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A Novel Strategy To Enhance Immunotherapy By Interleukin 2 Tethered To Its Receptor

Interleukin-2 a cytokine secreted by T cells has stimulating effects on T cells and natural killer (NK) cells. Systemic IL2 administration could, therefore, enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its use is restricted by its serious side effects that cause pulmonary edema and mimic sepsis.

Although injections of smaller doses of IL2 could be tolerated and might activate the immune system, there is, however, the potential to activate another subset of T cells (T-regulatory or T-regs), which reside in tumors and also uses IL2, for the purpose of suppressing the immune system. T-regs with their extraordinary ability to deplete IL2 work in concert with other cells called myeloid-derived suppressor cells in the tumor to suppress NK cells and allow for tumor growth.  Another problem encountered during Il2 administration is its short half-life (less than 10min)

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As a consequence, many clinical trials where IL2 was infused to patients were met with limited success due to either its toxicity at higher doses or inefficacy at lower doses. To resolve these issues many groups have tried to genetically modify IL2 to only modestly reduce its toxicity, or to activate NK cells isolated from patients and returned after stimulation with IL2. Unfortunately, it was discovered that this stimulation did not last enough to achieve an objective response. It was also found that NK cells from another donor were more capable of attacking tumor cells than the patient own NK cells. However, Il2 administration with its severe side effects was necessary to achieve any activation in the patient.

It is now accepted that NK cells limited success in many immunotherapy strategies is due to the inability of NK cells to compete with T-regs for IL2 to achieve activation and their inability to escape the immunosuppressive effects of myeloid suppressive cells in tumors.

In this paper, a novel chimera composed of Il2 fused directly to one of its receptor (beta) was introduced in a cell line called NK92, thus providing continuous self-activation. NK92 cells were originally derived from a patient with Hodgkin lymphoma and require IL2 for survival. The authors discovered that this genetic modification allowed NK92 cells to kill cancer cells without IL2 present and were also more able to resist transforming growth factor beta (TGFb1) a powerful immunosuppressive factor found in tumors. Moreover, these genetically modified NK cells resisted dexamethasone an immunosuppressive glucocorticoid often used in combination with several cancer treatments.

The authors also found a remarkable anti-tumor effect in mice bearing prostate and brain tumors. This anti-tumor activity in vivo was achieved with irradiated NK92 cells in order to prevent their growth in mice. FDA approved NK92 cells for cancer treatment in human patients, but they require irradiation in order to prevent proliferation in patients. The authors postulate that non-irradiated NK92 cells will be able to achieve a more remarkable anti-tumor effect if their growth in mice could be controlled.

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Experimental Results Of Treatment

Results showed that introduction of the novel chimera led to many interesting changes in gene expression in NK92 cells. Important among them was the expression of CD16, which is normally absent in NK92 cells and allows NK cells to kill cancer cells to which an antibody is attached. Several therapeutic antibodies such as Trastuzumab, which is used against breast cancer, are FDA approved and could be combined with NK cells expressing the novel IL2-receptor beta chimera. The expression of other genes involved in cancer cells killing was also found to increase upon this chimera expression in NK cells. Unlike immunotherapy strategies using T cells, those using donor NK cells could achieve significant anti-cancer effects, safely and without the risk of inducing graft-versus-host disease which is an attack of host organs by donor immune cells.

IL2 is normally secreted in determined quantities and NK cells responses are therefore quantal and specific in duration.  The key to understanding the underlying mechanisms behind the enhanced activation of NK cells after transduction of this novel chimera is the fact that this expression is continuous in recipient NK cells. This ensures a resistance to most immunosuppressors that could in normal settings turn off NK cells and render them inactive or anergic.

This new cytokine-cytokine receptor platform may be further improved to enhance NK cells anticancer and possibly antiviral activity. Further studies will aim at understanding how IL2 fused to its receptor leads to all these favorable characteristics that provide a superior antitumor effect.

This study, Tethering IL2 to its receptor IL2Rβ enhances anti-tumor activity and expansion of natural killer NK92 cells was recently published in the journal Cancer Research.

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