Cytokine Therapy

Cytokines play a central role in the pathogenesis of many diseases, and are vital modulators of immune function. As a result, cytokines and their signaling pathways have become important targets for the development of new therapeutic agents. Currently, most treatments involve direct administration of cytokines, such as IL-2, or neutralizing antibodies and receptor antagonists, as in the case of anti-TNFα. However, treatments that inhibit cytokine signal transduction are under development, such as the use of STAT3 decoys and cpSOCS3.

Many of the early cytokine therapies involved direct administration of the particular cytokine itself. A combination of TNFα and IFNγ was injected into cancer patients after the observation that both cytokines induced tumor cell death in vitro; but, as with many direct cytokine therapies, the side-effects were very severe. In this case, toxicity was severe enough to discontinue use, even in cancer patients with advanced disease. On the other hand, single cytokine therapy with IL-2, IFNα, or IFNγ, are used to treat certain cancers and infections. Nonetheless, these cytokines frequently have severe side-effects. The toxicity associated with cytokine-based therapy, especially following systemic administration, has dampened enthusiasm for further investigation of direct treatment with cytokines.

Enhancing cytokine signaling through their direct administration has proven to be poorly tolerated by patients. However, antibody or receptor antagonist inhibition of cytokines frequently, but not always, shows more moderate toxicity. Infliximab, etanercept and adalimumab, which all target TNFα, are among the best known anti-cytokine therapeutics, and they are beneficial to patients with IBD and RA. Anti-TNFα therapy is tolerated well in most patients, although it can increase the risk of infection, and can cause reactivation in patients infected with Mycobacterium tuberculosis. Similar to TNFα, IL-6 is associated with inflammatory diseases; but in contrast to the anti-tumor effects of TNFα, IL-6 is a growth factor for many tumors. Due to the involvement of IL-6 in many diseases, tocilizumab, an IL-6R blocking antibody, has been developed as a therapeutic agent with potential as a treatment for inflammatory and malignant diseases.

In contrast to TNFα and IL-6, which are important in many inflammatory diseases, IL-4 is critical in the induction of allergic diseases and asthma. Clinical trials are underway to determine the efficacy of nuvance, a soluble IL-4R, as a treatment for asthma. Thus, therapeutic inhibition of cytokines is an area of intense research due to potentially high efficacy and relatively low side-effects. Although these treatments usually demonstrate low toxicity, this is not always the case; and there are several drawbacks, including: 1) some patients do not tolerate the infusions; 2) since these agents are proteins, they must be administered intravenously; 3) patients can develop immune responses against the antibody or receptor antagonist, reducing or eliminating treatment efficacy; and 4) relatively high concentrations of agent are required to neutralize the cytokine or block its receptor.

The cytokine-targeted therapeutic approaches described above rely on modulation of extracellular components of the signal transduction pathway, i.e. the cytokine and its receptor. Several preliminary therapeutic approaches are designed to act on intracellular signaling molecules, which may prove more potent than extracellular targets because they are further downstream and will inhibit signaling by several cytokines simultaneously.

Highlighting its importance in many diseases, the main cytokine targeted by three different approaches was IL-6. One group created an oligonucleotide sequence containing a STAT3 binding site that inhibited IL-6-induced transcription, proliferation, and survival in IL-6-dependent tumor cells in vitro and in vivo. Although injections would still be required for therapeutic use, intratumoral administration may allow for the use of lower doses; and due to the small size of the agent, patients are less likely to initiate immune responses against the treatment compared to antibody and receptor antagonist-based approaches. Another manuscript described two reagents, a dominant-negative STAT3 (dnSTAT3) adenoviral construct, which has a mutation at either a tyrosine that is phosphorylated by gp130 or a mutation at the DNA binding domain, and a SOCS3 adenoviral construct. Both the dnSTAT3 and SOCS3 viruses inhibited disease in a murine model of rheumatoid arthritis. Interestingly, SOCS3 over-expression ameliorated disease more potently than dnSTAT3, implying that additional signaling pathways are probably being inhibited by SOCS3. The potential for simultaneous inhibition of multiple signaling pathways could be a significant advantage of SOCS3 therapy over specific cytokine or STAT directed approaches. While adenoviral SOCS3 therapeutic strategies will require significant study before approval for clinical use, the generation of cpSOCS3 may enable relatively rapid progress to the bedside. Animals injected with cpSOCS3 were protected in a model of sepsis, demonstrating the potential efficacy of cpSOCS3 in vivo. Nonetheless, a significant drawback to the use of cpSOCS3 is the cost of production, especially during early studies, in comparison with antibody, oligonucleotide, or adenoviral approaches. However, the most likely initial use of SOCS3 in the clinic will not be as a therapy, but rather as a prognostic marker. For example, in patients infected with HCV, hepatocyte SOCS3 levels inversely correlate with clinical responsiveness to IFNα therapy.