Lymphohaematopoietic Growth Factors in Cancer Therapy

92 Pages·1990·7.871 MB·English

by  Roland Mertelsmann (auth.), Roland Mertelsmann (eds.)

Monographs
Series Editor: U.Veronesi
R. Mertelsmann (Ed.)
Lymphohaematopoietic
Growth Factors
in Cancer Therapy
With 8 Figures and 14 Tables
Springer-Verlag Berlin Heidelberg New York
London Paris Tokyo Hong Kong Barcelona
Abteilung Innere Medizin I
Klinikum der Albert-Ludwigs-Universitat
Hugstetter StraBe 55
7800 Freiburg
Federal Republic of Germany
The European School of Oncology gratefully acknowledges sponsorship for the Task
(ROCho/
Force received from Prodotti Roche S.p.A. - Milano
Library of Concress Cataloging-in-Publication Data
Lymphohaematopoietic growth factors in cancer therapy 1 R. Mertelsmann (ed.). p. cm.-(Monographs 1 European School of
Oncology)
ISBN-13: 978-3-642-76039-6 e-ISBN-13: 978-3-642-76037-2
001: 10.1007/978-3-642-76037-2
1. Cancer-Immunotherapy. 2. Hematopoietic growth factors
Therapeutic use. 3. Lymphokines-Therapeutic use. 4. Interleukins-Therapeutic use. I. Mertelsmann, Roland. II. Series:
Monographs (European School of Oncology) [DNLM: 1. Growth Substances. 2. Interleukin-2-therapeutic use. 3. Inter
leukins-therapeutic use. 4. Killer Cells, Lymphokine-Activated. 5. Neoplasms-therapy. OZ266 L9864] RC271.145L9441990
616.99'4061-dc20 DNLMIDLC for Library of Congress 90-10303 CIP
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Foreword
The European School of Oncology came into existence to respond to a need for informa
tion, education and training in the field of the diagnosis and treatment of cancer. There are
two main reasons why such an initiative was considered necessary. Firstly, the teaching of
oncology requires a rigorously multidisciplinary approach which is difficult for the Univer
sities to put into practice since their system is mainly disciplinary orientated. Secondly, the
rate of technological development that impinges on the diagnosis and treatment of cancer
has been so rapid that it is not an easy task for medical faculties to adapt their curricula
flexibly.
With its residential courses for organ pathologies and the seminars on new techniques
(laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic
controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy,
radiotherapy alone or integrated), it is the ambition of the European School of Oncology
to fill a cultural and scientific gap and, thereby, create a bridge between the University and
Industry and between these two and daily medical practice.
One of the more recent initiatives of ESO has been the institution of permanent study
groups, also called task forces, where a limited number of leading experts are invited to
meet once a year with the aim of defining the state of the art and possibly reaching a
consensus on future developments in specific fields of oncology.
The ESO Monograph series was designed with the specific purpose of disseminating the
results of these study group meetings, and providing concise and updated reviews of the
topic discussed.
It was decided to keep the layout relatively simple, in order to restrict the costs and make
the monographs available in the shortest possible time, thus overcoming a common
problem in medical literature: that ofthe material being outdated even before publication.
UMBERTO VERONESI
Chairman Scientific Committee
European School of Oncology
Contents
Introduction
R. MERTELSMANN . . . . . . . . . . . . . . . . .. 1
Interleukins and Haematopoietic Growth Factors
F. M. ROSENTHAL, A. LINDEMANN, F. HERRMANN and R. MERTELSMANN . . . . . . . . . . .. 3
Mechanisms ofT-Ceil Activation
H. WAGNER and K. HEEG . . . . . . .......... 19
Characteristics of LAK Cells and Their Use in Adoptive Therapy
of Cancer in Experimental Animals
R. B. HERBERMAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 25
Interleukin 2: In Vivo Induction of Effector Cells
G. FORNI, M. C. Bosco, S. VAl and M. GIOVARELLI ................... 37
Cellular Immunotherapy of Cancer:
The Use of Lymphokine-Activated Natural Killer (LANAK) Cells
F. FARACE, B. ESCUDIER, F. TRIEBEL and T. HERCEND .................... 47
Interleukin 2: Clinical Aspects
N . THATCHER .. . . . . .. ............. . . . . . . . . . . . . . . . 57
Interleukin 2 and LAK Cells
F. CALABRESI and E. M. RUGGERI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Introduction
Roland Mertelsmann
Department of Medicine I, Division of HaematologylOncology, Albert-Ludwig's University Medical Centre, Hugstetter
Strasse 55, 7800 Freiburg, FRG
Proliferation, differentiation and functional activity of haematopoietic and immunological
progenitor and effector cells are regulated by a family of peptide hormones called
cytokines. Recent information suggests an important role for these mediators not only in
the elimination of pathogenic organisms and cells but also in the pathogenesis of
infectious and neoplastic disorders. Studies of gene structure, gene expression,
induction requirements and cellular sources using molecular probes and biological
assays, have demonstrated a complex cascade of synergising activation signals that
amplify immune and inflammatory responses. Through recombinant DNA technology,
sufficient quantities of highly purified cytokines have become available for clinical
evaluation.
Conceptually, cytokine-based treatment strategies are directed towards 1) stimulation of
host antitumour defense mechanisms, 2) direct effect on tumour cell proliferation and
differentiation, and 3) increasing host resistance to neoplasia- or therapy-induced
Iympho- and myelosuppression.
Interleukin 2 is the prime example of a cytokine which induces host effector cells with
tumour killing capacities, resulting in reproducible albeit 'rare remissions in malignant
melanoma and renal cell carcinoma. The interferons are thought to exert their most
prominent clinical benefits in hairy cell leukaemia and chronic myelogenous leukaemia
by direct effects on the respective leukaemic cell populations. Major progress has
recently been made by using haematopoietic growth factors (haemopoietins) including
erythropoietin, G-CSF, GM-CSF and Interleukin 3 in ameliorating disease- and therapy
induced myelosuppression with significant clinical benefits for patients. A survival
advantage for patients receiving haemopoietins in conjunction with chemo/radiotherapy
has already been demonstrated in some studies. A significant improvement in the quality
of life of patients receiving cancer chemotherapy has been documented in all 'clinical
studies so far, making the introduction of cytokines into the clinic one of the major
advances in cancer therapy of the 1980s.
In preparing this monograph, the editor has had the privilege and pleasure to collaborate
with an outstanding group of experts in clinical and experimental cytokine research, for
which he expresses his warmest appreciation.
Interleukins and Haematopoietic Growth Factors
F.M. Rosenthal, A. Lindemann, F. Herrmann and R. Mertelsmann
Department of Medicine I, Division of HaematologylOncology, Albert-Ludwig's University Medical Centre, Hugstetter
Strasse 55, 7800 Freiburg, FRG
One of the most challenging areas of con tients or by depletive immunotherapy, and fi
temporary oncological and immunological re nally by adoptive immunotherapy, entailing
search is represented by investigation of the the transfer of immunocompetent cells from
potential clinical use of human cytokines. one individual to another or the administra
In recent years, a breakthrough was provided tion of ex vivo activated autologous immune
by cloning of the genes of some of these cells.
growth factors. It was thus made possible to In this chapter, we will concentrate on the ex
obtain homogeneous preparations of individ perience that has been gained with the use of
ual factors in sufficient quantities to permit cytokines in cancer therapy.
large-scale laboratory and clinical trials. Cytokines are polypeptide products of acti
For many years, standard treatment of malig vated cells which, in most instances, provide
nant disease has focussed on local surgery, relatively short-range communication be
radiation and systemic chemotherapy. As the tween a wide variety of cells by influencing
available therapy for the more frequent their proliferation, differentiation and state of
cancers has remained unsatisfactory, oncol activation. They are produced by multiple cell
ogists are forced to explore novel therapeutic types and several of them have pleiotropic
approaches. and overlapping, sometimes synergistic or
Improved understanding of tumour patho additive, activities that are not restricted to in
physiology and immunology raises the pos fluencing one cell lineage only. The majority
sibility of introducing additional treatment of growth factors appear to have the capacity
modalities: the stimulation of host defense of inducing other cytokines, including HGFs,
mechanisms including specific and non-spe in activated white blood cells. This complex
cific immunological approaches as well as network of interactions renders the evaluation
effects to directly affect tumour growth and dif of clinical studies conducted with these fac
ferentiation by therapeutically influencing tors very complex, since multifaceted direct
pathophysiological mechanisms. The com and indirect effects on many organ systems
plexity of the immune response to tumours have to be expected.
necessitates a multifaceted approach to the The potential clinical use of human cytokines
problem of immunotherapy. Ideally, such an can arbitrarily be ramified into 4 strategies:
approach should attempt to minimise the 1. Stimulation of the immune response in
ability of a tumour to escape immunological order to enhance immunosurveillance of
control, reduce tumour viability and enhance neoplasms (e.g., 1L2).
specific or non-specific host resistance. In 2. Mitigation of cancer therapy and cancer
practice, this may be achieved either by ac related immuno- and myelosuppression
tive manipulation of the immune response by and augmentation of non-specific mech
vaccination against tumours or by administra anisms of host resistance. (e.g., GM-CSF,
tion of immunoregulatory factors such as cy G-CSF, EPO).
tokines. Another possible access to this 3. Indirect improvement of antitumour re
problem is by passive immunotherapy involv sponse and survival by reducing toxicity
ing the transfer of antibodies to cancer pa- and thus altering the definition of the
4 F.M. Rosenthal, A. Lindemann, F. Herrmann and R. Mertelsmann
Table 1. Cytokines involved in immunoregulation and haematopoietic blood cell development
Family Molecules Synonyms Chromosomal Molecular weight"
localisation (kilodalton)
1 . Growth factors Multi-CSF IL-3 5q23-q31 14-28
GM-CSF CSF-alpha 5q21-q32 14-35
G-CSF CSF-beta 17q11-q22 18-22
M-CSF CSF-1 5q33 47-74
EPO 7q11-q22 34-39
2. Interleukins IL-1 Hematopoietin-1 2q14 31 ;17
IL-2 TCGF 4q2S-q28 15.5
IL-3 Multi-CSF 5q23-q31 14-28
IL-4 BSF-1 5q 15-20
IL-5 BCGF-II, TRF 5q 12-18
IL-S BSF-2 7q 24
3. Interferons IFN-alpha Leukocyte-IFN 9 18-20
IFN-beta Fibroblast-IFN 9 23
IFN-gamma Immune-IFN 12 20-25
4. Tumor necrosis TNF-alpha Cachectin S 17
factors TNF-beta Lymphotoxin S 25
5. Others PDGF
(examples) TGF-alpha
TGF-beta
TCGF, T-cell growth factor; BSF, B-cell stimulatory factor; BCGF, B-cell growth factor; TRF, T-cell replacing factor;
PDGF, platelet-derived growth factor; TGF, transforming growth factor
For other abbreviations see text
" Variations in molecular weight are in most cases due to different degrees of glycosylation
maximum tolerated doses of conventional Haematopoletlc Growth Factors
chemotherapeutic regimens (CSFs).
4. Direct influence on tumour cell growth
and differentiation via cytotoxic, cytostatic The haematopoietic growth factors (HGFs)
or regulatory mechanisms (e.g., TNF). are a family of glycoprotein hormones which
regulate survival, proliferation and differentia
Apart from this potential use in cancer ther tion of haematopoietic progenitor cells as well
apy, there are a number of non-neoplastic as the functional activities of mature cells [1]
disorders associated with neutropenia, where (see Fig. 1). During the past few years, the
the application of growth factors may prove to genes for 5 of the human factors have been
be beneficial. defined and cloned, and recombinant forms
Cytokines involved in immunoregulation or of the proteins have been produced and puri
cell proliferation can be divided into several fied. The different factors have been opera
groups (Table 1), such as haematopoietic tionally defined by prefixes based on the pre
growth factors, interleukins, interferons, tu dominant type of colony found in vitro in re
mour necrosis factors, and others. sponse to these molecules. The factors cur
Since most cytokines possess pleiotropic bio rently under active clinical investigation in
logical properties, there are overlapping ac clude multipotential colony-stimulating factor
tivities between groups, which makes any (Multi-CSF or interleukin 3), granulocyte
classification somewhat arbitrary. macrophage CSF (GM-CSF), granulocyte
Interleukins and Haematopoietic Growth Factors 5
Il-3 Gran~ytes
1l-4
baso
?
GM-CSF
L-3
11..-5
-----------------~ eos
1l-3 ?
GM-CSF
G-CSF
neut
3d
3d
t.4onocyte
Epo .- -. •· .•·7 d
1l-3 Platelet.
Gt.4-CSF t.4egakaryocyte
Epo
_120c1
Epo
BFU-E CFU-E RBe
Fig. 1. Influence of haematopoietic growth factors on different cell types
CSF (G-CSF), macrophage CSF (M-CSF), sentation [10] and to release oxygen radicals
and erythropoietin (EPO). [11 ].
Although these in vitro findings suggested a
possible role for inducing indirect and direct
Granulocyte-Macrophage Colony antitumour effects, no such effects of GM-CSF
Stimulating Factor could be observed in any of the clinical stud
ies [12-14]. Induction of in vivo tumour cyto-'
The human gene encoding GM-CSF is lo toxicity might be achieved by combining GM
cated on chromosome 5q21-5q32 [2]. CSF with more traditional macrophage acti
Probably due to variable glycolysation, the vating factors like interferon-gamma (IFN-y):
molecular mass of the mature protein, which GM-CSF delivering large numbers of effector
comprises 127 amino acids, ranges from 14- cells and IFN-y triggering the response.
35 kD [3]. A variety of cells producing GM Apart from its possible role as an antitumour
CSF have been identified, among them agent, which requires further evaluation, GM
monocytes, fibroblasts, endothelial cells, ep CSF demonstrates an already well charac
ithelial cells and T lymphocytes [4]. GM-CSF terised activity in reducing chemotherapy-as
stimulates granulocyte/macrophage and sociated morbidity.
eosinophil colony formation in vitro and acts Severe and prolonged myelosuppression
in combination with erythropoietin as ery after chemotherapy in neoplastic disease rep
throid burst promoting activity [5]. In addition resents a fundamental problem,
to its effect on progenitor cell differentiation, Complications during this myelosuppressive
GM-CSF also induces a variety of functional period often limit the practicability of
changes in mature cells. It increases neu chemotherapeutic regimens. Frequently, pa
trophil phagocytic activity, inhibits the migra tients receiving high-dose chemotherapy de
tion of neutrophil granulocytes [6] and in velop neutropenia that often results in bacte
duces the production of other cytokines (e.g., rial and secondary fungal infections.
TNF, IL1) by these same cells [7,8]. It also in Shortening the period and degree of neu
duces macrophage tumour cytotoxicity [9], tropenia should decrease the incidence and
activates macrophages to synthesise MHC severity of infections and thereby also shorten
class II molecules, to augment antigen pre-
6 F.M. Rosenthal, A. Lindemann, F. Herrmann and R. Mertelsmann
hospital stay and even reduce mortality as nesis induced in vivo, by augmenting the
sociated with chemotherapy. proportion of malignant cells recruited into the
In our own phase II clinical trial, it was shown S-phase of the cell cycle and thus obtain en
that the neutrophil nadir was significantly ele hanced cytotOXiC effects with drugs such as
vated and time of relevant neutropenia was Ara-C, that kill cycle-activated cells [27,28].
abbreviated with a single daily subcutaneous The value of" GM-CSF in the treatment of
dose of GM-CSF (250 1l9/m2 body surface aplastic al}aemia appears to be limited, as
area) given over a period of 10 days [15]. reported by Champlin and Nissen [29,30].
Patients were protected from febrile events Combinations of haematopoietic growth fac
and incidence of mucositis was reduced as tors acting on early progenitors with later
well. No significant effect was seen regarding acting factors might have synergistiC effects in
platelet counts, haemoglobin levels or dura accelerating repopulation of the bone marrow
tion of chemotherapy-related thrombocy and warrant further investigation in this dis
topenia and anaemia. ease.
The toxicity encountered was tolerable. The Ultimately, GM-CSF may find a place in the
adverse effects consisted mainly of discrete treatment of other non-malignant conditions
bone pain, skin rash and weakness. Short which are characterised by leukopenia (e.g.,
lived dyspnoea was occasionally seen in pa AIDS) [31], or in the improvement of host de
tients receiving the factor intravenously, fence in infectious disease complications [32].
especially if white blood cell counts exceeded
normal values by far. Dose-limiting toxicities
reported were serositis and thrombosis with Granulocyte Colony-Stimulating Factor
pulmonary emboli [16-21].
Effects of GM-CSF were also studied in the By recombinant DNA technology, 2 cDNAs
clinical setting of autOlogous bone marrow representing a 177 amino-acid protein form
transplantation [17,22,23]. It has been shown and a 174 amino-acid protein form of human
that this growth factor increases the circulat granulocyte colony-stimulating factor (G-CSF)
ing pool of peripheral blood haematopoietic could be isolated [33-35]. It is not known,
progenitors and thus accelerates the rate of however, whether both forms do physiologi
neutrophil recovery. No difference was seen cally exist in man. The shorter version of the
with respect to the first appearance of neu molecules seems to be more active in vivo.
trophils in the circulation when comparing The gene which encodes for G-CSF is lo
GM-CSF-treated patients with non-treated cated on chromosome 17 in region q11-q22
patients [24]. This may open new perspec [36].
tives in the field of bone marrow transplanta G-CSF is a rather lineage-specific
tion. The need for bone marrow harvesting haematopoietic growth factor in that it acts on
might be avoided by using peripheral blood cells capable of forming one differentiated
stem cells for transplantation. cell type: the neutrophil granulocyte. In com
Application of GM-CSF to patients with bination with other haematopoietic growth
myelodysplastic syndrome (MDS) has been factors, it acts synergistically to stimulate a
described to normalise red-cell, white-cell broader spectrum of colony-forming units [33].
and platelet counts in some patients [25]. In addition, G-CSF increases antibody-de
More recent studies, however, have not been pendent cellular cytotoxicity of peripheral
able to confirm this optimistic report, demon blood granulocytes as well as several other
strating rises in neutrophil counts only. At aspects of neutrophil activity [37].
higher GM-CSF doses, an increase in Like GM-CSF, G-CSF has been utilised in the
leukaemic blast cells in the bone marrow was prevention of chemotherapy-induced neu
seen, indicating that GM-CSF can stimulate tropenia [38-42] and in the setting of autolo
the proliferation of human leukaemic blast gous bone marrow transplantation [22,43]. A
cells as well as normal haematopoietic cells dose-dependent increase in absolute neu
in vivo [19,20,26]. Even a possible progres trophil counts (at least 3-fold) and shortening
sion to frank leukaemia has been observed of the neutropenic period was observed. At
[26]. On the other hand, in the future one higher doses, an up to 10-fold increase in
might be able to take advantage of blastoge- monocytes was also seen [40]. In one study,