Year: 2002
Type: dissertation
Study design: Clinical Trial
Abstract: Il-12 has a number of immunoregulatory properties indicating its therapeutic\npotential against cancer. The encouraging anti-tumor effects, observed in a\nvariety of animal tumor models, have stimulated the development of Il-12 as a\nsingle agent for systemic cytokine therapy of cancer in humans. Metastatic renal\ncell cancer is one of the few human cancers that are more responsive to\nimmunotherapy than to conventional cytotoxic therapies. Therefore, a phase I\nstudy of Il-12 was performed in patients with advanced renal cell cancer. The\nchoice of schedule and route of administration were based on experiments in\ncynomolgus monkeys. Il-12 in s.c. doses of 0.1 to 1.0 Jlg /kg /day, three times a\nweek, was shown to modulate immune activity without provoking substantial\ntoxicity in these animals.\nThe objective of the study described in chapter 2 was to evaluate the safety\nand tolerability of subcutaneous IL-12 in humans and establish the\npharmacokinetic profile. The observation of a non-linear relationship between\ndose and drug exposure in animal models formed the rationale to study the\neffects of a single and multiple doses of Il-12. In chapter 3 the\nimmunomodulatory activities of IL-12 in humans are described in detail, with\nemphasis on the induction of secondary cytokines and the effects on circulating\nleucocyte subset counts. Based on the observation that side effects decreased\nupon repeated injections of IL-12, we specifically studied whether or not\nimmunomodulatory effects were downregulated in the course of multiple IL-12\ninjections with special attention for the role of the immunosuppressive cytokine\nIL-10.\nChapter 4 describes a study of the effect of IL-12 on fibrinolysis and\ncoagulation in humans. This study was performed because several bleeding\nepisodes were reported in simultaneously performed clinical studies, whereas\nstudies in mice and non-human primates had shown that IL-12 induced\nactivation of coagulation and fibrinolysis.\nIl-12 is a strong pro-inflammatory cytokine. Studies in patients and\nexperimental animals have demonstrated that endogenously produced IL-12\nplays an important role in the toxic sequel of sepsis and endotoxemia. In these\nsituations, excessive activation of various components of the inflammatory\ncascade contributes to the development of tissue injury and mortality. In chapter\n5 we describe the in-vivo effects of different doses of subcutaneous Il-12 on\ncomponents of the inflammatory cascade. We specifically addressed the degranulation of neutrophils and the formation of secretory phospholipase Az, a\nregulatory enzyme in the formation of eicosanoids.\nThe study described in chapter 2 was one of four phase I studies, that were\nsimultaneously performed in Europe and the US. Subsequent phase II studies in\npatients with advanced renal cell cancer and ovarian cancer demonstrated\ndisappointing anti-tumor effects. The results described in chapter 3, together\nwith other pharmacodynamic studies, indicate that the lack of efficacy was\naccompanied by, and probably related to, declining biological effects of IL-12 in\nthe course of repeated administrations at doses approaching the maximum\ntolerated dose (MTD). Nevertheless, IL-12 remains a promising immunotherapeutic\nagent because recent cancer vaccination studies in animal models\nand humans have demonstrated its powerful adjuvant properties. Chapter 6\nreviews the adjuvant properties of IL-12 and delineates how the immuneregulatory\nproperties of IL-12 described in the previous chapters may contribute\nto the adjuvant effects. In addition, it is discussed how the studies presented in\nthis paper, together with other clinical studies of systemic IL-12, indicate that IL-\n12 may exert optimal adjuvant effects only at low dose levels. Finally, the future\nperspectives of IL-12 in the treatment of cancer are addressed.
Author: Johanneke E.A. Portielje
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2151645148