Biologic Therapy of Leukemia 1st Edition
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To Linda, Mollie, Jason, and Rachel
PREFACE
In the latter part of the 20th century, hematologists and medical oncologists
were trained to treat leukemia with systemic therapy that was cytotoxic to both
normal and malignant cells. Some of these therapies, such as methotrexate and
L-asparaginase, were developed within the context of known biologic patho-
physiology, but most were developed in relative ignorance of biologic mecha-
nisms and cannot therefore be considered “biologic.” The usual goal of treatment
was to eliminate rapidly dividing, or malignant, cells with DNA-damaging agents
that spared normal tissue only in a relative sense. The paradigm of systemic, non-
specific therapy dominated oncologic thought at the time:
Leukemia is by very definition a wide-spread systemic disease at the time of
diagnosis. For this reason systemic therapy which reaches simultaneously
every cell in the body is the most logical form of treatment and is probably the
only type which offers, theoretically, the possibility of complete cure. (1)
To an extent, the systemic, nonspecific treatment approach was successful and
certainly resulted in cures when before none were possible. However, this
approach failed to cure the majority of patients with leukemia and is usually
associated with significant toxicity. No other way was known, and for a time, no
other way seemed possible.
The frequent failure of nonspecific treatments, remarkable advances in
molecular biology, and well-timed serendipity, led to new approaches that are
revolutionizing the management of leukemia as we enter the 21st century. In
contrast to the treatments of the past, the new approaches can collectively be
classified as truly “biologic” therapies because they take advantage of the known
biology of leukemia. Thus, treatment can often be directed at the leukemia,
sparing normal tissues and causing less tissue damage. These new targeted treat-
ments represent the beginning of a new age in leukemia therapeutics.
As exciting as these are, clinicians often find it difficult to access appropriate
medical information on these new treatments when faced with a patient who may
benefit from them. The advances are coming so often, and so quickly, that treat-
ments are sometimes approved for use before the information that supports their
claimed efficacy can be published in peer-reviewed literature. Large textbooks
attempting to publish accurate and current information on leukemia are doomed
to obsolescence before reaching print.
These practical concerns prompted the publication of this book. Biologic
Therapy of Leukemia is devoted to these new biologic therapies and provides a
vii
viii Preface
rapidly accessible, authoritative source of practical information for clinicians
attempting to use these treatments for their patients.
Some of the treatments described in this text, such as interferon and all-trans
retinoic acid, have been available for some time and are well-described in the
medical literature. However, that information is difficult to access when contrast-
ing their efficacy with newer treatments, such as imatinib mesylate and arsenic
trioxide, which are also described in this text. Other treatments, such as P-glyco-
protein inhibitors and interleukins, have been dancing on the edges of clinical
practice and may yet find their place based on emerging data. The graft vs leu-
kemia effect has been better defined and promises to completely alter the way
allogeneic stem cell transplant is employed in the future. Finally, therapeutic
approaches that reverse failure of apoptosis, alter genetic codes, and modulate
immunologic mechanism are no longer mere theory, but are now being tested in
the clinic and warrant close attention by the oncologic community.
The authors and I hope that clinicians treating patients will find Biologic
Therapy of Leukemia helpful. We all share the goal of eradicating leukemia and
I believe the information contained in these pages moves us closer to that goal.
I thank the contributors for their expertise and willingness to share it. I stand in
awe of their knowledge and dedication.
Matt Kalaycio, MD
REFERENCE
1. Burchenal, J.H. Treatment of the leukemias. Semin Hematol 1966;3:122.
CONTENTS
Preface ........................................................................................................... vii
Contributors .................................................................................................... xi
PART I: IMMUNOTHERAPY
1 Human Leukemia-Derived Dendritic Cells as Tools
for Therapy .......................................................................................... 3
David Claxton
2 The Graft vs Leukemia Effect ............................................................... 13
Brian J. Bolwell
3 Unconjugated Monoclonal Antibodies ................................................. 29
Matt Kalaycio
4 Drug Immunoconjugate Therapy of Acute Myeloid
Leukemia ........................................................................................... 43
Arthur E. Frankel, Bayard L. Powell, Eli Estey,
and Martin S. Tallman
5 Radiolabeled Monoclonal Antibodies .................................................. 59
John M. Burke and Joseph G. Jurcic
PART II: CYTOKINES
6 Interferons.............................................................................................. 81
Thomas Fischer
7 Interleukin-2 Treatment of Acute Leukemia ........................................ 93
Peter Kabos and Gary J. Schiller
PART III: TARGETED THERAPEUTICS
8 Antisense Therapy ............................................................................... 109
Stanley R. Frankel
9 Signal Transduction Inhibitors ............................................................127
Michael E. O’Dwyer and Brian J. Druker
10 P-Glycoprotein Inhibition in Acute Myeloid Leukemia .................... 145
Thomas R. Chauncey
ix
x Contents
11 Targeting the Apoptotic Machinery as a Potential
Antileukemic Strategy ....................................................................163
Benjamin M. F. Mow and Scott H. Kaufmann
PART IV: DIFFERENTIATION AGENTS
12 Arsenicals: Past, Present, and Future ................................................189
Chadi Nabhan and Martin S. Tallman
13 All-Trans-Retinoic Acid in the Treatment of Acute
Promyelocytic Leukemia ................................................................205
Pierre Fenaux and Laurent Degos
PART V: GENE THERAPY
14 Gene Therapy ......................................................................................225
Paul J. Orchard and R. Scott McIvor
Index ............................................................................................................. 261
CONTRIBUTORS
BRIAN J. BOLWELL, MD • Bone Marrow Transplant Program, Department
of Hematology and Medical Oncology, Cleveland Clinic Foundation,
Cleveland, OH
JOHN M. BURKE, MD • Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY
THOMAS R. CHAUNCEY, MD, PhD • University of Washington School
of Medicine, VA Pugent Sound Health Care System, Seattle, WA
DAVID CLAXTON, MD • Division of Hematology/Oncology, Penn State Hershey
Medical Center, Hershey, PA
LAURENT DEGOS, MD, PhD • Institut d’Hematologie, Hôpital Saint Louis, Paris,
France
BRIAN J. DRUKER, MD • Leukemia Center, Oregon Health & Science
University Cancer Institute, Portland, OR
ELI ESTEY, MD • Section of Acute Leukemia and Myelodysplastic Syndromes,
MD Anderson Cancer Center, Houston, TX
PIERRE FENAUX, MD • Service des Maladies du Sang, CHU, Lille, France
THOMAS FISCHER, MD • Johannes Gutenberg University of Mainz, Mainz, Germany
ARTHUR E. FRANKEL, MD • Department of Medicine, Wake Forest University
School of Medicine, Winston Salem, NC
STANLEY R. FRANKEL, MD, FACP • Medical Operations, Genta Incorporated,
Chicago, IL, and Department of Medicine, Greenbaum Cancer Center,
University of Maryland, Baltimore, MD
JOSEPH G. JURCIC, MD • Leukemia Service, Memorial Sloan-Kettering Cancer
Center, New York, NY
PETER KABOS, MD • Maxine Dunitz Neurosurgical Institute, Cedars-Sinai
Medical Center, Los Angeles, CA.
MATT KALAYCIO, MD • Leukemia Program, Department of Hematology
and Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH
SCOTT H. KAUFMANN, MD, PhD • Division of Oncology Research, Mayo Clinic,
and Department of Molecular Pharmacology, Mayo Graduate School,
Rochester, MN
R. SCOTT MCIVOR, MD, PhD • Department of Genetics, Cell Biology,
and Development, Institute of Human Genetics, University of Minnesota,
Minneapolis, MN
BENJAMIN M. F. MOW, MD • Division of Hematology, National University
Hospital, Singapore
xi
xii Contributors
CHADI NABHAN, MD • Division of Hematology/Oncology, Northwestern
University Medical School, Chicago, IL
MICHAEL E. O’DWYER, MD • Leukemia Center, Oregon Health & Science
University Cancer Institute, Portland, OR
PAUL J. ORCHARD, MD • Department of Pediatrics, Institute of Human
Genetics, University of Minnesota, Minneapolis, MN
BAYARD L. POWELL, MD • Section of Hematology/Oncology, Wake Forest
University School of Medicine, Winston Salem, NC
GARY J. SCHILLER, MD • Division of Hematology-Oncology, UCLA School
of Medicine, Los Angeles, CA
MARTIN S. TALLMAN, MD • Division of Hematology/Oncology, Northwestern
University Medical School, Chicago, IL
I IMMUNOTHERAPY
1 Human Leukemia-Derived Dendritic
Cells as Tools for Therapy
David Claxton, MD
CONTENTS
INTRODUCTION: IMMUNOTHERAPY OF LEUKEMIA
DENDRITIC CELLS AS TOOLS FOR THERAPY
HUMAN DENDRITIC CELLS DERIVED FROM MYELOID
LEUKEMIAS
CLINICAL STUDIES USING LEUKEMIA-DERIVED DENDRITIC
CELLS
FUTURE STUDIES AND OPPORTUNITIES
REFERENCES
1. INTRODUCTION: IMMUNOTHERAPY OF LEUKEMIA
Excluding selected subsets of human leukemia, progress in the therapy of
this group of disorders has been relatively modest since the late 1980s. In con-
trast, the elucidation of the pathogenesis and mechanisms of progression of
these diseases has been substantial. The development of specific agents tar-
geted at selected molecular changes specific to leukemic cells offers great hope
for the therapy of these disorders. Even these targeted therapies, such as the
recently developed tyrosine kinase inhibitor Imatinib Mesylate, may fail to
control advanced forms of the target disease (1). Additionally, for many human
leukemias, no such well-defined genetic background is available at present.
Accordingly, efforts to advance the therapy for these diseases must focus on
other approaches.
There is substantial experimental and clinical data suggesting the usefulness of
T-cell-mediated antigen-specific immunotherapy for leukemia. The central prin-
ciple common to all these approaches is the development of effective cell-medi-
ated immunity able to selectively or semiselectively target leukemic or malignant
cells. Thus, these approaches ultimately yield an active immune process with the
potential for ongoing control of residual malignant cellular elements.
From: Biologic Therapy of Leukemia
Edited by: M. Kalaycio © Humana Press Inc., Totowa, NJ
3
4 Claxton
Alloimmune antileukemic effects are well established, both experimentally
and clinically. Several investigators have described animal models that docu-
ment the ability of allogeneic immune cells to cure transplantable experimental
leukemias. In human clinical studies, this effect is also clearly active. Thus, for
both matched sibling and unrelated donor hematopoietic stem cell transplants,
the acquisition of an allodisparate T-cell population and the recognition of host
allo-antigens expressed on leukemias have been shown to be active in the ulti-
mate control of chronic myelogenous leukemia (CML) and acute myeloid
leukemia (AML). Relevant antigens targeted in clinical studies and identified
as active in this phenomenon include the minor histocompatiblity antigen
HA-1 (2). In certain cases, such antigens have been shown to be hematopoi-
etic-specific polymorphic proteins (3). Thus, the graft vs hematopoietic effects
developing after allogeneic stem cell transplantation control the normal
hematopoietic and leukemic elements derived from the host simultaneously.
Autologous cellular immune activity directed toward leukemias has also
been described in experimental and clinical systems. Several murine systems
have been described that demonstrate the activity of autologous immunity
(4–7) against transplantable congenic leukemia. Several authors have pub-
lished clinical series suggesting therapeutic effects of systemic IL-2 with (8) or
without (9–12) IL-2 activated cells for human leukemias. Antileukemic T-cell
clones or lines have been described (13).
2. DENDRITIC CELLS AS TOOLS FOR THERAPY
Human dendritic cells represent the so-called “professional antigen-present-
ing cells” responsible for initiating all antigen-specific cell-mediated immunity
from naïve T-cell elements. The development of techniques for the ex vivo dif-
ferentiation of dendritic cells from peripheral blood-derived monocytes or bone
marrow-derived CD34 cells has presented clinical investigators with the oppor-
tunity to use these cells for the initiation of antitumor immunity in experimental
and clinical studies. Several clinical trials have been reported in which allo-
geneic or autologous tumor lysates or antigen-specific peptides have been
pulsed into dendritic cells derived in one of these two ways (14–17). The devel-
opment of tumor-specific autologous cellular cytotoxicity has been demon-
strated in several human tumor systems, including human AML (18). Common
to all of these systems, however, is the use of normal autologous dendritic cells
brought to a state of maturation that are suitably primed to acquire fresh antigen
from the extracellular environment. These antigens then are provided by the
investigator and effectively presented to autologous T-cells through the antigen
processing and presenting machinery of the dendritic cells. In the following
pages, a similar system for the initiation of antileukemic cell-mediated immu-
nity is described that, however, stems from the ability of the original leukemic
cells to differentiate directly into effective antigen-presenting cells and to pre-
Chapter 1 / Dendritic Cells and Therapy 5
sent the endogenously expressed leukemic antigens. It is our contention that
this system may be the ideal one in which to study the therapeutic potency of
human dendritic cells for the initiation of antitumor cell-mediated activity.
3. HUMAN DENDRITIC CELLS DERIVED
FROM MYELOID LEUKEMIAS
In 1994, two groups independently described cellular differentiation of cells
with the characteristics of myeloid dendritic cells from AML (19,20). Cells
derived from patients and cultured ex vivo in recombinant cytokines, including
GM-CSF and tumor necrosis factor-alpha (TNF-α), matured into cells with the
morphology and activity of typical mature dendritic cells (19). These cells gen-
erated brisk allogeneic mixed lymphocyte reactions, as would be expected of
mature dendritic cells.
In 1996, Choudhury et al. demonstrated that CML cells could differentiate
into cells with the morphology, phenotype, and allostimulatory function of
mature dendritic cells (21). Simultaneously, these cells were shown to be
derived from the malignant clone by in situ hybridization to nucleic acid
probes specific for the Philadelphia chromosome breakpoints of the bcr-abl
genes. These leukemia-derived dendritic cells were able to stimulate autolo-
gous preactivated T-cells to acquire cytotoxicity specific for the leukemic clone
and not for normal human leukocyte antigen (HLA)-matched targets or autolo-
gous remission bone marrow cells. The cytotoxic activity demonstrated was
found within the CD8 cellular compartment. There was no NK type cytotoxic-
ity given the near absence of cytotoxicity for K562 cells. This was the first
report of a leukemia-derived dendritic cell-inducing autologous leukemia-spe-
cific cell-mediated cytotoxicity (21).
Since this publication, a total of 30 peer-reviewed publications describing
human leukemia-derived dendritic cells have been identified by literature
search. These publications have examined the differentiation of both CML and
AML into active antigen-presenting cells. Several authors have documented
the clonal origin of the culture-derived dendritic cells (22–26). Most reports
have shown the acquisition of relatively high expression of the critical costim-
ulatory molecules CD80 and 86, together with the mature dendritic cell marker
CD83, on the leukemia-derived dendritic cells. Five independent groups have
demonstrated the acquisition of leukemia-specific cellular cytotoxicity in
autologous T-cells stimulated by leukemia-derived dendritic cells in CML
(22,27–30). Five independent investigative groups, including our own group,
have also shown that AML may similarly differentiate into clonal dendritic
cells capable of stimulating cytotoxic leukemia-specific T-cell activity
(23,25,31–33). In the case of both anti-CML and anti-AML activities, these
autologous cytotoxic reactions have been shown to be major histocompatibility
complex (MHC) restricted as demonstrated by partial blocking of cytotoxicity
6 Claxton
by HLA class 1- or class 2-specific monoclonal blocking antibodies (23,27).
Thus, the cytotoxic activities identified have the characteristics expected for
dendritic cell-initiated T-cell mediated responses.
Several questions arise from this large body of work. Fundamental ques-
tions exist about the uncertainty concerning the details of the immune response
to leukemia-derived dendritic cells. Specifically, it is unclear what antigens are
being responded to and which subsets of effector cells are participating. Cur-
rently, there is little data to document which antigens may be responsible for
eliciting responses to leukemia-derived dendritic cells; however, our current
work has suggested that a limited number of target antigens may be shared
between patients. Yasukawa et al. have shown that CML-derived dendritic cells
may specifically present a bcr-abl B3A2 junction-specific peptide fragment to
CD4-positive T cells via an HLA-DRB1*0901 restricted mechanism (34). On
the other hand, Bertazzoli et al. have shown that T-cells derived from CML
patients respond less well to a B3A2 bcr-abl-specific peptide in a proliferative
assay than those from normal donors (35). Thus, the role of bcr-abl junction-
derived antigens and the responses elicited by leukemia-derived dendritic cells
remain unresolved but dubious.
4. CLINICAL STUDIES USING LEUKEMIA-DERIVED
DENDRITIC CELLS
Fujii et al. described a single patient with CML who was treated with autol-
ogous peripheral stem cell transplantation followed by a series of infusions of
leukemia-derived dendritic cells (22). The leukemia-derived dendritic cells
were generated in the cytokine combination GM-CSF, TNF-α, and IL-4. After
receiving four infusions of post-transplant-administered culture-derived autol-
ogous leukemic dendritic cells, the patient developed a partial cytogenetic
response because the total number of Philadelphia (Ph) chromosome-positive
metaphases in the bone marrow fell from 20 out of 20 to 7 out of 20 within sev-
eral months.
We carried out a study using CML-derived dendritic cells to stimulate autol-
ogous T-cells to develop a therapeutic cell line for adoptive immunotherapy.
This study, which enrolled five patients and treated two, has been briefly
reported and described elsewhere (36). A schematic diagram of this study is
shown in Fig. 1. Patients had CML cells collected by apheresis when they had
substantial numbers of circulating dendritic cells or after stimulation with GM-
CSF. These cells were subsequently used to stimulate autologous T-cells preac-
tivated with OKT3 and IL-2. After coculture, cells were cryopreserved in
aliquots and subsequently administered to patients. A schematic view of the
cell culture approach is given in Fig. 2.
Two days before cell infusion, modest doses of cyclophosphamide were
administered to cytoreduce the disease. After receiving the activated lympho-
Chapter 1 / Dendritic Cells and Therapy 7
Fig. 1. Schematic view of dendritic cell-activated lymphocyte therapy for CML.
Fig. 2. Culture procedures for the generation of autologous T-cells activated by leukemia-
derived dendritic cells. * Culture A (DC) must be >20% CD86 + and >40% HLA-DR +.
Culture B(AL) must be >60% CD3 +.
