Veteran Researcher Sees Many Gaps in Knowledge About IFNs

Ahmed Lasfar, PhD

Assistant Professor, Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University Piscataway, NJ

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How does your research relate to IFNs in cancer therapy?

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How has the role of IFNs as potential antitumor agents changed in recent years?

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Do all three classes of IFNs have potential antitumor activity?

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What are the biggest gaps in our understanding of the role of IFNs in cancer therapy?

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What does the future hold for IFNs in cancer therapy?

For more than 20 years, Ahmed Lasfar, PhD, has been exploring the cell-signaling activity of interferons (IFNs). His research focuses on cancer immunology and immunotherapy, and he has been involved in the characterization of a new type of interferon, IFNλ, and its antitumor activity.¹ He also collaborates with the Cancer Institute of New Jersey in the development of novel IFN therapy for cancer patients.I am a long-standing researcher in the fields of IFN and cancer. My research is specifically focused on understanding antitumor mechanisms of type I and type III IFNs alone and in combination. Since my doctoral training at the Curie Institute in Paris, France, I have been interested in antitumor mechanisms of IFN on hematological malignancies. At that time, my research was focused on the interaction of IFNα with other cytokines, such as IL-6 [interleukin-6] in multiple myeloma or TNFα [tumor necrosis factor-α] in hairy cell leukemia, the malignancies for which IFN was successfully used in the clinic.In recent years, important discoveries have been made in the IFN field and in cancer. In 2003, our laboratories identified and characterized a new IFN system named IFNλ, and we demonstrated for the first time its potent antitumor activity. Notably, we also demonstrated that in contrast to IFNα, IFNλ is highly tissue-specific, strongly suggesting that it would induce very limited side effects when used as an antitumor agent. In addition to its potent antitumoral effects against melanoma, we and other groups have demonstrated the efficacy of IFNλ in other cancer models.The current IFN therapy is mainly based on IFNα, a type I IFN. The clinical applications of IFNγ, or type II IFN, are limited. Thus far, IFNλ, classified as type III IFN, has only been tested clinically for the treatment of hepatitis C. We believe that all the IFN types have potential antitumor activities. Numerous studies suggest that IFNα will be effective in treating cancer. However, significant poorly tolerated side effects limit its usefulness. IFNλ constitutes a renewed hope for IFN therapy. This new IFN, although acting similarly to IFNα, is more specific, strongly suggesting that it may have fewer side effects.Although tremendous progress has been made in the IFN field, particularly on cell signaling, important gaps still persist on the mechanism of action of IFN. We still do not know why there are many types of IFN. In humans, type I IFNs include more than 13 IFNα subtypes, including IFNβ, IFNω, IFNκ, and IFNε. In contrast, IFNγ is the only identified type II IFN, while three subtypes have been characterized for type III IFN: IFNλ1, 2, and 3. More recently another IFNλ (IFNL4) has been described. This IFN plays an important role in the success of IFNα therapy in the clearance of hepatitis C. The antitumor mechanisms of IFN are not yet well understood. Questions remain, including: How is IFN involved in tumor immunosurveillance and immunotolerance? Does the current scheme of IFN administration take advantage of only some of the potential effects of IFN?Although IFN has been used for decades in cancer therapy, we believe complete benefits are not yet achieved. IFNα is indicated for numerous cancers, but its uses remain problematic for two main reasons: (1) low efficacy; and (2) numerous and significant side effects. Improvements in IFN therapy continue to be one of the major challenges to this research field, with a clear objective to increase its benefits for patients. With the emergence of IFNλ, new perspectives in IFN and cancer therapy can be offered. However, we believe that IFNλ cannot be viewed only as an alternative, but rather as an ally to IFNα.

Reference

1. Lasfar A, Lewis-Antes A, Smirnov SV, et al. Characterization of the mouse IFN-λ ligand-receptor system: IFN-λs exhibit antitumor activity against B16 melanoma. Cancer Res. 2006;66(8):4468-4477.