Novel Immunotherapeutic Approaches to the Treatment of Cancer: Drug Development and Clinical Application

285 Pages·2016·5.74 MB·English

by  Paul D. Rennert (eds.)

Paul D. Rennert Editor
Novel
Immunotherapeutic
Approaches to the
Treatment of Cancer
Drug Development and Clinical
Application
Novel Immunotherapeutic Approaches
to the Treatment of Cancer

Paul D. Rennert
Editor
Novel Immunotherapeutic
Approaches to the Treatment
of Cancer
Drug Development and Clinical Application
Editor
Paul D. Rennert
SugarCone Biotech LLC
Holliston , MA , USA
Aleta Biotherapeutics
Natick, MA, USA
ISBN 978-3-319-29825-2 ISBN 978-3-319-29827-6 (eBook)
DOI 10.1007/978-3-319-29827-6
Library of Congress Control Number: 2016939247
© Springer International Publishing Switzerland 2016
T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
T he publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Printed on acid-free paper
This Springer imprint is published by Springer Nature
The registered company is Springer International Publishing AG Switzerland
This book is dedicated to the memory of
Dr. Holbrook Edwin Kidd Kohrt (1977-2016).
Holbrook was born in Scranton, Pennsylvania, and at
an early age was found to have sporadic hemophilia
(factor VIII). He overcame amazing obstacles and
outlived the majority of his hemophiliac cohort, most
of whom succumbed to transfusion-related infections,
such as HIV/AIDS. Amazingly, Holbrook was able to
clear and recover from an HCV infection, then relying
on recombinant factor to keep him alive. Early on, he
realized the power of the immune system to control
such things as infection and cancer. Driven by not
only his own personal experiences, but also his desire
to help others, Holbrook pursued a career in medicine
and translational research. He graduated as
valedictorian of his class at Muhlenburg College. He
then went on to attend Stanford University Medical
School as a Baxter Foundation Scholar, going on to
complete residency and fellowship there as well. He
was a Howard Hughes Medical Institute Scholar,
American Society of Hematology Research Fellow,
and Damon Runyon Cancer Research Foundation
Clinical Investigator, amongst other numerous
awards. He completed his MD and obtained a PhD in
tumor immunology and clinical trials design during
fellowship. Holbrook worked tirelessly to drive
innovation in cancer immunotherapy, publishing
widely and impacting deeply, as he was involved with
numerous projects that spanned basic, translational,
and clinical boundaries. In his short time on earth, he
inspired, innovated, and intimately cared for not only
patients, but also anyone he touched.
I fi rst met Holbrook in residency when he was
fi nishing medical school at Stanford. We went through
oncology fellowship together, and shared the struggles
of training and postdoctoral fellowship – spending
countless hours in the lab, performing endless
experiments, struggling for funding – but ultimately,
we shared a passion for science, immunotherapy, and
a shared goal of improving lives. During my father’s
struggle with metastatic colon cancer, Holbrook was
there, providing critical support and after-hours
anti-emetic prescriptions. He was not only the type of
oncologist you wished for if you were a patient, he
was the type of physician-scientist you wished for as a
colleague, and the type of friend you’d be lucky to
have.
In thinking about how one might live a life, I think
Holbrook would answer: with passion, compassion,
and purpose…and there’s no doubt that is exactly how
he lived his life. He had written that his mission in life
was to “give people more time for them to express
their love.”
Without a doubt, that is exactly what he
accomplished

Russell K. Pachynski, MD
Assistant Professor
Division of Oncology
Washington University
Contents
1 Enhancing the Efficacy of Checkpoint Blockade
Through Combination Therapies .......................................................... 1
Vikram R. Juneja , Martin W. LaFleur , Robert T. Manguso ,
and Arlene H. Sharpe
2 Novel Immunomodulatory Pathways in the Immunoglobulin
Superfamily ............................................................................................. 41
Paul D. Rennert
3 Parallel Costimulation of Effector and Regulatory T Cells
by OX40, GITR, TNFRSF25, CD27, and CD137:
Implications for Cancer Immunotherapy ............................................. 59
Taylor H. Schreiber
4 NK Cell Responses in Immunotherapy: Novel Targets
and Applications ...................................................................................... 79
Russell Pachynski and Holbrook Kohrt
5 Reversing T Cell Dysfunction for Tumor Immunotherapy ................. 109
Lawrence P. Kane and Greg M. Delgoffe
6 Immunomodulation Within a Single Tumor Site to Induce
Systemic Antitumor Immunity: In Situ Vaccination for Cancer ........ 129
Linda Hammerich and Joshua D. Brody
7 Novel Targets and Their Assessment for Cancer Treatment .............. 163
Sheila Ranganath and AnhCo Nguyen
8 The New Frontier of Antibody Drug Conjugates:
Targets, Biology, Chemistry, Payloads .................................................. 181
Christopher D. Thanos and Paul D. Rennert
9 Cellular Therapies: Gene Editing and Next- Gen CAR T Cells .......... 203
Thomas J. Cradick
vii
viii Contents
10 Targeting the Physicochemical, Cellular, and Immunosuppressive
Properties of the Tumor Microenvironment by Depletion
of Hyaluronan to Treat Cancer .............................................................. 249
Christopher D. Thanos
Index ................................................................................................................. 269
Introd uction

The era of immuno-oncology is upon us, and we have just in a few years moved
from hypothesis testing and preclinical modeling to extraordinary and transforma-
tive advances in the development of therapeutics for cancer treatment. Diverse
classes of therapeutics contributed to the outstanding pace of progress, driven by
equally diverse technologies. Monoclonal antibodies continued to demonstrate
their importance, with outstanding data coming from clinical trials of antagonist
antibodies targeting immune checkpoint targets, high potency depleting antibodies
targeting tumor antigens, antibody-drug conjugates, and agonist antibodies, nota-
bly to members of the TNF receptor superfamily. Taylor Schreiber reviews this
latter class of antibodies that present interesting drug development challenges.
Importantly, all of these diverse therapeutics synergize, sometime dramatically, in
preclinical models, and in the case of immune checkpoint therapeutics, this has
been exploited clinically. Indeed the role of immune checkpoint therapy as a sin-
gular and unprecedented backbone for a vast array of combinations has become a
dominant theme, as discussed by Arlene Sharpe and colleagues. While the focus
until recently has really been on T cell responses to tumors, Russell Pachynski and
Holbrook Kohrt remind us that NK cells are potent anti-tumor lymphocytes, and
must be brought to bear as we attack cancer cells from multiple angles. Another
area ripe for combination with the immune checkpoint antibodies is the so-called
onco-vaccines that target tumor antigens. Vaccine development is transforming
from a once-neglected backwater into one of the dominant areas of cancer research,
driven by a new understanding of the breadth of tumor antigens that can be uncov-
ered, and to which T cells respond. Of note however, many of these novel antigens,
or neo-antigens, appear to be patient-specifi c, raising a new challenge for the fi eld.
At the same time novel approaches to adjuvancy are improving vaccine delivery
and potency—the complexities and advances in the vaccine fi eld are addressed by
Joshua D. Brody.
Antibody technology also contributed antigen-binding domains to chimeric-
antigen-r eceptor bearing T cells, termed CAR-T, a technology that has altered the
landscape of acute lymphocytic leukemia care and is making signifi cant inroads
into the treatment of several diffi cult B cell lymphomas. While the treatment of
ix