Advances in Experimental Medicine and Biology 1342
Aung Naing
Joud Hajjar Editors
Immunotherapy
Fourth Edition
,Advances in Experimental Medicine
and Biology
Volume 1342
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Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
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Haidong Dong, Departments of Urology and Immunology,
Mayo Clinic, Rochester, MN, USA
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Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany
Nima Rezaei, Research Center for Immunodeficiencies, Children's Medical
Center, Tehran University of Medical Sciences, Tehran, Iran
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Institute of Cardiovascular Science, School of Life Science,
Shanghai University, Shanghai, China
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,Aung Naing • Joud Hajjar
Editors
Immunotherapy
Fourth Edition
,Editors
Aung Naing Joud Hajjar
Professor, Dept. of Investigational Assistant Professor, Service Chief of
Cancer Therapeutics Adult Allergy & Immunology
The University of Texas MD Anderson Division of Immunology, Allergy &
Cancer Center Retrovirology
Houston, TX, USA Baylor College of Medicine and Texas
Children’ Hospital
Houston, TX, USA
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-030-79307-4 ISBN 978-3-030-79308-1 (eBook)
https://doi.org/10.1007/978-3-030-79308-1
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,Contents
Immune System in Action ���������������������������������������������������������������������� 1
Bettzy Stephen and Joud Hajjar
Resistance to Immunotherapy: Mechanisms
and Means for Overcoming�������������������������������������������������������������������� 45
Mohamad A. Salkeni, John Y. Shin, and James L. Gulley
Immunotherapy for Melanoma�������������������������������������������������������������� 81
Justin T. Moyers and Isabella C. Glitza Oliva
Immunotherapy in Lung Cancer: Are the Promises
of Long-Term Benefit Finally Met?�������������������������������������������������������� 113
Diego L. Kaen, Nicolas Minatta, Alessandro Russo,
Umberto Malapelle, Diego de Miguel-Pérez, and Christian Rolfo
Landscape of Immunotherapy in Genitourinary Malignancies���������� 143
Deepak Ravindranathan, Omar Alhalabi, Hind Rafei,
Amishi Yogesh Shah, and Mehmet Asim Bilen
Immuno-Oncology for Gynecologic Malignancies�������������������������������� 193
Jeffrey A. How, Ami Patel, and Amir A. Jazaeri
Immunotherapy for Neuro-oncology ���������������������������������������������������� 233
Nazanin K. Majd, Pushan R. Dasgupta, and John F. de Groot
Immunotherapy in Gastrointestinal Malignancies ������������������������������ 259
Rishi Surana and Shubham Pant
Update on Immune Based Therapies
An
in Acute Myeloid Leukemia: 2021 and Beyond! ���������������������������������� 273
Fadi Haddad and Naval Daver
CAR T Cells���������������������������������������������������������������������������������������������� 297
Ranjit Nair and Jason Westin
Skin Reactions to Immune Checkpoint Inhibitors ������������������������������ 319
Anisha B. Patel and Omar Pacha
Immunotherapy-Mediated Luminal Gastrointestinal Toxicities�������� 331
Anusha S. Thomas and Yinghong Wang
Hepatobiliary and Pancreatic Adverse Events�������������������������������������� 339
Hao Chi Zhang, Lan Sun Wang, and Ethan Miller
vii
,viii Contents
Pulmonary Toxicities of Immunotherapy���������������������������������������������� 357
Mehmet Altan, Linda Zhong, Vickie R. Shannon,
and Ajay Sheshadri
Immune Checkpoint Inhibitor (ICI)-Related Cardiotoxicity�������������� 377
Abdulrazzak Zarifa, Juan Lopez-Mattei, Nicolas L. Palaskas,
Cezar Iliescu, Jean-Bernard Durand, and Peter Y. Kim
Renal Toxicity ������������������������������������������������������������������������������������������ 389
Maen Abdelrahim and Ala Abudayyeh
Immune-Related Oral, Otologic, and Ocular Adverse Events������������ 399
Nagham Al-Zubidi, J. Cody Page, Dan S. Gombos,
Akanksha Srivastava, Eric Appelbaum, Paul W. Gidley,
Mark S. Chambers, and Marc-Elie Nader
Neurologic Toxicities of Immunotherapy���������������������������������������������� 417
Rebecca A. Harrison, Nazanin K. Majd, Sudhakar Tummala,
and John F. de Groot
Cancer Imaging in Immunotherapy������������������������������������������������������ 431
Murat Ak, Yousra Eleneen, Mira Ayoub, and Rivka R. Colen
, Immune System in Action
Bettzy Stephen and Joud Hajjar
Abstract the war against cancer. In this chapter, we pro-
vide an overview of the individual components
Tumor exists as a complex network of struc- of the human immune system and the transla-
tures with an ability to evolve and evade the tional relevance of predictive biomarkers.
host immune surveillance mechanism. The
immune milieu which includes macrophages, Keywords
dendritic cells, natural killer cells, neutrophils,
mast cells, B cells, and T cells is found in the Immune cells · Cancers · Cytokines · Innate ·
core, the invasive margin, or the adjacent stro- Adaptive · Checkpoints
mal or lymphoid component of the tumor. The
immune infiltrate is heterogeneous and varies
within a patient and between patients of the
same tumor histology. The location, density, The human immune system is an elaborate and
functionality, and the crosstalk between the dynamic network of cells that work together to
immune cells in the tumor microenvironment defend the human body against attacks by foreign
influence the nature of immune response, agents including malignant cells. There are two
prognosis, and treatment outcomes in cancer levels of immunity, the innate immunity and the
patients. Therefore, an understanding of the adaptive immunity. The innate immunity consti-
characteristics of the immune cells and their tutes the first line of defense against pathogens,
role in tumor immune surveillance is of para- which includes the anatomic and physiologic
mount importance to identify immune targets barriers, phagocytic leukocytes, dendritic cells
and to develop novel immune therapeutics in (DC), natural killer (NK) cells, and the circulat-
ing plasma proteins [1]. Elie Metchnikoff, a
pathologist and Father of natural immunity, was
B. Stephen () the first to describe the concept of leukocyte
The University of Texas MD Anderson Cancer
recruitment and phagocytosis of microorganisms
Center, Houston, TX, USA
e-mail: BAStephen@mdanderson.org [2]. The adaptive immune system is a more versa-
tile mechanism of defense provided by the B
J. Hajjar
Assistant Professor, Service Chief of Adult Allergy & lymphocytes and the T lymphocytes, which has
Immunology, Division of Immunology, Allergy & been attributed to Paul Ehrlich, the physicist who
Retrovirology, Baylor College of Medicine and Texas described the side-chain theory of antibody for-
Children’ Hospital, Houston, TX, USA
mation [3]. The innate and adaptive immune sys-
e-mail: joud.hajjar@bcm.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1
A. Naing, J. Hajjar (eds.), Immunotherapy, Advances in Experimental Medicine and Biology 1342,
https://doi.org/10.1007/978-3-030-79308-1_1
, 2 B. Stephen and J. Hajjar
tems are distinct but interactive components of this reason, tumors are sometimes described as
the human immune system that collectively con- “wounds that do not heal” [11].
tribute to the defense operations against foreign
proteins [4]. In this chapter, we will discuss the
fundamental components of the immune system 1.1 Cellular Components
and their development, how innate immunity of the Innate Immune System
interfaces with adaptive immune responses to
eliminate tumor cells, and the development of All the cells of the immune system originate from
immunotherapeutic strategies to combat cancer. the pluripotent hematopoietic stem cells (HSCs)
in the bone marrow. The HSCs divide to produce
the common lymphoid progenitor (CLP) and the
1 Innate Immune System common myeloid progenitor (CMP) cells. The
CLP gives rise to the T and B lymphocytes that
An association between inflammation and tumori- are responsible for adaptive immunity and the
genesis has long been described, but has been NK cells, while the CMP gives rise to the cells of
established with turn of the century [5]. The the innate immune system, leukocytes (neutro-
human body is constantly exposed to a highly phils, monocytes, basophils, and eosinophils),
diverse world of foreign proteins every day, which mast cells, DCs, erythrocytes, and the
are rapidly eliminated in a normal healthy indi- megakaryocytes.
vidual by the components of the innate immune
system. Speed is the essence of innate immune 1.1.1 Leukocytes
response; however, they are non-specific in nature The primary function of the leukocytes is to pro-
and of limited duration and lack immunologic tect the body against invading microorganisms.
memory [6]. Traditionally, the cellular compo- However, microenvironmental factors at the site
nents of the innate immune system, which of inflammation produce substantial changes in
includes the macrophages, neutrophils, eosino- the phenotype and functional status of individual
phils, basophils, mast cells, NK cells, and DCs, cells that favor initiation and progression of
are associated with elimination of microbial tumor [12, 13].
agents and activation of the more efficient,
antigen-specific adaptive immune response in the Neutrophils They account for 50–70% of circu-
event of failure [4, 6]. In addition, the humoral lating leukocytes [14] and form the indispensable
elements of the innate immune system that first line of defense against pathogenic microor-
includes the complement proteins and C-reactive ganisms. They originate from the CMP cells in
protein are considered as a regulator of inflamma- the bone marrow in response to several cytokines
tory process [4]. However, accumulating evidence including granulocyte colony-stimulating factor
suggests that the innate and adaptive immune sys- (G-CSF) and granulocyte macrophage colony-
tem, triggered by the tumor antigens, plays a sig- stimulating factor (GM-CSF) [14, 15]. They cir-
nificant role in the recognition and elimination of culate in the blood as dormant cells and are
malignant cells as well [7]. In the process, several recruited to sites of infection by specific chemo-
noxious reactive chemicals, cytokines, and che- kines, cytokines, and cell adhesion molecules
mokines are released, which damage the sur- [16]. The microbes are then taken up by the pro-
rounding healthy tissue [8]. The inflammatory cess of phagocytosis and destroyed by high con-
microenvironment also induces genomic instabil- centrations of microbicidal granules or by
ity and enhances rate of molecular alterations [9]. respiratory burst associated with production of
The resultant process of repeated cell renewal and highly toxic reactive oxygen species in the
proliferation sets the stage for chronic inflamma- pathogen-containing vacuole [14]. In addition,
tion that produces a microenvironment conducive the activated neutrophils, upregulate the produc-
for malignant transformation of cells [10]. For tion of cytokines [including tumor necrosis
