Abstract
Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR-engineered NK-92 cells as off-the-shelf cellular therapeutics, with special emphasis on ErbB2 (HER2)-specific NK-92 cells that are approaching clinical application.
Highlights
Natural killer (NK) cells are specialized effectors of the innate immune system and central players in the defense against viral infections and cancer
Hypoxia as well as immunosuppressive factors such as transforming growth factor (TGF)-β, indoleamine 2,3-deoxygenase (IDO), prostaglandin E2, nitric oxide (NO), and reactive oxygen species (ROS), which are produced by regulatory immune cells like regulatory T (Treg) cells and myeloid-derived suppressor cells, by stromal cells like cancer-associated fibroblasts, and by tumor cells themselves can inhibit expression of activating NK-cell receptors, disrupt the interactions between NK and other immune cells, and avert the contact of NK cells with tumor cells [17]
Target tumor cells ectopically overexpressing human HLA-G were unable to block specific cell killing by chimeric antigen receptor (CAR)-engineered NK-92 (Zhang et al, unpublished data), NK-92 cells express the immunoregulatory receptors KIR2DL4 and Ig-like transcript 2 (ILT-2), which are activated by HLA-G [34, 123]. These findings show that activated CAR NK-92 cells can maintain their cytotoxic potential in an immunosuppressive environment similar to the one found within a solid tumor
Summary
Natural killer (NK) cells are specialized effectors of the innate immune system and central players in the defense against viral infections and cancer. NK-92 readily express activating NK receptors such as NKp30 and NKG2D while most of the inhibitory KIRs are absent [34], which may make CAR NK-92 cells effective in aiding DC maturation and editing, and enhancing DC-mediated cross-priming of tumor-specific T cells and induction of adaptive antitumor immunity We recently investigated this possibility in an immunocompetent mouse model for glioblastoma and could demonstrate the induction of endogenous antitumor immunity following therapy with CAR-engineered NK-92 cells [69]. Addition of AP20187 rapidly induces activation of iCasp and cleavage of endogenous caspases, precluding any further cell killing by the CAR-engineered cells (Figure 5)
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