-
Trends in Cancer Oct 2019Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapy has had unprecedented impact in the treatment of hematological malignancies with few therapeutic options. However, it is clear that new strategies to enhance CAR-T cell function in solid tumors are needed to make these living drugs widely applicable. The roadblock in solid tumors has led to a surge in the development of strategies to enhance CAR-T cells through advanced receptor design, new tumor sensing mechanisms, coexpression of genes that improve T cell function or stimulate tumor immunity, and precise genome editing. Here we provide an overview of the current state of the art in CAR-T cell engineering and a framework for the development of next-generation immune cell therapies with synthetic biology.
Topics: Animals; Genetic Engineering; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Signal Transduction; T-Lymphocytes; Tumor Microenvironment
PubMed: 31706506
DOI: 10.1016/j.trecan.2019.09.005 -
International Journal of Laboratory... Aug 2023Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive T-cell immunotherapy for haematological malignancies. First introduced into clinical practice in 2017,... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive T-cell immunotherapy for haematological malignancies. First introduced into clinical practice in 2017, CAR T-cell therapy is now finding its place in the management of lymphoid malignancies, primarily of B-cell lineage, including lymphoblastic leukaemia, non-Hodgkin lymphoma and plasma cell myeloma, with remarkable therapeutic outcomes. CAR T-cells are a customised therapeutic product for each patient. Manufacture commences with collection of autologous T-cells, which are then genetically engineered ex vivo to express transmembrane CARs. These chimeric proteins consist of an antibody-like extracellular antigen-binding domain, to recognise specific antigens on the surface of tumour cells (e.g. CD19), linked to the intracellular co-stimulatory signalling domains of a T-cell receptor (e.g. CD137). The latter is required for in vivo CAR T-cell proliferation, survival, and durable efficacy. Following reinfusion, CAR T-cells harness the cytotoxic capacity of a patient's immune system. They overcome major mechanisms of tumour immuno-evasion and have potential to generate robust cytotoxic anti-tumour responses. This review discusses the background to CAR T-cell therapies, including their molecular design, mechanisms of action, methods of production, clinical applications and established and emerging technologies for CAR T-cell evaluation. It highlights the need for standardisation, quality control and monitoring of CAR T-cell therapies, to ensure their safety and efficacy in clinical management.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; T-Lymphocytes; Multiple Myeloma; Antineoplastic Agents; Quality Control
PubMed: 37337970
DOI: 10.1111/ijlh.14121 -
Cancer Control : Journal of the Moffitt... 2024Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a... (Review)
Review
Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a patient's T cells are programmed to act against tumor cells. We discuss the process of manufacturing CAR-T cells, the common side effects of therapy, and the recent emerging risk of T-cell malignancies after treatment.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Hematologic Neoplasms; Receptors, Antigen, T-Cell
PubMed: 38910268
DOI: 10.1177/10732748241263713 -
Zoological Research Mar 2022Chimeric antigen receptor T cells (CAR-T cells) are engineered recombinant T cells, which were initially used to treat hematopoietic malignancies and are now widely used... (Review)
Review
Chimeric antigen receptor T cells (CAR-T cells) are engineered recombinant T cells, which were initially used to treat hematopoietic malignancies and are now widely used in the treatment of various diseases. Considering their intrinsic targeting efficiency, CAR-T cells show considerable potential in the treatment of autoimmune diseases. Furthermore, regulatory T cells (Treg), a subset of CD4 T cells exhibiting immunosuppressive functions, have attracted increasing attention regarding CAR-Treg cell production. In this review, we report on recent developments in preclinical and clinical studies on CAR-T cells in autoimmune diseases and provide an outlook on opportunities and challenges of CAR-T application in such diseases.
Topics: Autoimmune Diseases; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35008131
DOI: 10.24272/j.issn.2095-8137.2021.363 -
Trends in Immunology Jan 2024In the quest for more precise and effective organ transplantation therapies, chimeric antigen receptor (CAR) regulatory T cell (T) therapies represent a potential... (Review)
Review
In the quest for more precise and effective organ transplantation therapies, chimeric antigen receptor (CAR) regulatory T cell (T) therapies represent a potential cutting-edge advance. This review comprehensively analyses CAR T and how they may address important drawbacks of polyclonal T and conventional immunosuppressants. We examine a growing body of preclinical findings of CAR T therapy in transplantation, discuss CAR T design specifics, and explore established and attractive new targets in transplantation. In addition, we explore present impediments where future studies will be necessary to determine the efficacy of CAR T in reshaping alloimmune responses and transplant microenvironments to reduce reliance on chemical immunosuppressants. Overall, ongoing studies and trials are crucial for understanding the full scope of CAR T therapy in transplantation.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Organ Transplantation; Immunosuppressive Agents; T-Lymphocytes, Regulatory; Receptors, Antigen, T-Cell
PubMed: 38123369
DOI: 10.1016/j.it.2023.11.005 -
Transfusion and Apheresis Science :... Dec 2023Chimeric antigen receptor (CAR) T-cell therapy is an effective, individualized immunotherapy, and novel treatment for hematologic malignancies. Six commercial CAR-T cell... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is an effective, individualized immunotherapy, and novel treatment for hematologic malignancies. Six commercial CAR-T cell products are currently approved for lymphatic malignancies and multiple myeloma. In addition, an increasing number of clinical centres produce CAR-T cells on-site, which enable the administration of CAR-T cells on site. The CAR-T cell products are either fresh or cryopreserved. Manufacturing CAR-T cells is a complicated process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is crucial step for a successful CAR-T cell therapy; therefore, it is imperative to understand the factors that may affect the quality or T cells. The leukapheresis for CAR-T cell production is well tolerated and safe for both paediatric and adult patients and CAR-Τ cell therapy presents high clinical response rate in many studies. CAR-T cell therapy is under continuous improvement, and it has transformed into an almost standard procedure in clinical haematology and stem cell transplantation facilities that provide both autologous and allogeneic stem cell transplantations. In patients suffering from advanced haematological malignancies, CAR-T cell therapy shows incredible antitumor efficacy. Even after a single infusion of autologous CD19-targeting CAR-T cells in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL), long lasting remission is observed, and a fraction of the patients are being cured. Future novel constructs are being developed with better T cell persistence and better expansion. New next-generation CAR-T cells are currently designed to avoid toxicities such as cytokine release syndrome and neurotoxicity.
Topics: Adult; Humans; Child; T-Lymphocytes; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Leukapheresis; Immunotherapy, Adoptive; Hematologic Neoplasms
PubMed: 37838564
DOI: 10.1016/j.transci.2023.103828 -
Immunological Reviews Nov 2023Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the... (Review)
Review
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on-target off-tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neoplasms; Immunotherapy, Adoptive; Killer Cells, Natural; Antigens, Neoplasm
PubMed: 37548050
DOI: 10.1111/imr.13255 -
Expert Review of Clinical Immunology 2023Chimeric antigen receptor (CAR) T-cell is among the most prevalent approaches that act by directing T-cells toward cancer; however, they need to be optimized to minimize... (Review)
Review
INTRODUCTION
Chimeric antigen receptor (CAR) T-cell is among the most prevalent approaches that act by directing T-cells toward cancer; however, they need to be optimized to minimize side effects and maximize efficacy before being used as standard treatment for malignancies. Neurotoxicity associated with CAR T-cell therapy has been well-documented in recent works.
AREAS COVERED
In this regard, two established syndromes exist. Immune effector cell-associated neurotoxicity syndrome (ICANS), previously called cytokine release encephalopathy syndrome (CRES), is a neuropsychiatric condition which can occur after therapy by immune effector cells (IEC) and T-lymphocytes utilizing treatments. Another syndrome is cytokine release syndrome (CRS), which may overlap with ICANS.
EXPERT OPINION
ICANS clinical manifestations include cerebral edema, mild lethargy, aphasia, and seizures. Notably, ICANS is associated with changes to EEG and neuroradiological findings. Therefore, it is necessary to make a timely and accurate diagnosis of neurological complications of CAR T-cells by clinical presentations, neuroimaging, and EEG. Since neurological events by different CAR T-cell products are heterogeneous, guides should be developed according to each product. Here, we provide an updated review of general information on CAR T-cell therapies and applications, neurological syndromes associated with their use, and risk factors contributing to ICANS.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Neurotoxicity Syndromes; Cytokine Release Syndrome; Cell- and Tissue-Based Therapy; Receptors, Antigen, T-Cell
PubMed: 37578341
DOI: 10.1080/1744666X.2023.2248390 -
Frontiers in Immunology 2023The recently determined cryo-EM structures of the T cell antigen receptor (TCR) and B cell antigen receptor (BCR) show in molecular details the interactions of the...
The recently determined cryo-EM structures of the T cell antigen receptor (TCR) and B cell antigen receptor (BCR) show in molecular details the interactions of the ligand-binding part with the signaling subunits but they do not reveal the signaling mechanism of these antigen receptors. Without knowing the molecular basis of antigen sensing by these receptors, a rational design of optimal vaccines is not possible. The existence of conserved amino acids (AAs) that are not involved in the subunit interaction suggests that antigen receptors form higher complexes and/or have lateral interactors that control their activity. Here, I describe evolutionary conserved leucine zipper (LZ) motifs within the transmembrane domains (TMD) of antigen and coreceptor components that are likely to be involved in the oligomerization and lateral interaction of antigen receptor complexes on T and B cells. These immunoreceptor coupling and organization motifs (ICOMs) are also found within the TMDs of other important receptor types and viral envelope proteins. This discovery suggests that antigen receptors do not function as isolated entities but rather as part of an ICOM-based interactome that controls their nanoscale organization on resting cells and their dynamic remodeling on activated lymphocytes.
Topics: Receptors, Antigen, B-Cell; Amino Acids; B-Lymphocytes; Biological Evolution; Leucine Zippers
PubMed: 37731510
DOI: 10.3389/fimmu.2023.1253412 -
Current Oncology (Toronto, Ont.) May 2023Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6... (Review)
Review
Chimeric Antigen Receptor T (CAR-T) cell therapy has dramatically changed prognosis and treatment of relapsed and refractory hematologic malignancies. Currently the 6 FDA approved products target various surface antigens. While CAR-T therapy achieves good response, life-threatening toxicities have been reported. Mechanistically, can be divided into two categories: (1) toxicities related to T-cell activation and release of high levels of cytokines: or (2) toxicities resulting from interaction between CAR and CAR targeted antigen expressed on non-malignant cells (i.e., on-target, off-tumor effects). Variations in conditioning therapies, co-stimulatory domains, CAR T-cell dose and anti-cytokine administration, pose a challenge in distinguishing cytokine mediated related toxicities from on-target, off-tumor toxicities. Timing, frequency, severity, as well as optimal management of CAR T-cell-related toxicities vary significantly between products and are likely to change as newer therapies become available. Currently the FDA approved CARs are targeted towards the B-cell malignancies however the future holds promise of expanding the target to solid tumor malignancies. Further highlighting the importance of early recognition and intervention for early and late onset CAR-T related toxicity. This contemporary review aims to describe presentation, grading and management of commonly encountered toxicities, short- and long-term complications, discuss preventive strategies and resource utilization.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; T-Lymphocytes; Treatment Outcome; Neoplasms
PubMed: 37232836
DOI: 10.3390/curroncol30050378