Fast Facts: CAR T-Cell Therapy

A.J. Kansagra, R.J. Buka

Description

Chimeric antigen receptor (CAR) T cells are genetically engineered immune cells that can seek out and destroy cancer cells. The results from their use in cancer immunotherapy have been very promising, but treatment is often associated with frequent, serious short-term toxicities. 'Fast Facts: CAR-T Therapy' explains what CAR T cells are and how they were developed, discusses the results of clinical trials and the management of toxicities, and outlines future improvements and applications. It is ideal reading for any healthcare professional wanting to know more about this exciting therapeutic field. Table of Contents: • CAR T cells • Clinical application • Practical aspects • Future directions

Informations

• Publié par: S. Karger AG
• Date de parution: 26 janvier 2021
• Nombre de lectures: 0
• EAN13: 9783318067422
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

CAR T-Cell Therapy

Richard J Buka MBChB(Hons) BMedSc(Hons) MRCP Specialist Registrar in Haematology West Midlands, UK

Ankit J Kansagra MD Assistant Professor of Medicine and Eugene P. Frenkel MD Scholar of Clinical Medicine Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center Dallas, Texas
Declaration of Independence
This book is as balanced and as practical as we can make it.
Ideas for improvement are always welcome: [e-mail]
Fast Facts: CAR T-Cell Therapy
First published 2021
Text 2021 Richard J Buka, Ankit J Kansagra
2021 in this edition S. Karger Publishers Ltd
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Cover image: chimeric antigen receptor (light blue, center) binding to CD19 molecules (pink, lower right and lower left) on a leukemia cell. Juan Gaertner/Science Photo Library.
ISBN 978-3-318-06741-5 eISBN 978-3-318-06743-9
Buka RJ (Richard)
Fast Facts: CAR T-Cell Therapy/
Richard J Buka, Ankit J Kansagra
Medical illustrations by Graeme Chambers, Belfast, UK.
Typesetting by Karger UK, Abingdon.
Printed in the UK with Xpedient Print.
List of abbreviations
Introduction
CAR T cells
Clinical application
Practical aspects
Future directions
Useful resources
Index
List of abbreviations
ALL: acute lymphoblastic leukemia
AML: acute myeloid leukemia
ASTCT: American Society for Transplantation and Cellular Therapy
B-ALL: B-cell acute lymphoblastic leukemia
BCMA: B-cell maturation antigen
BCR: B-cell receptor
CAPD: Cornell Assessment of Pediatric Delirium
CAR: chimeric antigen receptor
CD: cluster of differentiation
CIBMTR: Center for International Blood and Marrow Transplant Research
CR: complete response
CRS: cytokine release syndrome
CT: computed tomography
DLBCL: diffuse large B-cell lymphoma
DNA: deoxyribonucleic acid
EBMT: European Society for Blood and Marrow Transplantation
EBV: Epstein-Barr virus
FDA: Food and Drug Administration
Fab: fragment antigen-binding (region)
Fc: fragment crystallizable (region)
Fv: fragment variable (region)
GvHD: graft-versus-host disease
HIV: human immunodeficiency virus
HLA: human leukocyte antigen
ICANS: immune effector cell-associated neurotoxicity syndrome
ICE: Immune Effector Cell-associated Encephalopathy (score)
IL: interleukin
MHC: major histocompatibility complex
MRI: magnetic resonance imaging
NK: natural killer (cell)
OS: overall survival
PFS: progression-free survival
RCT: randomized controlled trial
RNA: ribonucleic acid
scFv: single-chain variable fragment (region)
SCT: stem cell transplantation
TCR: T-cell receptor
Introduction
Our immune system has roles in supporting and protecting against cancer development. In a highly complex network of interacting cells, immune cells both promote cancer cell growth and survival and selectively kill malignant cells. It is this killing ability that cancer cells must escape from to survive and flourish.
Research into the basic science of cancer immunology has enabled us to harness the power of the immune system to treat cancer. We are now entering a golden age of immunotherapy where new, sophisticated and innovative treatments are providing unprecedented cures for patients with advanced cancers.
Chimeric antigen receptor (CAR) T cells are genetically engineered immune cells that can seek out and destroy cancer cells. So far, results have been very promising, but the use of CAR T cells is associated with frequent, serious short-term toxicities.
Here, we explain what CAR T cells are and how they were developed, discuss the results of clinical trials and the management of toxicities, and outline future improvements and applications. It is ideal reading for any healthcare professional wanting to know more about this exciting therapeutic field.
1 CAR T cells
The immune system
B cells and T cells. In normal circumstances, the adaptive immune system, which consists of B cells and T cells, specifically recognizes and eliminates infections and forms an immunologic memory to protect the body from repeated infection. Although B cells and T cells have many similarities, they recognize their targets (antigens) in different ways. The B-cell receptor (BCR), which becomes an antibody when secreted, recognizes and binds to large molecules, interacting directly with pathogens and their toxic products. The T-cell receptor (TCR), on the other hand, only recognizes foreign peptide antigens displayed on the surfaces of the body s cells. Tiny fragments of protein - peptides - are processed inside the host cell and presented on the surface of the cell in a cup-like molecule known as the major histocompatibility complex (MHC). By this process, the host cell can alert the immune system, for example to the presence of a virus, which then attracts a T cell to kill the infected cell ( Figure 1.1 ).

Figure 1.1 Comparison of T cells versus B cells and antibodies versus T-cell receptors (TCRs) (not to scale). Antibodies are produced by B cells in response to infection with pathogens, such as viruses and bacteria. These antibodies can bind to live intact pathogens through recognition of whole intact antigens - usually proteins. Once bound, antibodies earmark their targets for recognition and destruction by other immune cells. Antibodies are able to bind with many biological molecules and recognize self-antigens , making them an attractive option for the treatment of diseases such as leukemia and lymphoma. T cells, on the other hand, possess a TCR, which is a complex of proteins that interact with small peptide fragments derived from pathogens. These peptide fragments are presented to T cells in a grooved cup-like molecule called the major histocompatibility complex (MHC) for recognition by the TCR.
Recognition of self and non-self. Through the rearrangement and mutation of genes, T cells collectively produce millions of unique receptors that recognize a vast range of antigens. Each T cell produces many copies of a single but genetically unique receptor. During T-cell development in the thymus, a checking mechanism ensures that the T cells do not recognize peptides derived from the body s proteins (self-proteins). As the development of an antibody response requires T cells, this system also prevents the production of strongly self-reactive antibodies.
However, for a successful immune response against cancer, the body s own cells must be targeted and destroyed. In the anti-infection immune response, T cells recognize peptides derived from pathogens relatively quickly, as they are very different from peptides derived from self-proteins. However, as cancer cells are very similar to healthy cells, recognition and elimination are much more difficult. The development of anticancer T-cell therapies has, therefore, been immensely challenging, and these difficulties have hindered the process of identifying targets that are cancer specific and expressed on all cells of a tumor.
Nevertheless, successful antibody-based therapies have been developed against various cancers. These antibodies target the intact proteins expressed on cancer cells, commonly shared across cancer types. However, they are often not specific to cancer cells and do not generally kill cancer cells directly. Therefore, they harm healthy cells and, because of indirect killing, their potency is much lower than that of a T cell. As such, antibody treatments are rarely a cure on their own and their use is complicated by allergic reactions and the requirement for repeated doses.
Chimeric antigen receptor T cells have been developed to marry the killing power of a T cell with the antigen recognition of an antibody. They are living drugs that can replicate rapidly and persist in vivo, providing anticancer activity for months and even years after a single infusion. Despite being in the infancy of development, CAR T-cell clinical trials have already shown impressive results in patients with aggressive and advanced lymphomas and leukemias.
Structure of CAR T cells
The CAR on CAR T cells is a hybrid of the antigen-recognition region of an antibody combined with the underlying machinery of a T cell ( Figure 1.2 ). To understand the CAR, it is necessary first to understand the structure o