7.1.1　Interferon-α

Since the first approval of IFN-α for the treatment of hairy cell leukaemia in 1986, this family of cytokines has been used for the treatment of several haematological malignancies and solid tumors at high doses to exploit their direct pro-apoptotic/antiproliferative activity on tumor cells.These high doses of IFN-α also exert anti-tumor activity due to effects on the tumor vasculature as IFN-α displays a potent antiangiogenic activity.PEGylated IFN-α was also approved for the adjuvant treatment of melanoma.This variant consists of a chemical modification that increases its half-life in circulation and therefore prolongs the exposure of the tumor cells to high IFN-α concentrations.However, the advent of targeted therapies and novel immunotherapies with superior safety and efficacy profiles has reduced clinical use of IFN-α in onco-haematology.This situation might be reverted with new cytokine modifications that exploit the immunostimulatory properties of IFN-α,as this cytokine is critical for the maturation of dendritic cells (DCs) and for the acquisition of effector function by T lymphocytes.(https://www.daowen.com)

One strategy to unplug the cytotoxic activity of IFN-α from its immunostimulatory activity involves its fusion to apolipoprotein A-I.The apolipoprotein A-I moiety incorporates the cytokine into high-density lipoproteins, improving the pharmacokinetics and anti-tumor activity of IFN-α.AcTakines (Activity-on-Target cytokines), activity-on-Target cytokines, can also minimize the toxicity of IFN-α and maximize its immunostimulatory activity.This strategy is based on the fusion of a mutated cytokine that shows reduced affinity for its receptor to a cell-specific targeting domain.IFN-α fused to single domain antibodies targeting Clec9A, a molecule expressed on DCs specialized in cross-priming, displays a potent anti-tumor effect.Finally, IFN-α immune cytokines have been demonstrated to exert an anti-tumor effect mediated by the activation of immune system cells.In summary, type I IFN immunobiology is likely to be exploited in the near future but is not currently in the frontline oncology armamentarium.