG2D receptor expression on NK cells from CLL patients is another crucial prerequisite for this clinical option.…”