Table Of ContentDr. Paul Koldovsky Professor Dr. Lutwin Beck
Hals-Nasen-Ohren-Klinik U niversitats-Frauenklinik
MoorenstraBe 5 MoorenstraBe 5
4000 Dusseldorf, FRG 4000 Dusseldorf, FRG
Dr. Ursula Koldovsky Professor Dr. Karl-Heinz Vosteen
Universitats-Frauenklinik Hals-Nasen-Ohren-Klinik
MoorenstraBe 5 MoorenstraBe 5
4000 Dusseldorf, FRG 4000 Dusseldorf, FRG
ISBN-13:978-3-540-50457-3 e-ISBN-13:978-3-642-74225-5
DOl: 10.1007/978-3-642-74225-5
Library of Congress Cataloging-in-Publication Data
Lymphocytes in immunotherapy of cancer 1 P. Koldovsky ... let al.I (eds.). p. cm. Based
on a meeting held at the Cancer Center of the University of Dusseldorf, FRG, in Sept.
1987. Includes bibliographies and index.
ISBN-13:978-3-S40-S04S7-3 (U.S.)
1. Cancer--Immunotherapy--Congresses. 2. Lymphocytes--Congresses. 3. Killer
cells--Congresses. I. Koldovsky, P. (Paul), 1933 - [DNLM: 1. Interleukin 2--therapeutic
use--congresses. 2. Killer Cells--immunology--congresses. 3. Lymphocyte
Transformation--congresses. 4. Lymphokines--pharmacology--congresses.
5. Neoplasms--therapy--congresses. QZ 266 L986 19871
RC271.145L94 1989 616.99'4061--dc19 DNLM/DLC 88-36749
This work is subject to copyright. All rights are reserved, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data
banks. Duplication of this publication or parts thereof is only permitted under the
provisions of the German Copyright Law of September 9, 1965, in its version of June 24,
1985, and a copyright fee must always be paid. Violations fall under the prosecution act of
the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1989
The use of registered names, trademarks, etc. in the publication does not imply, even in the
absence of a specific statement, that such names are exempt from the relevant protective
laws and regulations and therefore free for general use.
Product Liability: The publisher can give no guarantee for information about drug dosage
and application thereof contained in this book. In every individual case the respective user
must check its accuracy by consulting other pharmaceutical literature.
2123/3145-543210 - Printed on acid-free paper
P. Koldovsky U. Koldovsky L. Beck
K.-H. Vosteen (Eds.)
Lymphocytes
in Immunotherapy
of Cancer
With 33 Figures and 21 Tables
Springer-Verlag Berlin Heidelberg New York
London Paris Tokyo
Preface
In the past, research in cancer immunology has produced informa
tion important for other medical disciplines. It helped, for example,
in formulating the laws of immunogenetics and in achieving a better
understanding of the mechanism governing the fate of allotrans
planted tissue. Cancer has often been considered a foreign body,
and therefore many attempts have been made to cure it on the basis
of the immunological principles applicable to parasitic, bacterial, or
viral diseases. Vaccination has been investigated clinically for its po
tential to prevent cancer [1], and clinical research into the cure of
cancer has included active immunization [2], nonspecific stimulation
of defense mechanisms [3], and transfer of passive immunity by cells
[4] or by antibodies [5]. These experiments have been of limited value
and in some cases have even had an adverse effect. The reputation
of cancer immunology has suffered, and the concept has often been
severely criticized. However, the basic postulate that cancer must
originate from the body's own cells, and that the immune system
belongs to the principal regulatory mechanisms, remains valid. In
recent years new research into clinical cancer immunotherapy has
included critical appraisal of all its potential benefits, and also of the
risks and limitations. It is dangerous to make unrealistic promises or
to speak or think in terms of "miracle weapons" or a "magic bul
let. "
Several interweaving directions of cancer immunology are un
dergoing laboratory investigations and clinical trials: the mecha
nisms of host antitumoral immune reactions, the effect on defense
mechanisms of various biological response modifiers, active immu
nization with defined tumor-associated antigens, the passive transfer
of monoclonal antibodies (mouse or human origin) or of immuno
cytes, or combinations of these methods with each other and/or with
other conventional anticancer therapies.
A meeting held at the Cancer Center of the University of DUssel
dorf, Federal Republic of Germany, in September 1987 forms the
basis of this monograph on one of the promising approaches in the
field of cancer immunotherapy - the transfer of autologous lympho
cytes activated in vitro. This approach is, in its present form, rela
tively new, but has already been made known to the general public
via numerous articles in newspapers and magazines. It can be some-
VI Preface
what alarming to be confronted by a patient who demands treatment
with lymphokine-activated killer (LAK) cells after reading these arti
cles. We were delighted that some of the leading experts on therapy
with activated lymphocytes were willing not only to come and dis
cuss the theoretical and practical aspects of this form of cancer ther
apy but also to write contributions for this volume. The meeting be
gan with a general review of cancer immunotherapy, focusing on the
activity of cells able to inhibit tumor growth. An account of LAK
cells and how to test their biological potentials came next, followed
by discussion of ways of increasing their anticancer specificity or at
least cancer selectivity, their potential for combination with cyto
kines, their efficacy in combination with monoclonal antibodies, and
the synergistic action of biological response modifiers. We also
wanted to know something about current clinical applications and
future potentials.
Both the time available for the discussions and formal presenta
tions and the size of this volume were limited, so only selected pa
pers on these exciting topics can be presented. The most interesting
section of the book seems to us the last, on the clinical relevance of
cancer immunotherapy with lymphocytes. Most of the questions
after the formal talks and the round-table debate were clinically
oriented. For many reasons it is not possible to print the verbatim
transcripts. We decided instead to write up our own impressions of
these discussions as a kind of summary of the current range of clin
ical applications. Some degree of subjectivity is inevitable, but we
hope and trust that we have faithfully rendered the information and
opinions expressed.
Dusseldorf, December 1988 Ursula and Paul Koldovsky
References
1. BjOrklund B (1980) On the nature and clinical use of tissue polypeptide anti
gen. Tumordiagnostik 1:9
2. Oettgen HF, Old U (1980) Immunotherapy of colon carcinoma: prospects for
developing immunogene vaccines, based on autologous serologic typing. Can
cer45:1218
3. Denotter W, Ruitenberg EJ (eds) (1987) Tumor immunology. Part C: Immuno
therapy. Elsevier, Amsterdam
4. Kedar E, Weiss WD (1983) The in vitro generation of effector lymphocytes and
their employment in tumor immunotherapy. Adv Cancer Res 38: 171
5. Reisfeld RA, Cheresh DA (1983) Human tumor associated antigens: targets
for monoclonal antibody mediated cancer therapy. Cancer Surv 4:271
Table of Contents
Therapy of Cancer with Interleukin-2-Activated Natural Killer
Cells
R. B. HERBERMANN ........ .. 1
T Cell Heterogeneity and Function
P.C. L. BEVERLEY, M.MERKENSCHLAGER, and L.TERRY 18
Human Lymphokine-Activated Killer Cells and Their
Potential for Cancer Therapy
E. A. GRIMM ........................ 26
In Vitro and In Vivo Induction of Lymphokine-Activated
Killer Cells in Patients with Gastric Cancer aQd Other Solid
Tumors
L. BERGMANN, P. S. MITROU, E. WEIDMANN,
A. SCHMIDT-MATHIESEN, P. HANKE, and D. HOELZER 32
Tests for Determination of Lymphocyte Activity
P. KOLDOVSKY and U. KOLDOVSKY . . . . . . . . 44
Lysis of Autologous Tumor Cells by Blood Lymphocytes In
Vitro Requires MHC Class I Antigen Expression
E. KLEIN, F. VA NKY, and G. STUBER ............. . 52
Target Structures for Cellular Immune Mechanisms on the
Surface of Epstein-Barr Virus-Infected Malignant and
Nonmalignant Lymphocytes
W.JILG, S.MODROW, R. VOLTZ, C.MARKERT,
H. MAIRHOFER, I. MDNZ, and H. WOLF 66
Human Lymphokine-Activated Killer Cells Activated with
Interleukin-2 and Tumor Necrosis Factor-a: Implications
for Immunotherapy
L. B. OWEN-SCHAUB . . . . . . . . . . . . . . . . . . . . . . 74
VIII Table of Contents
Interleukin-2 in the Treatment of Malignant Melanoma and
Renal Cell Carcinoma
A. LINDEMANN, W. OSTER, and R MERTELSMANN . . . . .. 80
Lymphokine-Activated Human Effector Cells Targeted by
Monoclonal Antiganglioside Antibodies: A Preclinical Model
for Immunotherapy of Human Melanoma
R A. REISFELD . . . . . . . . . . . . . . . . . . . . . . . . . .. 87
Comments on the Problems of Immunotherapy with
Autologous Lymphocytes
P. KOLDOVSKY and U. KOLDOVSKY . . . . . . . .. 95
A Clinician's Comments on Cancer Therapy with
Lymphocytes
H. G. BENDER . . . . . . . . . . . . . . . . . . . . . . . 98
List of Contributors
BENDER, H.-G.
UniversiHits-Frauenklinik, MoorenstraBe 5,4000 Dusseldorf, FRG
BERGMANN, L.
Division of Haematology/Oncology, Department of Internal
Medidne, University Clinics, Theodor-Stern-Kai 7,
6000 Frankfurt/Main, FRG
BEVERLEY, P. C. L.
ICRF Human Tumour Immunology Group, University College and
Middlesex School of Medicine, The Courtauld Institute of
Biochemistry, 91 Riding House Street, London W1P 8BT, UK
GRIMM, E. A.
Associate Professor of Tumor Biology and Surgery, University of
Texas, Cancer Center System, M. D. Anderson Hospital, Houston,
TX 77030, USA
HANKE, P.
Division of Urology, Department of Surgery, University Clinics,
Theodor-Stern-Kai 7, 6000 Frankfurt/Main, FRG
HERBERMANN, R. B.
Pittsburgh Cancer Institute, Departments of Medicine and
Pathology, University of Pittsburgh, School of Medicine,
Pittsburgh, PA 15213, USA
HOELZER, D.
Division of Haematology/Oncology, Department of Internal
Medicine, University Clinics, Theodor-Stern-Kai 7,
6000 Frankfurt/Main, FRG
JILG, W.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRG
x
List of Contributors
KLEIN, E.
Department of Tumor Biology, Karolinska Institutet, Box 60400,
10401 Stockholm, Sweden
KOLDOVSKY, P.
HNO-Klinik, MoorenstraBe 5,4000 Dusseldorf, FRG
KOLDOVSKY, U.
Universitats-Frauenklinik, MoorenstraBe 5,4000 Dusseldorf, FRG
LINDEMANN, A.
Department of Hematology, University of Mainz,
LangenbeckstraBe 1, 6500 Mainz, FRG
MAIRHOFER, H.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRG
MARKERT, C.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRG
MERKENSCHLAGER, M.
ICRF Human Tumour Immunology Group, University College and
Middlesex School of Medicine, The Courtauld Institute of
Biochemistry, 91, Riding House Street, London WIP 8BT, UK
MERTELSMANN, R
Department of Hematology, University of Mainz, LangenbeckstraBe
1, 6500 Mainz, FRG
MITROU, P. S.
Division of Haematology/Oncology, Department of Internal
Medicine, University Clinics, Theodor-Stern-Kai 7,
6000 Frankfurt/Main, FRG
MONZ, I.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRG
MODROW, S.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRG
List of Contributors XI
OSTER, W.
Department of Hematology, University of Mainz, LangenbeckstraBe
1, 6500 Mainz, FRO
OWEN-SCHAUB, L. B.
Department of Tumor Biology, M. D. Anderson Hospital, University
of Texas Cancer Center Systems, Houston, TX 77030, USA
REISFELD, R A.
Department of Immunology, Scripps Clinic and Research
Foundation, 10666 N. Torrey Pines Road, La Jolla, CA 92037,
USA
SCHMIDT-MATHIESEN, A.
Division of Abdominal Surgery, University Clinics,
Theodor-Stern-Kai 7, 6000 Frankfurt/Main, FRO
STUBER, O.
Radiumhemmet, Karolinska Hospital, 10401 Stockholm, Sweden
TERRY, L.
Effector Lymphocyte Biology Laboratory, Sloan Kettering
Memorial Institute for Cancer, Research, 1275 York Avenue,
New York, NY 10021, USA
VANKY, F.
Department of Tumor Biology, Karolinska Institutet, Box 60400,
10401 Stockholm, Sweden
VOLTZ, R
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRO
WEIDMANN, E.
Division of Haematology/Oncology, Department of Internal
Medicine, University Clinics, Theodor-Stern-Kai 7,
6000 Frankfurt/Main, FRO
WOLF, H.
Max von Pettenkofer Institute for Hygiene and Medical
Microbiology, University of Munich, PettenkoferstraBe 9a,
8000 Munchen 2, FRO
