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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 -
International Journal of Molecular... Apr 2019The generation of immune cells from human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) has been of keen interest to regenerative... (Review)
Review
The generation of immune cells from human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) has been of keen interest to regenerative medicine. Pluripotent stem cell-derived immune cells such as natural killer cells, macrophages, and lymphoid cells, especially T cells, can be used in immune cell therapy to treat incurable cancers. Moreover, since the advent of chimeric antigen receptor (CAR) technology, the success of CAR-T cells in the clinic has galvanized new efforts to harness the power of CAR technology to generate CAR-engineered immune cells from pluripotent stem cells. This review provides a summary of pluripotent stem cell-derived immune cells and CAR technology, together with perspectives on combining pluripotent stem-cell derived immune cells and CAR engineering to pave a new way for developing next generation immune cell therapy.
Topics: Animals; Cell Differentiation; Humans; Immunotherapy; Killer Cells, Natural; Pluripotent Stem Cells; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Stem Cell Transplantation; Stem Cells; T-Lymphocytes
PubMed: 31013813
DOI: 10.3390/ijms20081825 -
Cells May 2021Shark is a cartilaginous fish that produces new antigen receptor (IgNAR) antibodies. This antibody is identified with a similar human heavy chain but dissimilar... (Review)
Review
Shark is a cartilaginous fish that produces new antigen receptor (IgNAR) antibodies. This antibody is identified with a similar human heavy chain but dissimilar sequences. The variable domain (VNAR) of IgNAR is stable and small in size, these features are desirable for drug discovery. Previous study results revealed the effectiveness of VNAR as a single molecule or a combination molecule to treat diseases both in vivo and in vitro with promising clinical applications. We showed the first evidence of IgNAR alternative splicing from spotted bamboo shark (), broadening our understanding of the IgNARs characteristics. In this review, we summarize the discoveries on IgNAR with a focus on its advantages for therapeutic development based on its peculiar biochemistry and molecular structure. Proper applications of IgNAR will provide a novel avenue to understand its special presence in cartilaginous fishes as well as designing a number of drugs for undefeated diseases.
Topics: Animals; Antibodies; Fish Proteins; Receptors, Antigen; Sharks
PubMed: 34066890
DOI: 10.3390/cells10051140 -
Translational Research : the Journal of... Sep 2017Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte... (Review)
Review
Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells.
Topics: Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Receptors, Antigen; Recombinant Fusion Proteins; T-Lymphocytes
PubMed: 28651074
DOI: 10.1016/j.trsl.2017.06.003 -
International Journal of Biological... Mar 2020Conventional monoclonal antibodies (mAbs) have been widely used in research and diagnostic applications due to their high affinity and specificity. However, multiple... (Review)
Review
Conventional monoclonal antibodies (mAbs) have been widely used in research and diagnostic applications due to their high affinity and specificity. However, multiple limitations, such as large size, complex structure and sensitivity to extreme ambient temperature potentially weaken the performance of mAbs in certain applications. To address this problem, the exploration of new antigen binders is extensively required in relation to improve the quality of current diagnostic platforms. In recent years, a new immunoglobulin-based protein, namely variable domain of new antigen receptor (VNAR) was discovered in sharks. Unlike conventional mAbs, several advantages of VNARs, include small size, better thermostability and peculiar paratope structure have attracted interest of researchers to further explore on it. This article aims to first present an overview of the shark VNARs and outline the characteristics as an outstanding new reagent for diagnostic and therapeutic applications.
Topics: Animals; Antibodies, Monoclonal; Fish Proteins; Receptors, Antigen; Sharks; Single-Chain Antibodies
PubMed: 31926922
DOI: 10.1016/j.ijbiomac.2020.01.039 -
American Society of Clinical Oncology... Jan 2019Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although... (Review)
Review
Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%-40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.
Topics: Antigens, CD19; Antigens, Neoplasm; Combined Modality Therapy; Disease Progression; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Neoplasm Grading; Neoplasm Staging; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome
PubMed: 31099671
DOI: 10.1200/EDBK_238693 -
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 -
Journal of Immunology (Baltimore, Md. :... Oct 2010Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the... (Review)
Review
Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the importance of this process and the precise molecular mechanisms by which it is achieved have remained enigmatic. This brief review summarizes current knowledge of the extent to which Ig and TCR loci are subject to allelic exclusion. Recent progress in studying and defining mechanistic steps and molecules that may control the monoallelic initiation and subsequent inhibition of V-to-(D)-J recombination is outlined using the mouse TCRβ locus as a model with frequent comparisons to the mouse IgH and Igκ loci. Potential consequences of defects in mechanisms that control Ag receptor allelic exclusion and a reappraisal of the physiologic relevance of this immunologic process also are discussed.
Topics: Alleles; Animals; Autoimmunity; Mice; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Recombination, Genetic; Self Tolerance
PubMed: 20858891
DOI: 10.4049/jimmunol.1001158 -
Human Vaccines & Immunotherapeutics Aug 2023Recently, the remarkable success of chimeric antigen receptor T cell (CAR-T) therapy in treating certain tumors has led to numerous studies exploring its potential... (Review)
Review
Recently, the remarkable success of chimeric antigen receptor T cell (CAR-T) therapy in treating certain tumors has led to numerous studies exploring its potential application to treat non-oncology diseases. This review discusses the progress and evolution of CAR-T cell therapies for treating non-oncology diseases over the past 5 years. Additionally, we summarize the advantages and disadvantages of CAR-T cell therapy in treating non-oncological diseases and identify any difficulties that should be overcome. After conducting an in-depth analysis of the most recent studies on CAR-T technology, we discuss the key elements of CAR-T therapy, such as developing an effective CAR design for non-oncological diseases, controlling the rate and duration of response, and implementing safety measures to reduce toxicity. These studies provide new insights into different delivery strategies, the discovery of new target molecules, and improvements in the safety of CAR-T therapy for non-oncological diseases.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes, Regulatory; Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Cell- and Tissue-Based Therapy
PubMed: 37814513
DOI: 10.1080/21645515.2023.2251839