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146 | Chapter 6 NK cell cytotoxicity 14 . This shifted the focus to the use of IL-15 for clinical trials involving NK cells. Currently more potent and advanced heterodimeric IL-15, which has a longer half- life than scIL-15, is being tested in several studies 15 . IL-15 is known to be more effective in membrane-bound form (i.e. bound to its receptor), engaging target immune cells in a cell contact dependent manner. Campana and his team (from Nkarta Therapeutics) addressed this by stably transducing themembrane bound IL-15 (mbIL-15) gene into proliferating PBNK cells which were stimulated with K562-mb15-41BBL. mbIL-15 resulted in increased survival, proliferation and enhanced cytotoxic functions of NK cells 16 . Further, Cyto-Sen Therapeutics compared mbIL-15 to K562-based artificial APCs with mbIL-21. From their findings, it was evident that mbIL-21 NK cells have a significantly higher expansion and proliferation ability compared to mbIL-15 NK cells 17 . Cyto-Sen also developed plasma membrane particles (PM21) engineered from K562-mb21-41BBL cells and found that these PM21 particles stimulated efficient NK cell expansion in PBMC samples from AML patients 18 . Altor BioSciences came up with an alternative approach to overcome the limitations associated with the short-half-life of recombinant IL-15. It developed an IL-15 super agonist known as ALT-803. It consists of a human IL-15 mutant N72D variant which is stably complexed with a soluble human IL-15Rα sushi-Fc dimer protein. Enhanced biological activity of ALT-803 was reported in several pre-clinical studies showing durable anti- tumor activity in various solid and haematological malignancies 19-22 . Furthermore, ALT-803 facilitated expansion of effector and migratory NK cell subsets and significantly decreased the metastatic activity of tumor cells in a murine colon cancer pulmonary metastasis model 23 . ALT-803 stimulated primary human NK cells to exhibit increased degranulation, IFNγ production and ADCC when exposed to B cell lymphoma cell lines coated with IgG 1 therapeutic anti-CD20 mAbs 24 . Several clinical trials are currently ongoing with ALT-803 as monotherapy in patients with advanced solid tumors, haematological malignancies, and AIDS as summarized in Table 1. Priming NK cells to enhance tumor killing Mark Lowdell and his team, proposed that for an NK cell to be able to kill tumor cells, it requires a priming and triggering signal. NK cells failing to kill tumor cells, though they are exposed to the triggering signal, would remain inactive due to the absence of a priming ligand. To address this, Fortress Biotech (previously known as Coronado Biosciences) developed a technology to increase NK cell tumor killing using cell lysates from the leukemia cell line CTV-1, known as CNDO-109, to prime NK cells. A phase I/II clinical trial of activated PBNK cells from haploidentical donors co-incubated with CNDO-109, infused at doses of up to 3 x 10 6 kg/recipient/body weight was tolerable without any adverse reactions. Out of 7 evaluable patients, 4 remained disease relapse free for more than 1 year 25 .