Elsevier

Cytokine & Growth Factor Reviews

Volume 18, Issues 5–6, October–December 2007, Pages 395-402
Cytokine & Growth Factor Reviews

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

https://doi.org/10.1016/j.cytogfr.2007.06.005Get rights and content

Abstract

Interferon alfa (IFNα) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNα causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNα activities. To a large extent other agents have supplanted IFNα as treatments for KS, but there may still remain a therapeutic role for IFNα, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling.

Section snippets

IFNα as single agent therapy—a requirement for high IFN doses

My colleagues and I treated our initial group of patients with AIDS-associated KS with recombinant IFNα2a in late 1981 and early 1982 during the course of one of the first phase I clinical trials of this agent in cancer patients. This trial, which involved the administration of escalating doses of IFNα2a to successive patient cohorts, had as its primary aim the evaluation of the safety, toxicity and maximum tolerated dose of this agent in a diverse group of cancer patients, and as a secondary

IFNα combined with first-generation antiretroviral therapy—lower IFN doses are active

The FDA approval of the nucleoside reverse transcriptase inhibitor zidovudine (ZDV; known also as azidothymidine, or AZT) for treatment of HIV infection in 1987, and the demonstration that the combination of ZDV and IFNα synergistically inhibited HIV replication in vitro [12], led logically to studies of this combination in HIV-infected individuals, including those with KS. Our phase I trial of the combination showed that the addition of ZDV resulted in a decrease in the maximum tolerated dose

Is less IFN more?

Our early experiences strongly suggested that optimal KS responses to IFNα required that we use the highest doses that could be administered without causing unacceptable toxicity. However, the realization that lower doses could be active in combination with antiretroviral therapy, as well as a desire to minimize the significant toxicities sometimes associated with high-dose treatment, led us to evaluate the combination of lower doses of IFNα with didanosine, a nucleoside reverse transcriptase

Developing a better understanding of KS pathogenesis

KS has long been described as an “angiogenic” neoplasm, in the sense that a characteristic histologic feature is the proliferation of endothelial cell-lined slit-like vascular spaces. Recent gene expression profiling analyses have shown that spindle cells, which form the major cellular component of the lesions, most closely resemble lymphatic endothelium [19]. The lesions also contain a variable inflammatory and mononuclear cell infiltrate. Studies published beginning in the late 1980s

IFN activities in the context of KS pathogenesis

A strong and specific rationale for treating AIDS-associated KS with IFN has accumulated over the past 25 years. This can be divided, broadly, into antiviral and angiogenesis-inhibitory activities of IFN, as follows.

Barriers to the further development of IFN therapy for KS

Although there is clearly a strong and multifaceted rationale for its use, several factors have impeded the further development of IFNα for KS treatment.

The future for IFN in KS

For all these reasons, it is not highly likely that the studies that would be required to optimize the use of IFNα in KS, to clarify its mechanisms of action, and to identify the patients most likely to benefit, will be conducted. This is too bad, because in spite of the barriers limiting its use, IFNα has proven to be one of the more active agents in the treatment of KS, and was shown to induce sustained and sometimes dramatic tumor regression in some patients even before the development of

Acknowledgment

I would like to thank Dr. Dirk P. Dittmer for helpful discussion and comment on this manuscript.

Susan E. Krown is a member and attending physician in the Department of Medicine at the Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill/Cornell Medical College. She received her MD degree from the State University of New York, Downstate Medical Center. Dr. Krown completed internship and residency training in Internal Medicine at the Mount Sinai Hospital in New York and fellowships in clinical immunology and medical oncology at Memorial Sloan-Kettering. She currently

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    Susan E. Krown is a member and attending physician in the Department of Medicine at the Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill/Cornell Medical College. She received her MD degree from the State University of New York, Downstate Medical Center. Dr. Krown completed internship and residency training in Internal Medicine at the Mount Sinai Hospital in New York and fellowships in clinical immunology and medical oncology at Memorial Sloan-Kettering. She currently leads the Kaposi's Sarcoma Working Group of the AIDS Malignancy Consortium, an NCI-supported multicenter cooperative group dedicated to the development of treatments for HIV-associated malignancies. Her research interests include the development of novel, pathogenesis-based treatments for Kaposi's sarcoma, and management of non-AIDS defining cancers in HIV-infected individuals. Dr. Krown was a 1995 recipient of the Milstein Award from the International Society for Interferon and Cytokine Research. She has been a member of several Editorial Boards and serves as an advisor to several community-based AIDS organizations.

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