Interferon Therapy: A Growing Family Feeds New Interest in an Older Treatment

More than half a century has passed since interferons (IFNs) were first discovered. Since then, they have evolved from a “cure-all” for cancer, as they were initially touted, to a more tempered yet equally vital role in treating a number of different disease states, including many different types of cancer.

What Are Interferons?

Although they have been replaced by more targeted molecular therapies in some instances, IFNs still have an important role to play in cancer therapeutics. This potential is becoming increasingly evident as researchers gain a better understanding of the biology of IFNs and uncover new isoforms and genetic variants, including the discovery last year of a new class of IFNs (type III).IFNs were first characterized in 1957 and were named for their role in a process called viral interference, in which one virus interferes with the growth of another, unrelated virus. By the mid-1970s, IFN research began to take off and, following reports of antitumor activity in mice, they began to be used in the treatment of a wide range of different cancers.

IFNs are part of the cytokine family of proteins⎯small, hormone-like proteins that play an important role in communication between cells and their external environment, produced in response to external stimuli. They are classified into three groups according to which receptor they bind:

• Type I IFNs, which all use the type I IFN receptor, include IFNα, β, δ, ε, κ, and ω
• Type II IFNs, which use the type II IFN receptor, consist of IFNγ
• Type III IFNs, which use an IFNλ-specific receptor, consist of IFNλ

The groups differ not just in which receptor they bind, but also in the cells that produce them and in their genetic variation. While IFNγ is encoded by a single gene, IFNλ has four subtypes, and IFNα has up to 14. The type I IFNs are the most broadly expressed and can be produced by virtually any cell in the body, though IFNα is produced primarily by macrophages and dendritic cells, while IFNβ is expressed predominantly by fibroblasts. The type II and type III IFNs are much more restricted in the types of cells that both produce and respond to them.

A Glimpse at IFN Pathways

IFN indicates interferon; IRF, interferon regulatory factor; ISG, interferonstimulated gene; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; TYK, tyrosine kinase; STAT, signal transducer and activator of transcription.

Adapted from Katsoulidis E, Kaur S, Platanias LC. Deregulation of interferon signaling in malignant cells. Pharmaceuticals. 2010;3:406-418.

Interferons as Anticancer Therapy

IFNs exert their cellular effects by binding to their specific receptor on the membrane of a target cell and initiating intracellular signaling events. This is another important point of divergence between the three groups. The type I and type III IFNs have significant overlap in the downstream signaling events that they initiate. They activate the tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), resulting in the formation of heterodimers of signal transducer and activator of transcription 1 and 2 (STAT1/2), which subsequently migrate into the nucleus and associate with the transcription factor IFN regulatory factor 9 (IRF9) to form the IFN-stimulated gene factor 3 (ISGF3) complex. This complex in turn activates the transcription of IFN target genes. On the other hand, the type II IFN, IFNγ, signals via JAK1 and JAK2 and activates different downstream signaling events.IFNs clearly act upstream of many important signaling pathways, and researchers have elucidated a plethora of different cellular roles besides their namesake activity of viral interference. For example, they play vital roles in regulating both the innate and adaptive immune responses, and in the activation, migration, differentiation, and survival of various different types of immune cell. In the 1990s, the role of IFNs began to be further delineated, and there was much excitement as it became apparent that they had so-called non-antiviral effects⎯a variety of effects on cell growth, apoptosis, and angiogenesis (new blood vessel formation) were observed, and this is when clinicians began to realize the potential anticancer applications of IFNs.

Over the decades that followed the discovery of the cytotoxic effects of IFNs, they were touted as a potential “magic bullet” treatment for cancer. While they ultimately did not offer the cure-all that many had hoped, they did become the first treatment for numerous types of hematological cancers and solid tumors, and offered significant hope to patients. At one time or another, they were used clinically and were standard-of-care treatment for chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T- and B-cell lymphomas, melanomas, renal cell carcinomas, and AIDS-associated Kaposi sarcoma.

Alpha IFNs are the only type of IFN that is currently approved for the treatment of cancer in the United States. However, all the IFN types are being evaluated in clinical trials in cancer patients to some degree or another, although the focus has typically been on the type I IFNs.

Although IFNs have been replaced by more effective targeted molecular therapies, such as tyrosine kinase inhibitors and monoclonal antibodies, as standard of care in many cases, they are still used or being investigated as salvage or adjunctive therapies. They have entered a new era in which there is significant renewed interest in IFN therapy and the potential for improved anticancer efficacy by combining IFNs with other agents.

Combination therapy is proving to be effective in many cases thus far. For example, a combination of daily, low-dose IFNα with dacarbazine and bevacizumab (an inhibitor of angiogenesis) produces a trend toward enhanced progression-free survival in metastatic melanoma. In CML, a combination of IFNα with the tyrosine kinase inhibitor imatinib produces a more rapid response than imatinib alone, and IFNα can be used as maintenance therapy, allowing discontinuation of imatinib while maintaining the molecular response. IFNα is also being examined in combination with the cancer vaccine TG4010 (which targets the cell-surface protein mucin-1) in renal cell carcinoma, and has demonstrated stable disease over six months and is well tolerated. In combination with the targeted agents sunitinib and erlotinib, there is a trend toward increased overall survival.

A significant issue with type I IFN therapy is the substantial side effects experienced by patients, which include myelosuppression and nervous system disorders, and likely occur as a result of the broad cellular activity of this group of IFNs. The recently identified third type of IFNs, the IFNλs, activate similar downstream signaling pathways to the type I IFNs and have been shown to share the same biological properties, including the antitumor activity. In fact, some studies suggest that IFNλ may have even more pronounced antiapoptotic and antiproliferative effects than IFNα. Since the lambda IFNs act through a unique receptor whose expression is limited to only certain cell types, it is possible that IFNλ could offer a lesstoxic therapeutic alternative for certain types of cancer. This is a hypothesis that is being heavily investigated.

Interferons in the Treatment of Cancer

Interferon alpha

IFNα is the only IFN that the FDA has approved for use in cancer patients; specifically, it is indicated for use in patients with hairy cell leukemia (HCL), melanoma, chronic myeloid leukemia (CML), and AIDS-related Kaposi sarcoma.

Roferon-A

Roche

This recombinant IFNα-2a is approved for use in HCL and chronic-phase CML patients who are Philadelphia chromosome—positive and have been minimally pretreated.

Intron A

Merck

This recombinant IFNα-2b is approved for use in HCL, malignant melanoma, AIDS-related Kaposi sarcoma, and follicular non-Hodgkin lymphoma (NHL).

Sylatron

Merck

This pegylated IFNα-2b is indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of surgical resection. At the time of its approval in 2011, the injectable drug was the first new option for melanoma that the FDA had approved in 15 years, according to Merck.

Pegasys

Genentech

Pegintron

Merck

Two pegylated IFNα agents, Pegasys and Pegintron, are approved for the treatment of chronic hepatitis B and C virus (HBV/HCV). The addition of several polyethylene glycol (PEG) molecules to IFNα helps to improve its pharmacokinetic and pharmacodynamic properties, shielding it from enzymatic degradation and increasing its half-life and stability. Since HBV and HCV infection is one of the leading causes of hepatocellular carcinoma (HCC), IFN treatment could help in the prevention of many cases of HCC, researchers hypothesize. Indeed, IFN treatment, either alone or in combination with the purine analogue ribavirin, has been shown to decrease the incidence of HCC in patients with chronic HCV and HBV.

Multiferon

Swedish Orphan Biovitrum AB

This agent is a human multisubtype leukocyte IFNα consisting of six alpha IFN subtypes released by human leukocytes in response to the Sendai virus. Multiferon is used for the adjuvant treatment of high-risk patients with cutaneous melanoma, stages IIB-III, after two cycles of dacarbazine chemotherapy. It is also used in the treatment of patients with melanoma who initially respond to IFNα but for whom treatment subsequently fails. Multiferon is currently approved in a number of countries worldwide, though not yet in the United States.

In the Pipeline

IFNα is also being evaluated in a variety of clinical trials for different types of cancer. For example, pegylated IFNs are undergoing phase II testing in CML and phase III trials as adjuvant therapy in ulcerated melanoma. Highdose IFNα-2b is being evaluated as neoadjuvant combination therapy with the CTLA4 antibody ipilimumab in melanoma. Phase I/II trials of IFNα-2a in combination with the tyrosine kinase inhibitor pazopanib are under way in patients with advanced renal cell carcinoma.

NCT01392170, NCT01502696, NCT01608594, NCT01513187

Interferon beta

Several beta IFNs, including IFNβ-1a and IFNβ-1b, are approved for use in the treatment of multiple sclerosis, but not in cancer. The FDA has granted IFNβ orphan drug status for the treatment of many different cancers, including primary brain tumors and metastatic renal cell carcinoma. A number of clinical trials of IFNβ in many different types of cancer have been completed or are under way. These include an ongoing study to evaluate the safety of recombinant vesicular stomatitis virus expressing IFNβ in patients with HCC. NCT01628640

Interferon gamma

An approved IFNγ therapeutic, Actimmune (Vidara Therapeutics, Inc), is approved in the United States for patients with severe osteoporosis and with infections associated with chronic granulomatous disease, but not for cancer. However, IFNγ is approved for use in adult T-cell leukemia/lymphoma in Japan. It is also being evaluated in cancer patients, including as adjuvant treatment to vaccine therapies and chemotherapies in melanoma. NCT00977145

Interferon lambda

IFNλ is the newest of the IFN subtypes. It is currently being heavily investigated in the treatment of HCV and HBV in many different clinical trials.

Source note: Information gathered from ClinicalTrials.gov, Key Research cited, company websites

The Future of Interferon Therapy

Besides the discovery of a distinct third type of IFNs, which has rejuvenated the field, there have been several other exciting discoveries relating to IFNs in recent years that have contributed to a better understanding of their biology and may have therapeutic implications in cancer.

IFNλ was previously thought to be represented by three genes: IFNL1 (IFN lambda 1), IFNL2, and IFNL3. However, a new genetic variant has since been identified, IFNL4, which has been shown to be strongly associated with response to one of the leading causes of liver cancer, namely chronic hepatitis C virus (HCV) infection. IFNL4 is a particularly strong predictor of IFNα treatment response in African Americans, who make up nearly a quarter of all patients with HCV infections. It is thought that this could lead to the development of a new universal genetic test to guide treatment in all ethnicities. Researchers are also interested in examining whether IFNL4 affects response to IFN treatment in patients with melanoma.

Another significant finding in the IFN field is that IFNs may not always play a preventive role in cancer. IFNγ has fared poorly in clinical trials of cancer patients, with low response rates and, in some cases, treated patients actually doing worse than untreated patients. This could be explained in part by the recent revelation that, depending on the cellular context, IFNγ can in fact play a protumorigenic role, driving cellular and inflammatory mechanisms that underlie tumor initiation and survival. IFNλ has also been implicated in playing a direct role in the development of certain cancers.

Therefore, in the future it will become increasingly important to gain a complete understanding of the biology of IFNs and the precise cellular roles that they play in order to most successfully exploit IFN therapy in the treatment of cancer.

Key Research

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.

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