Biological Response Modifiers. New Approaches to Disease Intervention

394 Pages·1985·6.061 MB·English

by  Paul Torrence (Eds.)

Biological Response Modifiers
New Approaches to Disease Intervention
Edited by
Paul F. Torrence
Laboratory of Chemistry
National Institute of Arthritis,
Diabetes and Digestive and Kidney Diseases
U.S. National Institutes of Health
Bethesda, Maryland
1985
@
ACADEMIC PRESS, INC.
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LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA
Main entry under title:
Biological response modifiers.
Includes index.
1. Biological response modifiers. 2. Immune
response — Regulation. 3. Immunotherapy. I. Torrence,
Paul F. [DNLM: 1. Adjuvants, Immunologic —therapeutic
use. 2. Antineoplastic Agents — therapeutic use.
3. Biological Products —therapeutic use.
4. Immunotherapy. QW 800 B6146]
QR185.7.B56 1986 615.7 85-13395
ISBN 0-12-695770-3 (alk. paper)
ISBN 0-12-695771-1 (paperback)
PRINTED IN THE UNITED STATES OF AMERICA
86 87 88 89 9 8 7 6 5 4 3 2 1
To my parents
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Françoise Audibert (307), Immunothérapie Expérimentale, Institut Pasteur,
75724 Paris, France
Louis Chedid (307), Immunothérapie Expérimentale, Institut Pasteur,
75724 Paris, France
Jieping Chen] (121), Department of Biochemistry, The George Washington
University School of Medicine and Health Sciences, Washington, D.C.
20037
Barbara Detrick (57), Clinical Branch and Experimental Immunology Sec-
tion, National Eye Institute, National Institutes of Health, Bethesda,
Maryland 20205
David A. Flick (171), Department of Immunology and Medical Microbiol-
ogy, College of Medicine, University of Florida, Gainesville, Florida
32610
George E. Gif ford (171), Department of Immunology and Medical Micro-
biology, College of Medicine, University of Florida, Gainesville, Florida
32610
Allan L. Goldstein (121), Department of Biochemistry, The George Wash-
ington University School of Medicine and Health Sciences, Washington,
D.C. 20037
Gale A. Granger (293), Department of Molecular Biology and Biochemistry,
University of California, Irvine, California 92717
John J. Hooks (57), Clinical Branch and Experimental Immunology Sec-
tion, National Eye Institute, National Institutes of Health, Bethesda,
Maryland 20205
Arthur G. Johnson (107), Department of Medical Microbiology and Im-
1 Present address: Department of Immunology, Medical Research Institute, China-Japan
Friendship Hospital, Beijing, China.
xiii
xiv Contributors
munology, University of Minnesota School of Medicine, Duluth, Minne-
sota 55812
Howard M. Johnson (245), Department of Comparative and Experimental
Pathology, The University of Florida, Gainesville, Florida 32610
Margaret I. Johnston (21), Department of Biochemistry, Uniformed Ser-
vices University of the Health Sciences, Bethesda, Maryland 20815
Charles H. Kirkpatrick2 (329), Department of Medicine, The Conrad D.
Stephenson Laboratory for Research in Immunology, National Jewish
Hospital and Research Center/National Asthma Center, Denver, Colo-
rado 80206
Nicola M. Kouttab (361), Department of Pathology, The University of
Texas M. D. Anderson Hospital, Houston, Texas 77030
Peter Langen (265), Central Institute of Molecular Biology, Academy of
Sciences of the GDR, Berlin 1115, German Democratic Republic
Claude Leclerc (307), Immunothérapie Expérimentale, Institut Pasteur,
75724 Paris, France
Abby L. Maizel (361), Department of Pathology, The University of Texas
M. D. Anderson Hospital, Houston, Texas 77030
James J. Mascali (329), Department of Medicine, The Conrad D. Stephen-
son Laboratory for Research in Immunology, National Jewish Hospital
and Research Center/National Asthma Center, Denver, Colorado 80206
Shashikant R. Mehta (361), Department of Pathology, The University of
Texas M. D. Anderson Hospital, Houston, Texas 77030
Victor A. Najjar (141), Division of Protein Chemistry, Department of Mo-
lecular Biology, Tufts University School of Medicine, Boston, Massachu-
setts 02111
Robert K. Oldham (1), Biological Therapy Institute, Franklin, Tennessee
37064
Sally L. Orr (293), Department of Molecular Biology and Biochemistry,
University of California, Irvine, California 92717
Stephen J. Rozzo (329), Department of Medicine, The Conrad D. Stephen-
son Laboratory for Research in Immunology, National Jewish Hospital
and Research Center/National Asthma Center, Denver, Colorado 80206
Richard K. Shadduck (245), University of Pittsburgh School of Medicine,
Montefiore Hospital, Pittsburgh, Pennsylvania 15213
Paul F. Torrence (77), Laboratory of Chemistry, National Institute of Ar-
2
Present address: Department of Medicine, Division of Allergy and Clinical Immunology,
National Jewish Hospital and Research Center, and University of Colorado School of
Medicine, Denver, Colorado 80206.
Contributors XV
thritis, Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Maryland 20205
Edward J. Wing (219), University of Pittsburgh School of Medicine, Monte-
fiore Hospital, Pittsburgh, Pennsylvania 15213
Robert S. Yamamoto (293), Department of Molecular Biology and Bio-
chemistry, University of California, Irvine, California 92717
Preface
The purpose of this volume is to introduce to as wide an audience as possi-
ble a fascinating group of diverse agents with rather dramatic biological
properties. These are molecules of natural or sometimes synthetic origin that
act through an organism's own biological response mechanisms and thus
have been termed biological response modifiers (BRMs) (defined further by
R. Oldham in Chapter 1). In many respects, the evaluation of various
biological response modifiers has followed a course similar to that of the
development of interferon, perhaps the best known BRM. Biological activity
was first described in studies either in vitro or in vivo on some biological
product. Definitive studies on therapeutic efficacy and mechanism of action
have been confounded by the difficulties of working with impure prepara-
tions of materials that have been contaminated with other biologically active
materials. Once the agent has been purified to homogeneity, its structure
defined, and procedures for its production in useful quantities have been
developed, meaningful studies of clinical usefulness can be initiated. As the
mechanism of action of the purified BRM is clarified, novel approaches to
biological control become apparent. Thus, from interferon came the
discovery of the 2',5'-oligoadenylate system, which is currently being ex-
plored as an approach to control of virus or cell reproduction.
The molecules described in this volume deserve the attention not only of
the immunologist and clinician but also of the biochemist and
organic/medicinal chemist. The latter may uncover new insights into the
mechanisms of BRM action and generate new modalities of chemotherapy
based upon the mechanisms involved. To this end and to reduce the in-
evitable and considerable language barriers between such diverse fields of
endeavor, an introductory chapter on basic concepts of immunity (M. I.
Johnston) has been provided to introduce biochemists and chemists to what
may seem to be the arcane field of immunology. In addition, the various con-
tributors were requested to aim their chapters to the nonspecialist as much as
possible.
In the most optimistic sense, the molecules described herein not only in
themselves provide novel approaches to disease control, but also may lead to
the discovery of unrecognized biochemical mechanisms that may provide a
basis for new drug development.
xvii
1
Introduction
ROBERT Κ. OLDHAM
Biological Therapy Institute
Franklin, Tennessee
I. Biologicals and Biological Response Modifiers 1
II. Clinical Approaches 2
III. BRM Screening 6
A. Detection of Biological Activity in Preclinical Models . .. 6
B. Criteria for Successful Screening 6
C. Efficacy Testing 7
D. Screening Evaluation 8
IV. Biological Therapy: Specific Agents and Approaches 9
A. Immunomodulating Agents 9
B. Tumor Antigens and Active Specific Immunotherapy . . .. 9
C. Thymic Factors 13
D. Interferons 13
E. Lymphokines and Cytokines 15
F. Monoclonal Antibody 17
V. Perspectives 17
References 18
I. BIOLOGICALS AND BIOLOGICAL
RESPONSE MODIFIERS
Biologicals are products of the mammalian genome, and biological re-
sponse modifiers (BRM) are agents and approaches whose mechanisms of
action involve the individual's own biological response. Biologicals and
BRM can act in several ways:
1. Increase the host's defenses by administering natural biologicals or the
synthetic derivatives thereof as effectors or mediators of an antitumor
response
2. Increase the individual's antitumor responses through augmentation
and/or restoration of effector mechanisms, and/or decrease a com-
ponent of the host's reaction that may be deleterious
3. Augment the individual's responses to modified tumor cells or vac-
BIOLOGICAL RESPONSE MODIFIERS 1 Copyright © 1985 by Academic Press, Inc.
All rights of reproduction in any form reserved.
2 Robert Κ. Oldham
eines, which might stimulate a greater response by the individual or
increase tumor cell sensitivity to an existing response
4. Decrease the transformation and/or increase differentiation (matur-
ation) of tumor cells
5. Increase the ability of the host to tolerate damage by cytotoxic mo-
dalities of cancer treatment
While several of the approaches described here involve the augmentation
of biological responses, an understanding of the biological properties of
immune response molecules, growth and maturation factors, and other bi-
ological responses will assist in the development of specific molecular en-
tities that have directed actions on both biological responses and tumor
cells. Thus, one can visualize the development of biological agents with
response-modifying as well as direct cytostatic, cytolytic, or maturational
effects on tumor cells.
It is clear that the mechanisms are now available for the discovery and
development of biological molecules and response modifiers for cancer
treatment. To put these into clinical practice it is important to dispel a his-
torical dogma of immunotherapy. Biologicals (biotherapy) can have activity
on clinically apparent disease, and their testing is not restricted to situations
where the tumor cell mass is imperceptible (Oldham and Smalley, 1983).
Thus, the clinical trial designs necessary to test new biologicals and new
BRM can be similar to those used previously for other modalities of cancer
treatment, as long as one is sensitive to the need to measure both the phar-
macokinetics of the biological or BRM and the biological response affected
by these approaches (Oldham, 1984a). Testing is continuing for the inter-
ferons (α, β, and 7), lymphokines-cytokines, growth and maturation fac-
tors, monoclonal antibodies and immunoconjugates thereof, and adoptive
cellular therapy.
II. CLINICAL APPROACHES
Given the variability of cancer's clinical presentation, it is not surprising
that randomized trials of nonspecific and specific immunotherapy, as trans-
lated from animal models, have not been uniformly successful in cancer
treatment (Hewitt, 1982; Herberman, 1982). Naturally occurring cancer
arises from one cell or a few cells under some carcinogenic stimulus in a
particular organ. In humans, these initial foci of cancer cells may grow over
very long periods of time (from 1 to 10% of the human life span) before
there is any clinical evidence of the disease. Dissemination of cells from the
initial focus may occur at any time during the development of the primary
1. Introduction 3
tumor. Thus, metastasis can disseminate over a long growth period, allow-
ing complex biological interactions to occur during the process.
By contrast, experimentally induced cancer is an artificial situation. The
tumor cells are injected into young, normal animals, thereby circumventing
the influences of environmental or genetic factors that may be operative in
the natural host during tumor development, and the injection represents a
single instantaneous point source for a defined tumor load. Regardless of
whether that tumor load consists of 10 1 or 108 cells, it is being placed ar-
tificially into a single site and allowed to grow and metastasize from that
artificially selected single site. Thus, these transplantable cancers are not
analogous to clinical cancer.
The traditional modalities used in cancer treatment are surgery, radiation
therapy, and chemotherapy. The recognition that carcinomas spread re-
gionally and often systemically made evident the limitations of surgery and
radiotherapy. The modern era of cancer treatment began in the 1950s with
the recognition that most cancers were systemic problems. It became ob-
vious that lymphatic and blood-borne metastases often occurred simulta-
neously with local growth and regional spread. The early success of
alkylating agents in the systemic treatment of lymphoma prompted a mas-
sive search for drugs that might have cytolytic or cytostatic effects on cancer
cells. There is now widespread recognition that drugs not only can effec-
tively palliate in the treatment of cancer but also can cure. The development
of these three modalities and their subsequent integration into what is now
multimodal cancer treatment have been recently summarized (De Vita,
1983a).
In the last 5 years, we have reached another plateau in cancer treatment.
New surgical techniques and new methods of radiotherapy have been de-
veloped. Still, these two modalities are useful mainly in the local and re-
gional treatment of cancer. Chemotherapy continues to evolve, with new
drugs and new combinations of drugs being developed for cancer treatment.
There has been continued slow progress in the treatment of highly repli-
cative and sensitive malignancies since the early to mid-1970s. It is now
apparent that further progress with chemotherapy will probably depend on
a greater understanding of the metabolic processes of cancer cells and the
differences between these and normal cells. In addition, there are the prob-
lems of selectivity of action and drug delivery. Clearly, cancer cells are more
like than unlike normal cells with respect to sensitivity to current chemo-
therapeutic agents. There is little evidence of selectivity in the delivery or
effects of drugs on neoplastic tissue. Many chemotherapeutic agents are
highly cytolytic, but the problems of normal tissue toxicity, drug delivery,
and tumor cell resistance remain with us (De Vita, 1983b; Hanna et aL,