Nk Cells In Therapy Of Cancer

From the evidcncc reviewed above, indicating that chronically low levels of NK activity or numbers in patients with cancer or other diseases may be associated with more severe symptoms or increased risk of disease progression, one might infer that augmentation of NK activity in disease may be of benefit to the patient. Therapy aimed at augmenting NK activity could be particularly advantageous for patients with cancer or immunodeficiencies. Such therapy is available today, and it generally consists of attempts to increase NK activity in vivo by the administration of agents with known NK-potentiating activity or adoptive transfer of activated autologous NK cells either locally or systemically to patients deficient in NK activity.

A variety of agents, generally referred to as biologic response modifiers (BRMs), are known to increase the activation, proliferation, or cytotoxicity of existing NK cells; other BRMs promote NK cell extravasation and accumulation in tissues, e.g., lung and liver, resulting in higher local cytotoxic activity. A partial list of commonly used BRMs includes a spectrum of cytokines such as interferons, IL-2 and IL-12; bacterial products such as OK432 (picibanil); plant lectins such as lentinan; monoclonal antibodies (Mabs) that bind to triggering structures on NK cells (e.g., anti-CD16 Mab); and interferon inducers such as polyribonucleotides. The effects of BRMs, especially cytokines, on signal transduction in NK cells, their mobility in tissues or ECM, and their ability to lyse tumour cells or virally infected targets are under intense investigation at this time.

Among the best-known activators of NK cells are IL-2 and IFNa [28,73], These two cytokines have been used extensively not only for patients with malignancies but also for those with viral infections. For example, IFNa has been therapeutically effective in a proportion of patients with chronic hepatitis B infection [74], and patients with human immunodeficiency virus have received systemic IL-2 therapy in combination with zidovudine [75], For patients with advanced malignancies unresponsive to other treatments, both IL-2 and IFNa therapies have resulted in a low frequency of durable responses [76,77], Systemic or locoregional therapy with IL-2, even at low or moderate doses, leads to well-documented increases in the number of circulating NK cells and NK activity [78], Although the extent of this IL-2-induced stimulation of NK activity in vivo could not be directly linked to clinical response, it may be at least partly responsible for the antitumour effectiveness of cytokine-based immunotherapy.

Immunotherapy with adoptively transferred activated NK cells and cytokines has been used mainly for patients with advanced malignancies in the hope of capitalizing on the well-documented antimetastatic activity of NK cells. The earliest clinical trials were performed with LAK cells and high-dose IL-2 in patients with metastatic melanoma or renal cell carcinoma [79], The results of these trials have been only mildly encouraging in that the rate of objective clinical responses achieved was about 20-30% [79], However, it is important to note that these responses, some of long duration (>2 years), were achieved in patients with metastatic diseases unresponsive to conventional therapies. The LAK cells for the adoptive cellular therapy were autologous and mainly contained IL-2-activated NK cells [29], More recently, clinical trials with purified NK cells, selected and expanded in vitro from patients' PBMNC, have been done on the hypothesis that transfer of a selected subset of highly activated antitumour effector cells may be therapeutically more effective and require fewer cells and possibly lower doses of cytokines to support their viability and in vivo activity. The results of two preliminary phase I trials with patients with metastatic melanoma or renal cell carcinoma demonstrated that immunotherapy with selected, highly purified, and in vitro-expanded subsets of NK cells is feasible, well tolerated and, in some cases, effective for metastatic disease [80,81],

Increasingly often, bone marrow transplantation or peripheral stem cell transfer has been used for the treatment of malignancies. The transfer of activated NK cells after transplantation is based on the rationale that NK cells have potent antitumour effects and thus can help eliminate minimal residual disease. Purified and activated human NK cells have been used for the therapy of patients with cancer after high-dose chemotherapy and peripheral blood stem cell transplantation [82], Preliminary results from clinical trials evaluating this therapy suggest that systemic transfer of A-NK cells plus IL-2 within 2-3 days after peripheral blood stem cell transplantation may not only help eliminate minimal residual disease, but facilitate haematopoietic recovery [82],

While both in vivo augmentation of NK activity with BRMs and adoptive transfer of activated NK cells are promising new therapies, additional clinical and basic studies are needed to build on the progress achieved to date and to acquire a better understanding of the interactions between activated NK cells and their targets in vivo.

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