Vaccines for Cancer Immunotherapy

An Evidence-Based Review on Current Status and Future Perspectives

Nima Rezaei, Mahsa Keshavarz-Fathi

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128140390
• eBook ISBN: 9780128140406
• Topic: Biological Sciences
• Subtopic: Oncology
• Index: Biological Sciences

Therapeutic cancer vaccines represent a type of active cancer immunotherapy. Clinicians, scientists, and researchers working on cancer treatment require evidence-based and up-to-date resources relating to therapeutic cancer vaccines. Vaccines for Cancer Immunotherapy provides a reference for cancer treatment for clinicians and presents a well-organized resource for determining high-potential research areas. The book considers that this promising modality can be made more feasible as a treatment for cancer. Chapters cover cancer immunology, general approaches to cancer immunotherapy, vaccines, tumor antigens, the strategy of allogeneic and autologous cancer vaccines, personalized vaccines, whole-tumor antigen vaccines, protein and peptide vaccines, dendritic cell vaccines, genetic vaccines, candidate cancers for vaccination, obstacles to developing therapeutic cancer vaccines, combination therapy, future perspectives and concluding remarks on therapeutic cancer vaccines.- Introduces the feasible immunotherapeutic vaccines for patients with different types of cancer- Presents the status of past and current vaccines for cancer treatment- Considers advantages and disadvantages of different therapeutic cancer vaccines- Looks at the combination of vaccines and other modalities, including immunotherapeutic and conventional methods- Analyzes obstacles to development of therapeutic cancer vaccines- Gives a view on future perspectives in the application of therapeutic cancer vaccines

Chapter 1

Cancer Immunology

Mahsa Keshavarz-Fathi ^{1 , 2 , 3} , and Nima Rezaei ^{3 , 4 , 5 1} School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ² Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran ³ Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran ⁴ Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ⁵ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Abstract

To understand the fundamental interactions between tumor cells and the immune system, immunosurveillance and evolutionally immunoediting hypothesis were proposed. When tumor cells overcome mechanisms of the immune system in the elimination phase, they proceed with the equilibrium and probably escape phases. In each phase, various immune cells and cytokines are involved. Moreover, several mechanisms are considered for the tumor escaping form the immune system, including defect in tumor antigen presentation and recognition, dominance of inhibitory mechanisms and lack of activating effects, and resistant subtypes of tumor cells such as cancer stem cells. In this chapter, various immune cells, which play a role in the immune response against tumor cells and immunoediting hypothesis, will be reviewed.

Keywords

Adaptive immunity; Cytokines; DCs; Elimination; Equilibrium; Escape; Immunoediting; Innate immunity; Lymphocytes; Macrophages; MDSCs; NK cells; Tregs

Innate and Adoptive Immunity

Pathogens and endogenous dangerous mutated and cancerous cells must be distinguished and destroyed by the immune system, which has two main arms: innate and adaptive immunity. Each arm has its own specialized cell-based and humoral responses. The first responder to exogenous and endogenous threats is the innate immune system, which operates as a nonspecific arm and rapidly acts through pattern recognition receptors (PRRs). These receptors are located on the surface of innate cells including tissue-resident cells such as macrophages, dendritic cells (DCs), monocytes, and neutrophils, which circulate in the blood. Most of the PRRs bind to the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to recognize the potential danger. ^1,2 Toll-like receptors (TLRs) are one of the significant PRRs, present on the surface of antigen-presenting cells (APCs), such as DCs. By recognition of PAMPs and DAMPs, they initiate activation of the signaling pathways such as transcription factor nuclear factor-kappa B (NF-κB) and interferon regulatory transcription factor, which are inflammatory and induce type I interferons and cytokines to recruit and activate lymphocytes. ^3,4

The innate immune system is not capable of forming an immunological memory. Therefore, the role of the adaptive immune system in providing immunological memory and specific responses is manifest. Adaptive immune cells are capable of recognizing a single specific antigen because each lymphocyte, before facing any antigen, carries only one receptor, which is specific for one antigen. Therefore, to cover recognition of the variety of antigens, which the immune system meets through its lifespan, millions of antigen-specific receptors must exist. In order to provide this vast variety, the genes of variable chains of the receptors randomly recombine during development of lymphocytes in the central lymphoid organs, the bone marrow, and thymus. Then, various variable chains are paired to create the whole lymphocyte receptor repertoire of a person. ⁵

Clonal selection of lymphocytes is the central feature of the adaptive immune system, which leads to developing specific responses. As described earlier, lymphocytes bear a variety of receptors specific for different antigens, named antigen-specific receptors. These cells are activated and proliferated only after exposure to the specific antigens. The receptor of a lymphocyte's descendants, i.e., the effector cells, are the same with their ancestor's, and this is the concept of a clone. Clonal deletion is also crucial to omit autoreactive lymphocytes, which respond to the self-antigens. ⁵

To induce an immune response against cancer, two central phases are performed, i.e., the priming and effector phases. In the first phase, the APCs such as DCs prime the T cells. They obtain the tumor antigens of dying cancer cells. If a danger signal is not available, immune tolerance toward the antigen is induced. Immunogenic cell death is responsible to generate danger signals, which are recognized by PRRs on DCs. The stress induced during cell death leads to providing danger signals such as type I interferons, chemokine ligand 10 (CXCL10), CXC‑chemokine receptor 3 (CXCR3), heat shock protein 70 kDa (HSP70), and HSP90. The danger signals function as adjuvants to increase the immunogenicity. ⁶ Antigens and danger signals lead to the maturation of DCs, and then they travel toward the draining lymph nodes. ⁶ To induce effector T cells, DCs transduce three signals to T cells. The first signal is transduced through antigen presentation by the major histocompatibility (MHC) molecules on DCs to T cell receptors (TCRs) on the T cells. The second signal results from costimulatory or coinhibitory molecules. The second signal adjusts and modulates the type of immune response against the danger signal. Following these signals, in the third signal a number of cytokines are produced to direct the type of following immune response. ⁷ The type of DC maturation affects on determining the phenotype of T cells (Fig. 1.1). As a consequence of priming, CD4+ and CD8+ effector T cells, necessary to evoke a robust immune response, are developed. Cytotoxic T lymphocytes, which are CD8+ T cells, are the main effector cells to destroy the tumor cells. However, CD4+ T cells are required for optimal and long-lived effector CD8+ T cells and for induction and maintenance of CD8+ memory cells. ^8,9

Antigens are processed through two different mechanisms. MHC-I restricted peptides undergo the proteasome dependent mechanism. The proteasome changes the long peptides to small peptides containing 9–15 amino acids, to be delivered to the endoplasmic reticulum (ER) via the transporter of antigen processing (TAP). In the ER, the peptides with 9–12 amino acids bind to the MHC-I molecules to be transported to the surface of cells. The MHC-II restricted peptides use the endosomal system. Cathepsins process the antigens in endosomes, and peptides with 12–15 amino acids bind to the MHC-II, which are transported to the surface of DCs. ¹⁰

There are some barriers that hamper the function of effector T cells. Immunosuppressive phenotype of tumor microenvironment is one of the barriers generated due to the function of some immune cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as well as the cytokines, chemokines, and indoleamine 2,3-dioxygenase (IDO) secreted by the tumor cells. ^11–14

Activating Immune Cells

In bot...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Chapter 1. Cancer Immunology
• Chapter 2. Immunotherapeutic Approaches in Cancer
• Chapter 3. Vaccines, Adjuvants, and Delivery Systems
• Chapter 4. Tumor Antigens
• Chapter 5. Strategy of Allogeneic and Autologous Cancer Vaccines
• Chapter 6. Personalized Cancer Vaccine
• Chapter 7. Whole Tumor Cell Vaccine for Cancer
• Chapter 8. Peptide and Protein Vaccines for Cancer
• Chapter 9. Immune Cell Vaccine for Cancer
• Chapter 10. Genetic Vaccine for Cancer
• Chapter 11. Candidate Cancers for Vaccination
• Chapter 12. Obstacles in the Development of Therapeutic Cancer Vaccines
• Chapter 13. Combination Therapy: Cancer Vaccines and Other Therapeutics
• Chapter 14. Concluding Remarks and Future Perspectives on Therapeutic Cancer Vaccines
• Index