Genetic modification of natural killer cells for adoptive cellular immunotherapy

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Date: July 2009
From: Immunotherapy(Vol. 1, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Article
Length: 6,000 words
Lexile Measure: 1470L

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Author(s): Hollie J Pegram 1 , Michael H Kershaw 1 2 , Phillip K Darcy [[dagger]] 1 2



cancer; chimeric receptor; cytokine transgene; electroporation; gene modification; natural killer cell; redirection; retroviral vector; transduction

Natural killer (NK) cells were originally identified upon their ability to respond to tumor cells without prior sensitization. NK cells are innate lymphocytes with an immediate response capability and are now known to be an integral part of the link between the adaptive and innate immune systems [1,2] . The recognition of target cells by NK cells is a tightly regulated process that involves a balance of signals from various activating and inhibitory receptors that dictate their overall response [3] . NK cells mediate lysis of target cells predominantly through the granule exocytosis pathway involving release of the pore-forming molecule perforin. However, NK cells have also been reported to mediate apoptosis of target cells through other pathways involving Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [4,5] .

Owing to their immune stimulatory and direct cytotoxic functions, NK cells are appealing to be exploited for immunotherapy. Immunotherapy has previously utilized NK and NK-like cells in the lymphokine-activated killer (LAK) cell setting in the 1980s [6,7] and also more recently in allogeneic hematopoietic stem cell transplantation, whereby NK cell alloreactivity is exploited to improve leukemia treatment [8,9] . Another approach to employ NK cells in immunotherapy is through gene modification to improve their function and specificity, or endow them with additional capabilities. This review will cover the techniques involved and results obtained from the gene modification of NK cells.

Genetic modification is showing promise for redirecting the function of various cell types including T cells [10] , dendritic cells [11] , monocytes [12] and NK cells [13] . Much work has been done particularly on genetically redirecting T cells against a range of tumor antigens. For example, T cells have been demonstrated to acquire potent antitumor activity against CD19+ B-cell malignancies, renal cell carcinoma expressing carbonic anhydrase IX and breast cancer expressing ErbB2 [14-16] . Difficulties in gene-modifying primary NK cells have caused this field to lag somewhat behind that of T cells, but recent developments in vectors and methods have rendered genetic modification of NK cells more feasible.

Natural killer cells bring some unique qualities that make them a suitable alternative and auxiliary cell type to redirect against cancer. For example, NK cells are the quintessential killer cell, able to destroy target cells very efficiently. They also have unique trafficking capabilities, and being innate immune cells, they can efficiently penetrate tissues [17] . In addition, they are likely to be subject to different immunoregulatory mechanisms mediated by cells such as regulatory T cells that afflict some T-cell-directed approaches [18] . These qualities make NK cells an exciting alternative cell type to use against cancer, either alone or together with other cell types to complement or enable their abilities to impact on tumors.

Several studies have modified NK cells with cytokine transgenes in order to enhance NK cell function by providing necessary cytokines directly to the cell [19-21]...

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Gale Document Number: GALE|A237223323