Abstract
Natural killer (NK) cells are known to play a role in mediating innate immunity, in enhancing adaptive immune responses, and have been implicated in mediating anti-tumor responses via antibody-dependent cell-mediated cytotoxicity (ADCC) by reactivity of CD16 with the Fc region of human IgG1 antibodies. The NK-92 cell line, derived from a lymphoma patient, has previously been well characterized and adoptive transfer of irradiated NK-92 cells has demonstrated safety and shown preliminary evidence of clinical benefit in cancer patients. The NK-92 cell line, devoid of CD16, has now been engineered to express the high affinity (ha) CD16 V158 FcγRIIIa receptor, as well as engineered to express IL-2; IL-2 has been shown to replenish the granular stock of NK cells, leading to enhanced perforin- and granzyme-mediated lysis of tumor cells. The studies reported here show high levels of granzyme in haNK cells, and demonstrate the effects of irradiation of haNK cells on multiple phenotypic markers, viability, IL-2 production, and lysis of a spectrum of human tumor cells. Studies also compare endogenous irradiated haNK lysis of tumor cells with that of irradiated haNK-mediated ADCC using cetuximab, trastuzumab and pertuzumab monoclonal antibodies. These studies thus provide the rationale for the potential use of irradiated haNK cells in adoptive transfer studies for a range of human tumor types. Moreover, since only approximately 10% of humans are homozygous for the high affinity V CD16 allele, these studies also provide the rationale for the use of irradiated haNK cells in combination with IgG1 anti-tumor monoclonal antibodies.
Highlights
Natural killer (NK) cells are essential in mediating innate immune responses and in the enhancement of the adaptive immune response [1,2,3]
Since only approximately 10% of humans are homozygous for the high affinity V CD16 allele, these studies provide the rationale for the use of irradiated haNK cells in combination with immunoglobulin G1 (IgG1) anti-tumor monoclonal antibodies
As shown previously [18], NK-92 cells have considerably higher levels of endogenous granzyme when compared to NK cells or IL-2‒activated NK cells. haNK cells have been engineered to express the high affinity CD16 Fc receptor FcγRIIIa (158V)
Summary
Natural killer (NK) cells are essential in mediating innate immune responses and in the enhancement of the adaptive immune response [1,2,3]. In addition to these mechanisms, NK cells can play a role in anti-tumor immunity alone, or in combination with select antibodies via antibody-dependent cell-mediated cytotoxicity (ADCC). NK-92 cells grow well in culture and are dependent on exogenous IL-2 for propagation. They lack or have extremely low levels of the inhibitor killer immunoglobulin (Ig)like receptors (KIR), which allows for lysis of tumor cells expressing major histocompatibility complex (MHC) molecules. Preclinical studies have shown that NK-92 cells do not form tumors when transplanted into severe combined immunodeficiency (SCID) or athymic mice
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