Cancer Immunotherapy

Immune Suppression and Tumor Growth

George C. Prendergast, Elizabeth M. Jaffee

• Publisher: Academic Press
• Year: 2013
• eBook ISBN: 9780123946331
• Edition: 2
• Topic: Medicine
• Subtopic: Immunology

There has been major growth in understanding immune suppression mechanisms and its relationship to cancer progression and therapy. This book highlights emerging new principles of immune suppression that drive cancer, and it offers radically new ideas about how therapy can be improved by attacking these principles. Following work that firmly establishes immune escape as an essential trait of cancer, recent studies have now defined specific mechanisms of tumor immune suppression. It also demonstrates how attacking tumors with molecular targeted therapeutics or traditional chemotherapeutic drugs can produce potent anti-tumor effects in preclinical models. This book provides basic, translational, and clinical cancer researchers with an indispensable overview of immune escape as a critical trait in cancer and how applying specific combinations of immunotherapy and chemotherapy to attack this trait may radically improve the treatment of advanced disease.- Offers a synthesis of concepts that are useful to cancer immunologists and pharmacologists, who tend to work in disparate fields with little cross-communication- Drs. Prendergast and Jaffee are internationally recognized leaders in cancer biology and immunology who have created a unique synthesis of fundamental and applied concepts in this important new area of cancer research- Summarizes the latest insights into how immune escape defines an essential trait of cancer- Includes numerous illustrations, including how molecular-targeted therapeutic drugs or traditional chemotherapy can be combined with immunotherapy to improve anti-tumor efficacy and how reversing immune suppression by the tumor can cause tumor regression

Chapter 1

Introduction

George C. Prendergast^1,2,3 and Elizabeth M. Jaffee⁴, ¹Lankenau Institute for Medical Research, Wynnewood, PA USA, ²Department of Pathology, Anatomy & Cell Biology, ³Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University, Philadelphia, PA USA, ⁴The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, The Johns Hopkins University, Baltimore, MD USA

Acknowledgments

Work in the authors’ laboratories has been supported by NIH grants CA109542, CA159337 and CA159315, New Link Genetics Corporation, Sharpe-Strumia Research Foundation, Lankenau Hospital Foundation and the Main Line Health System (G.C.P.) and by NIH grants R01CA122081, P50CA062924, and P50CA088843 (E.M.J.). Dr. Jaffee is the first recipient of the Dana and Albert “Cubby” Broccoli Professorship in Oncology and the co-director of the Skip Viragh Pancreatic Cancer Center at Johns Hopkins University. G.C.P. declares competing interests as a scientific advisor, grant recipient and stockholder in New Link Genetics Corporation, which is developing HyperAcute vaccines and which has licensed patented technology from the author’s institution to develop small molecule inhibitors of IDO and the IDO pathway for the treatment of cancer and other diseases. E.M.J. declares competing interests based upon licensing of patented vaccines from the author’s institution to BioSante Pharmaceuticals and Aduro BioTech Inc. The inventions from both authors have the potential to generate future royalties.

I Summary

Immunological thought is exerting a growing effect in cancer research, correcting a divorce that occurred in the mainstream of the field decades ago as cancer genetics began to emerge as a dominant movement. During the past decade, a new general consensus has emerged among all cancer researchers that inflammation and immune escape play crucial causal roles in the development and progression of malignancy. This consensus is now driving a new synthesis of thought with great implications for cancer treatments of the future. In this book, we introduce new concepts and practices that will dramatically affect oncology by adding new immune modalities to present standards of care in surgery, radiotherapy and chemotherapy. We aim in particular to cross-fertilize ideas in the new area of immunochemotherapy, which strives to develop new combinations of immunological and pharmacological agents as cancer therapeutics. Specifically, our goals are to (1) highlight novel principles of immune suppression in cancer, which represent the major salient breakthroughs in the field of cancer immunology in the last decade, and to (2) discuss the latest thinking in how immunotherapeutic and chemotherapeutic agents might be combined, not only to defeat mechanisms of tumoral immune suppression but also to reprogram the inflammatory microenvironment of tumor cells to enhance the long-term outcomes of clinical intervention. Many immune-based therapies have focused on activating the immune system. However, it is now clear that these therapies are often thwarted by the ability of cancers to erect barricades that evade or suppress the immune system. Mechanistic insights into these barricades have enormous medical implications, not only to treat cancer but also many chronic infectious and age-associated diseases where relieving pathogenic immune tolerance is a key challenge. In this book, contributors with a wide diversity of perspectives and experience provide an introductory overview to the immune system; how tumors evolve to evade the immune system; the nature of various approaches used presently to treat cancer in the oncology clinic; and how these approaches might be enhanced by inhibiting important mechanisms of tumoral immune tolerance and suppression. The overarching aim of this treatise is to provide a conceptual foundation to create a more effective all-out attack on cancer. In this chapter, we offer a historical perspective on the development of immunological thought in cancer, a discussion of some of the fundamental challenges to be faced, and an overview of the chapters which frame and address these challenges.

II Historical Background

“I can’t understand why people are frightened of new ideas. I’m frightened of the old ones.”

– John Cage (1912–1992)

Starting about 1980, research investigations in cancer genetics and cell biology began to assume the prominence in cancer research that they now hold today. Hatched initially from studies of animal tumor viruses, the field of cancer genetics has contributed significantly to our understanding of the biologic pathways involved in tumor initiation and progression, and has identified specific targets for therapeutic intervention. With the discovery of cellular oncogenes, the once radical idea that cancer was a disease of normal cellular genes gone wrong not only came to be established as the dominant idea in the field but also to strongly influence how to develop new drugs to treat cancer, with the goal of attacking the products of those genes. At the same time, these developments outpaced other concepts of cancer as a systemic disease involving perturbations in the immune system. Now, after decades of mutual skepticism, a historically important consensus among cancer researchers is emerging about the causality of chronic inflammation and altered immunity in driving malignant development and progression. Ironically, this synthesis is having the effect of making the “new” genetic ideas of the past two decades about cancer seem somewhat dated: in particular, it is becoming apparent that the tumor cell-centric focus championed by cancer genetics is unlikely to give a full understanding of clinical disease, without knowing about the systemic and localized tissue conditions that surround and control the growth and activity of the tumor cell. Perhaps contributing to some consternation about the conceptual weight of the “new” ideas, few of the molecular therapeutics developed from them have had much major clinical impact (the Bcr-Abl kinase inhibitor Gleevec^® still perhaps the most notable success among present molecular cancer therapeutics).

Among the earliest pathohistological descriptions of cancer, Virchow in the 1800s first noted the surfeit of inflammatory cells in many tumors. From this root, tumor immunologists have for many years struggled to fully understand the precise relationships between inflammation, immunity, and cancer, and to develop principles that can robustly impact the diagnosis, prognosis, and treatment of cancer. With the emergence of cancer genetics and tumor cell-centric concepts of disease as major conceptual drivers in the late 20^th century, roles identified for tumor stromal cells and immunity in cancer became marginalized or simply ignored by many investigators. Indeed, old skepticisms about whether immunity was important or not in cancer have persisted until quite recently, as can be illustrated by the omissions of immune escape and inflammation as critical traits of cancer in influential reviews as recently as the turn of the new century [1]. However, since 2000 perspectives in the field have once again undergone a radical shift, with many cancer researchers now focusing intensely on how tumorigenesis and tumor dormancy versus progression are shaped by the stromal microenvironment, inflammation, and alterations in the immune system. Indeed, a recent update to the prominent review cited above recognized the conceptual movement in this rapidly moving area of the field, including inflammation and immune escape as critical traits of cancer [2].

The restoration of immunological thought in the mainstream of cancer research is proceeding rapidly, creating a historically important synthesis that is seeding radically new approaches of immunochemotherapy and radioimmunotherapy [3]. Over the past 25 years, as a result of historical and scientific divisions, there have been limited communication, understanding, and collaboration between tumor immunologists, molecular geneticists, and cell biologists working in the field. On one hand, this situation has been exaggerated by what now seems like an overly narrow focus of geneticists and cell biologists on tumor cell-centric concepts of cancer, which continues to persist to some degree. On the other hand, immunologists have struggled to establish a clear understanding of how inflammation and immune cells can contribute to promoting or controlling cancer. Biases rooted to some extent in old controversies that have been transmitted to younger scientists entering each field have further limited communication and interaction between the two camps. Happily, in recent years many of these old issues have been put to rest, by experiments in modern transgenic animal model systems and by carefully controlled clinical observations, such that the key pathophysiological foundations of inflammation and immune dysfunction in cancer are now firmly established [4]. Contributing to the new perspective, there is a wider appreciation of both the critical role of the tumor microenvironment in malignant development and the power of immune suppression mechanisms in licensing cancer cell proliferation, survival, and metastasis. In terms of immunotherapeutic responses, it seems increasingly clear that in order to “push on the gas” of immune activation, it will be necessary to “get off the brakes” of immune suppression—an idea that cancer geneticists may recognize as analogous to the concept in their field that oncogenes can drive neoplastic cell proliferation only when the blockades imposed by tumor suppressor genes are relieved.

III The Challenge of Cancer

Clearly, the goal of cancer therapy is to kill residual tumor that cannot be excised surgically. However, the inherent nature of the cancer cell limits the full effectiveness of therapies that have been developed, or that arguably can be developed. Being of host origin, cancer cells share features of the host that make effective treatment difficult, due to side effects that limit the therapeutic window. Moreover, the plastic nature of tumors makes them remarkably resilient in rebounding from clinical regimens of radiotherapy and chemotherapy that are traditionally used. For example, even when the vast majority of cancer cells are killed by a cytotoxic chemotherapeutic drug, a small number of residual cells that are resistant to the agent can be sufficient to seed the regrowth of a tumor. Making matters worse, the regrown tumor may no longer respond to the previously successful therapy, due to the capacity of tumor cells to evolve resistance under selective pressures applied by cytotoxic agents. Indeed, the concept of selection is integral to understanding this disease: development and progression in cancer is driven by the selection of cells that survive conditions that are normally lethal. Resistance to any normally lethal pressure can be selected by evolution in a cancer cell population because of the genetic plasticity, an important characteristic of cancer cells. As demonstrated in the treatment of other diseases caused by a highly mutable entity, e.g., HIV, successful targeting of tumor cells may require the application of multiple agents that target different survival mechanisms. However, compared to HIV, the genetic space available for the evolution of a cancer cell is far larger, due to the far greater size of the cancer cell genome. Thus, effective eradication of tumors has proven —and may continue to prove to be—quite challenging, even using multiple agents in combination, because of the diversity of options that the cancer genome can realize to evolve mechanisms of survival in response to multiple selection pressures these agents apply. Our best chance is to identify as many of these mechanisms as possible, and to discover approaches that synergize to inhibit these many mechanisms.

Two general solutions to this dismal situation may be to redirect the focus of attack from the tumor cell itself to the environment that sustains its growth and survival or to engage the immune system in ways that allows it to eradicate tumor cells like an infection. The former strategy is essentially passive in nature insofar as cancer cells are killed by an indirect route. For example, by depriving tumors of a blood supply anti-angiogenic therapies can indirectly kill cancer cells. Resistance to such therapies should be difficult to evolve, as the argument goes, because stromal cells in the tumor environment are not genetically plastic. However, due to their passive nature such therapies are still prone to circumvention through tumor cell evolution (e.g., vascular mimicry in the case of anti-angiogenesis therapies [5]). In contrast, active strategies to engage or “awaken” active immunity in the cancer patient has many appeals, the chief of which is its capability to “dodge and weave” with tumor heterogeneity, the inherent outcome of the response of tumor cells to selection pressures. In this regard, the immune system may be particularly well suited to clear the small numbers of residual tumor cells, particular dormant cells or cancer stem cells, that may be poorly eradicated by radiotherapy and chemotherapy and which could help lengthen remission periods. Indeed, even treatments that did not cure but rather converted cancer to a long-term subclinical condition, by analogy to HIV infections, would represent a resounding success. Therefore, the key question becomes how a tumor can outrun an activated immune system, given that precisely this event has occurred during tumorigenesis, so that the balance might be tipped back in favor of the immune system.

IV Parts of the Book

The second edition of this book provides a significant expansion upon the first edition, reflecting rapid developments in cancer immunology and the new field of immunochemotherapy. The book encompasses two general parts, which are subdivided into three sections each. The first part of the book introduces key concepts, with Sections I–III to introduce basic principles of immunology, cancer immunobiology and cancer therapeutics. The second part of the book introduces strategies to stimulate or heighten (and measure) immunotherapeutic responses, with Sections IV–VI devoted to passive and active immunotherapy, potential improvements with existing tools, and emerging strategies to target mechanisms of tumoral immunosuppression that are being discovered along with novel experimental tools to do so.

Section I introduces basic principles in immunology for the large number of individuals working or interested in cancer research who remain relatively unschooled in this discipline. This section does not delve into every topic but offers rudiments relevant to key directions in the field. Fundamental components of the immune system are introduced in Chapter 2 spanning both innate and adaptive immunity. The following chapters focus more deeply on the adaptive immune system, which tumors must ultimately erect powerful barricades against, with Chapter 3 addressing B cells and antibodies and Chapter 4 addressing T cells and cytokines. Chapter 5 introduces antigen processing and presentation to the adaptive immune system as carried out by dendritic cells, a class of myeloid cells specifically dedicated to antigen presentation. This chapter addresses an important area of cancer immunobiology and therapy at present, insofar as it encompasses the first active immunotherapy to be approved in the U.S. for cancer treatment. Chapter 6 introduces mucosal immunity, an area of rapidly expanding influence due in part to a growing appreciation of how the aerodigestive tracts not only shape tolerance to environmental antigens but also to how the gut microbiome programs immunity overall [6].

Section II moves specifically into the general principles of cancer immunobiology, a seminal area that is renewing its historical impact on cancer research after the divorce of immunology from the mainstream of the field with the molecular genetics revolution of the 1980s. Key chapters highlight the significanc...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Chapter 1. Introduction
• Section 1: Principles of Basic Immunology
• Section 2: Principles of Cancer Immunobiology
• Section 3: Introduction to Cancer Therapeutics
• Section 4: Strategies of Passive and Active Immunotherapy
• Section 5: Improving Immunotherapeutic Responses
• Section 6: Targeting Strategies to Defeat Immune Suppression
• Index