Research Is Expanding Into the Use of Interleukin-12 as an Anticancer Agent
Premal Thaker, MD, and Charles Leath, MD
Based on the development of more effective delivery technologies and advances in clinical research, the focus on interleukin-12 (IL-12) in oncology is continuing to expand.
Recent research has indicated the potential for IL-12 therapy to be effective in combination with new and emerging biologics including other immunomodulatory drugs.1-4
Interest in IL-12 is being driven further by research showing the potential for curative benefits in treatment in certain forms of cancer, potentially transforming them into chronically managed conditions.
Researchers Renewing Focus on IL-12
IL-12, a cytokine that acts as a key regulator for certain immune responses, was an important focus in oncology research in the late 1980s.5 In multiple research efforts, IL-12 was shown to have potent anticancer activity (Figures 1-2). Based on these early results, researchers advanced development programs targeting IL-12 in treatment of several human cancers including melanoma, renal carcinoma, and lymphocytic lymphoma.6
However, early clinical research also indicated that cell culture-derived recombinant IL-12 (rIL-12) therapy was associated with systemic toxicity that could lead to potentially serious adverse events and put patients at risk.7-8 In some clinical research programs, IL-12 treatment was associated with patient deaths.
Figure 1. Interleukin-12 has multiple distinct mechanisms of action that lead to tumor cell death.
Figure 2. Interleukin-12 addresses cancer cells by recruiting the immune system, inducing powerful anti-cancer mechanisms for an immune attack.
Analysis showed that adverse events were attributed to the therapy's short half-life and generally poor pharmacokinetics. Based on these risks, IL-12 clinical trials slowed; however, research that focused on efforts to improve pharmacokinetics and safety of IL-12 continued.
After many years of effort, researchers have reported progress in the development of alternative strategies to improve both the pharmacokinetics and safety of rIL-12 therapies based on the use of more advanced delivery mechanisms.
Of these, 3 distinct approaches have thus far reported proof-of-concept studies in experimental models. These include gene therapy approaches to IL-12 (viral or plasmid DNA approaches)9-10 and attachment of polyethylene glycol (PEG) to improve IL-12 half-life and membrane-bound IL-12.11