thesis
Clinical and biological effects of interleukin 12 in patients with renal cell carcinoma
- Publication date
- 6 November 2002
- Publisher
- Il-12 has a number of immunoregulatory properties indicating its therapeutic
potential against cancer. The encouraging anti-tumor effects, observed in a
variety of animal tumor models, have stimulated the development of Il-12 as a
single agent for systemic cytokine therapy of cancer in humans. Metastatic renal
cell cancer is one of the few human cancers that are more responsive to
immunotherapy than to conventional cytotoxic therapies. Therefore, a phase I
study of Il-12 was performed in patients with advanced renal cell cancer. The
choice of schedule and route of administration were based on experiments in
cynomolgus monkeys. Il-12 in s.c. doses of 0.1 to 1.0 Jlg /kg /day, three times a
week, was shown to modulate immune activity without provoking substantial
toxicity in these animals.
The objective of the study described in chapter 2 was to evaluate the safety
and tolerability of subcutaneous IL-12 in humans and establish the
pharmacokinetic profile. The observation of a non-linear relationship between
dose and drug exposure in animal models formed the rationale to study the
effects of a single and multiple doses of Il-12. In chapter 3 the
immunomodulatory activities of IL-12 in humans are described in detail, with
emphasis on the induction of secondary cytokines and the effects on circulating
leucocyte subset counts. Based on the observation that side effects decreased
upon repeated injections of IL-12, we specifically studied whether or not
immunomodulatory effects were downregulated in the course of multiple IL-12
injections with special attention for the role of the immunosuppressive cytokine
IL-10.
Chapter 4 describes a study of the effect of IL-12 on fibrinolysis and
coagulation in humans. This study was performed because several bleeding
episodes were reported in simultaneously performed clinical studies, whereas
studies in mice and non-human primates had shown that IL-12 induced
activation of coagulation and fibrinolysis.
Il-12 is a strong pro-inflammatory cytokine. Studies in patients and
experimental animals have demonstrated that endogenously produced IL-12
plays an important role in the toxic sequel of sepsis and endotoxemia. In these
situations, excessive activation of various components of the inflammatory
cascade contributes to the development of tissue injury and mortality. In chapter
5 we describe the in-vivo effects of different doses of subcutaneous Il-12 on
components of the inflammatory cascade. We specifically addressed the degranulation of neutrophils and the formation of secretory phospholipase Az, a
regulatory enzyme in the formation of eicosanoids.
The study described in chapter 2 was one of four phase I studies, that were
simultaneously performed in Europe and the US. Subsequent phase II studies in
patients with advanced renal cell cancer and ovarian cancer demonstrated
disappointing anti-tumor effects. The results described in chapter 3, together
with other pharmacodynamic studies, indicate that the lack of efficacy was
accompanied by, and probably related to, declining biological effects of IL-12 in
the course of repeated administrations at doses approaching the maximum
tolerated dose (MTD). Nevertheless, IL-12 remains a promising immunotherapeutic
agent because recent cancer vaccination studies in animal models
and humans have demonstrated its powerful adjuvant properties. Chapter 6
reviews the adjuvant properties of IL-12 and delineates how the immuneregulatory
properties of IL-12 described in the previous chapters may contribute
to the adjuvant effects. In addition, it is discussed how the studies presented in
this paper, together with other clinical studies of systemic IL-12, indicate that IL-
12 may exert optimal adjuvant effects only at low dose levels. Finally, the future
perspectives of IL-12 in the treatment of cancer are addressed.