Phase IB trial of picibanil (OK-432) as an immunomodulator in patients with resected high-risk melanoma |
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Authors: | John M Kirkwood John Wilson Theresa L Whiteside Sandra Donnelly Ronald B Herberman |
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Institution: | (1) Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pa., USA, US;(2) University of Pittsburgh Cancer Institute, Melanoma Center/Biologic Therapy Programs, Pittsburgh, Pa., USA, US;(3) Department of Medicine, University of Pittsburgh Medical Center, Division of Medical Oncology, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA, US |
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Abstract: | The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer
agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation
of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in
25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as
the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma
participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages
ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison
to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients
treated with OK-432. Patients who participated in this trial had a significant depression of OK-432- inducible cytokine production
(interleukin-1β, interferon γ, and tumor necrosis factor α) at baseline. Treatment with OK-432 reversed this deficit for interferon γ (IFNγ)
production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The
impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear
cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate
a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated
with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible
superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected
high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFNγ release associated with melanoma may be mitigated
by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with
one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients
with resected melanoma.
Received: 2 October 1996 / Accepted: 28 January 1997 |
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Keywords: | Picibanil (OK-432) Cancer Melanoma Immunostimulants Immunomodulator OK-432 |
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