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Current Clinical Oncology
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For further volumes:

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Thomas F. Gajewski ●
F. Stephen Hodi
Editors

Targeted Therapeutics
in Melanoma
Editors
Thomas F. Gajewski, MD, PhD F. Stephen Hodi, MD
Departments of Pathology and Medicine Department of Medical Oncology
Section of Hematology/Oncology Dana-Farber Cancer Institute
University of Chicago and Melanoma Disease Center
Chicago, IL, USA Dana-Farber/Brigham
[email protected] and Women’s Cancer Center
Boston, MA, USA
[email protected]

ISBN 978-1-61779-406-3 e-ISBN 978-1-61779-407-0

DOI 10.1007/978-1-61779-407-0
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011942473

© Springer Science+Business Media, LLC 2012

All rights reserved. This work may not be translated or copied in whole or in part without the written
permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street,
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Use in connection with any form of information storage and retrieval, electronic adaptation, computer
software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they
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Preface

Cracking the Melanoma Nut

For decades, melanoma has retained a reputation as one of the last major tumor
types to lack any therapy shown to improve patient survival in the metastatic setting.
The standard chemotherapeutic agent, dacarbazine, was approved in 1976, and the
immunotherapeutic agent IL-2 was FDA approved in 1998. However, neither drug
traversed the hurdle of a randomized phase III clinical trial. Dozens of chemothera-
peutic agents, and more recently signal transduction inhibitors, have been shown to
have insignificant clinical activity in phase II clinical trials. Combination chemo-
therapy has been shown to be no better than single agent dacarbazine, and combined
delivery of chemotherapy plus IL-2-based immunotherapy has been reported to
offer no additional survival benefit compared to chemotherapy alone. Melanoma
also is known to be relatively resistant to standard regimens of ionizing radiation.
Based on these facts, it is not difficult to suggest that the traditional empiric oncol-
ogy drug development paradigm has essentially failed when applied to the treatment
of patients with melanoma.
Excitingly, this situation is in the midst of a tremendous change, and that change
has been catalyzed by significant advances in fundamental and translational science.
Genomic technologies have enabled the identification of driver oncogene mutations
in specific kinases that are present in defined subsets of melanoma. These mutated
kinases are now targetable with kinase inhibitors which are having potent clinical
activity. In addition, tremendous advances in our understanding of immune regula-
tion, with insights derived from analysis of patient material in search for mecha-
nisms of tumor resistance to immune attack, have led to novel therapeutic approaches
designed to overcome these barriers and tip the balance toward immune-mediated
tumor destruction. While these are still early days, these new discoveries are likely
to lead to the FDA approval of several new agents for the treatment of melanoma in
2011 – on the heels of a dry spell of two approvals in 35 years!
This volume, Targeted Therapeutics of Melanoma, aims to present the state-of-the-
art information driving the clinical pursuit of agents that target either specific oncogenic

v
vi Preface

pathways that contribute directly to melanoma growth, or immunoregulatory processes

that enable tumor escape from immune attack. It is fully anticipated that persever-
ance to understand additional molecular details of key events that drive melanoma
growth will lead to continued development of novel targeted therapies to improve
even further the clinical outcome of patients with this disease.

Chicago, IL, USA Thomas F. Gajewski

Boston, MA, USA F. Stephen Hodi
Acknowledgments

This book is dedicated to the many basic science, clinical, and translational investigators
who continue to devote their time to the challenges of increasing our understanding,
and optimizing the treatment for this often dreadful disease. Perhaps more impor-
tantly, it is dedicated to the thousands of melanoma patients who enroll in investiga-
tional clinical trials, without whom the development of new and effective therapies
would not be possible.

vii
Contents

Part I Advances in Melanoma Biology

1 Molecular Targets and Subtypes in Melanoma ................................... 3

Michael A. Davies
2 Melanoma Genomics ............................................................................. 17
Mohammed Kashani-Sabet
3 Predictive Biomarkers as a Guide to Future Therapy
Selection in Melanoma........................................................................... 27
Thomas F. Gajewski

Part II Signaling Molecules as Molecular Targets

4 KIT as a Therapeutic Target for Melanoma ........................................ 43

Nageatte Ibrahim and F. Stephen Hodi
5 Targeted Inhibition of B-Raf ................................................................. 63
Paul B. Chapman and Keith Flaherty
6 The Notch and b-Catenin Pathways ..................................................... 77
John T. Lee and Meenhard Herlyn
7 STAT3 and Src Signaling in Melanoma ............................................... 89
Maciej Kujawski, Gregory Cherryholmes,
Saul J. Priceman, and Hua Yu
8 Targeting the mTOR, PI3K, and AKT Pathways
in Melanoma ........................................................................................... 107
Kim A. Margolin
9 Targeting Apoptotic Pathways in Melanoma ...................................... 125
Peter Hersey and Xu Dong Zhang

ix
x Contents

10 Anti-Angiogenesis Therapy in Melanoma ........................................... 155

Daniel S. Chen

Part III Rational Immunotherapy Approaches in Melanoma

11 Melanoma Antigens Recognized by T Lymphocytes .......................... 187

Nicolas van Baren, Jean-François Baurain,
Francis Brasseur, and Pierre G. Coulie
12 Melanoma Vaccines................................................................................ 207
Pedro Romero and Daniel E. Speiser
13 Adoptive Cell Therapy for the Treatment
of Metastatic Melanoma ........................................................................ 233
Jessica Ann Chacon, Patrick Hwu, and Laszlo G. Radvanyi
14 Anti-CTLA-4 Monoclonal Antibodies.................................................. 273
Arvin S. Yang and Jedd D. Wolchok
15 Anti-PD-1 and Anti-B7-H1/PD-L1 Monoclonal Antibodies .............. 291
Evan J. Lipson, Janis M. Taube, Lieping Chen,
and Suzanne L. Topalian
16 Treatment of Melanoma with Agonist Immune
Costimulatory Agents ............................................................................ 307
Andrew Weinberg, Robert H. Vonderheide,
and Mario Sznol
17 Novel Cytokines for Immunotherapy of Melanoma ........................... 333
Shailender Bhatia and John A. Thompson
18 Modulating the Tumor Microenvironment .......................................... 353
Carl E. Ruby and Howard L. Kaufman

Index ................................................................................................................ 371

Contributors

Jean-François Baurain, MD, PhD Centre du Cancer, Cliniques universitaires

Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Shailender Bhatia, MD Department of Medicine, Division of Medical Oncology,
University of Washington School of Medicine, Fred Hutchinson Cancer
Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA
Francis Brasseur, PhD de Duve Institute and Université catholique de Louvain,
Brussels, Belgium
Ludwig Institute for Cancer Research, Brussels Branch, Belgium
Jessica Ann Chacon, MSc Department of Melanoma Medical Oncology,
Immunology Program of the University of Texas Health Science Center, Graduate
School of Biomedical Sciences, The University of Texas M.D. Anderson
Cancer Center, Houston, TX, USA
Paul B. Chapman, MD Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY, USA
Daniel S. Chen, MD, PhD Medical Oncology, Stanford University,
Stanford, CA, USA
Oncology Clinical Development, Genentech, Inc., South San Francisco, CA, USA
Lieping Chen, MD, PhD Department of Immunobiology,
Yale University School of Medicine, New Haven, CT, USA
Gregory Cherryholmes, MSc The Irell and Manella Graduate School
of Biological Sciences, Beckman Research Institute and City of Hope
Comprehensive Cancer Center, Duarte, CA, USA
Pierre G. Coulie, MD, PhD de Duve Institute and Université catholique
de Louvain, Brussels, Belgium

xi
xii Contributors

Michael A. Davies, MD, PhD Departments of Melanoma Medical Oncology

and Systems Biology, University of Texas M.D. Anderson Cancer Center,
Houston, TX, USA
Keith Flaherty, MD Massachusetts General Hospital Cancer Center,
Boston, MA, USA
Thomas F. Gajewski, MD, PhD Departments of Pathology and Medicine,
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
Meenhard Herlyn, DVM Molecular and Cellular Oncogenesis Program,
The Wistar Institute, Philadelphia, PA, USA
Peter Hersey Oncology & Immunology Unit, University of Newcastle,
Kolling Institute Univesity of Sydney, Room 443, David Maddison Clinical
Sciences Building, Cnr King & Watt Streets, Newcastle, NSW, Australia
F. Stephen Hodi, MD Department of Medical Oncology, Dana-Farber Cancer
Institute and Melanoma Disease Center, Dana-Farber/Brigham and Women’s
Cancer Center, Boston, MA, USA
Patrick Hwu, MD Department of Melanoma Medical Oncology, Immunology
Program of the University of Texas Health Science Center, Graduate School
of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center,
Houston, TX, USA
Nageatte Ibrahim, MD Department of Medical Oncology, Dana-Farber Cancer
Institute and Melanoma Disease Center, Dana-Farber/Brigham and Women’s
Cancer Center, Boston, MA, USA
Mohammed Kashani-Sabet, MD Center for Melanoma Research
and Treatment, California Pacific Medical Center Research Institute,
San Francisco, CA, USA
Howard L. Kaufman, MD Rush Medical College, Rush University
Cancer Center, Rush University Medical Center, Chicago, IL, USA
Maciej Kujawski, PhD Department of Cancer Immunotherapeutics
and Tumor Immunology, Beckman Research Institute and City of Hope
Comprehensive Cancer Center, Duarte, CA, USA
John T. Lee, PhD Molecular and Cellular Oncogenesis Program,
The Wistar Institute, Philadelphia, PA, USA
Evan J. Lipson Department of Oncology, The Johns Hopkins University School
of Medicine and the Sidney Kimmel Comprehensive Cancer Cente,
Baltimore, MD, USA
Kim A. Margolin, MD Department of Medical Oncology, University of
Washington and Seattle Cancer Care Alliance, Seattle, WA, USA
Contributors xiii

Saul J. Priceman, PhD Department of Cancer Immunotherapeutics

and Tumor Immunology, Beckman Research Institute and City of Hope
Comprehensive Cancer Center, Duarte, CA, USA
Laszlo G. Radvanyi, PhD Department of Melanoma Medical Oncology,
Immunology Program of the University of Texas Health Science Center,
Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson
Cancer Center, Houston, TX, USA
Pedro Romero, MD Ludwig Center for Cancer Research, University of
Lausanne, Lausanne, Switzerland
Carl E. Ruby, PhD Department of General Surgery, Rush University Medical
Center, Chicago, IL, USA
Daniel E. Speiser, MD Ludwig Center of the University of Lausanne,
Lausanne, Switzerland
Mario Sznol, MD Yale Cancer Center, New Haven, CT, USA
Janis M. Taube, MD Departments of Dermatology and Pathology,
Johns Hopkins Hospital, Baltimore, MD, USA
John A. Thompson, MD Department of Medicine, Division of Medical
Oncology, University of Washington School of Medicine, Fred Hutchinson
Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA
Suzanne L. Topalian, MD Departments of Surgery and Oncology,
The Johns Hopkins University School of Medicine and the Sidney Kimmel
Comprehensive Cancer Center, Baltimore, MD, USA
Nicolas van Baren, MD, PhD de Duve Institute and Université catholique
de Louvain, Brussels, Belgium
Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium
Centre du Cancer, Unité d’Oncologie Médicale, Cliniques universitaires
Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Robert H. Vonderheide, MD, DPhil Abramson Family Cancer
Research Institute, University of Pennsylvania School of Medicine,
Philadelphia, PA, USA
Andrew Weinberg, PhD Laboratory of Basic Immunology,
Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute,
Portland, OR, USA
Jedd D. Wolchok, MD, PhD Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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