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Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Apr 2022Chimeric antigen receptor (CAR) T cell therapy has shown significant efficacy for hematological malignancies, however, it needs to be further optimized. Recently, the... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy has shown significant efficacy for hematological malignancies, however, it needs to be further optimized. Recently, the lipid nanoparticle (LNP)-mRNA delivery system as a nonviral gene transfer vector has gained rapid progress in CAR-T cell therapy. The claudin-6 (CLDN6) mRNA is delivered to antigen presenting cells (APCs) through LNP system, thereby enhancing the function of CLDN6 CAR-T cells for the clearance of solid tumor cells. For treatment of acute cardiac injury, the fibroblast activation protein (FAP) CAR mRNA can be delivered to T cells through LNP system for the production of FAP CAR-T cells, thereby blocking the process of myocardial fibrosis. The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques. This article reviews the research advance in LNP-mRNA delivery system and its application in CAR-T cell therapy.
Topics: Cell- and Tissue-Based Therapy; Liposomes; Nanoparticles; RNA, Messenger; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 36161298
DOI: 10.3724/zdxbyxb-2022-0047 -
Frontiers in Immunology 2018Somatic assembly of T cell receptor and B cell receptor (BCR) genes produces a vast diversity of lymphocyte antigen recognition capacity. The advent of efficient... (Review)
Review
Somatic assembly of T cell receptor and B cell receptor (BCR) genes produces a vast diversity of lymphocyte antigen recognition capacity. The advent of efficient high-throughput sequencing of lymphocyte antigen receptor genes has recently generated unprecedented opportunities for exploration of adaptive immune responses. With these opportunities have come significant challenges in understanding the analysis techniques that most accurately reflect underlying biological phenomena. In this regard, sample preparation and sequence analysis techniques, which have largely been borrowed and adapted from other fields, continue to evolve. Here, we review current methods and challenges of library preparation, sequencing and statistical analysis of lymphocyte receptor repertoire studies. We discuss the general steps in the process of immune repertoire generation including sample preparation, platforms available for sequencing, processing of sequencing data, measurable features of the immune repertoire, and the statistical tools that can be used for analysis and interpretation of the data. Because BCR analysis harbors additional complexities, such as immunoglobulin (Ig) (i.e., antibody) gene somatic hypermutation and class switch recombination, the emphasis of this review is on Ig/BCR sequence analysis.
Topics: Animals; High-Throughput Nucleotide Sequencing; Humans; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Sequence Analysis, DNA
PubMed: 29593723
DOI: 10.3389/fimmu.2018.00462 -
Advances in Immunology 2023The key to mounting an immune response is that the host cells must be coordinated to generate an appropriate immune response against the pathogenic invaders. Antigen... (Review)
Review
The key to mounting an immune response is that the host cells must be coordinated to generate an appropriate immune response against the pathogenic invaders. Antigen receptors recognize specific molecular structures and recruit adaptors through their effector domains, triggering trans-membrane transduction signaling pathway to exert immune response. The T cell antigen receptor (TCR) and B cell antigen receptor (BCR) are the primary determinant of immune responses to antigens. Their structure determines the mode of signaling and signal transduction determines cell fate, leading to changes at the molecular and cellular level. Studies of antigen receptor structure and signaling revealed the basis of immune response triggering, providing clues to antigen receptor priming and a foundation for the rational design of immunotherapies. In recent years, the increased research on the structure of antigen receptors has greatly contributed to the understanding of immune response, different immune-related diseases and even tumors. In this review, we describe in detail the current view and advances of the antigen structure and signaling.
Topics: Humans; T-Lymphocytes; Lymphocyte Activation; Receptors, Antigen, T-Cell; Signal Transduction; Receptors, Antigen, B-Cell; Antigens
PubMed: 37061286
DOI: 10.1016/bs.ai.2023.01.001 -
Molecular Therapy : the Journal of the... Oct 2022Allogeneic CD19-specific chimeric antigen receptor (CAR) T cells with inactivated donor T cell receptor (TCR) expression can be used as an "off-the-shelf" therapeutic...
Allogeneic CD19-specific chimeric antigen receptor (CAR) T cells with inactivated donor T cell receptor (TCR) expression can be used as an "off-the-shelf" therapeutic modality for lymphoid malignancies, thus offering an attractive alternative to autologous, patient-derived T cells. Current approaches for T cell engineering mainly rely on the use of viral vectors. Here, we optimized and validated a non-viral genetic modification platform based on Sleeping Beauty (SB) transposons delivered with minicircles to express CD19-28z.CAR and CRISPR-Cas9 ribonucleoparticles to inactivate allogeneic TCRs. Efficient TCR gene disruption was achieved with minimal cytotoxicity and with attainment of robust and stable CD19-28z.CAR expression. The CAR T cells were responsive to CD19+ tumor cells with antitumor activities that induced complete tumor remission in NALM6 tumor-bearing mice while significantly reducing TCR alloreactivity and GvHD development. Single CAR signaling induced the similar T cell signaling signatures in TCR-disrupted CAR T cells and control CAR T cells. In contrast, TCR disruption inhibited T cell signaling/protein phosphorylation compared with the control CAR T cells during dual CAR/TCR signaling. This non-viral SB transposon-CRISPR-Cas9 combination strategy serves as an alternative for generating next-generation CD19-specific CAR T while reducing GvHD risk and easing potential manufacturing constraints intrinsic to viral vectors.
Topics: Animals; Antigens, CD19; CRISPR-Cas Systems; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Immunotherapy; Immunotherapy, Adoptive; Mice; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35711141
DOI: 10.1016/j.ymthe.2022.06.006 -
Leukemia Oct 2023Chimeric antigen receptor T (CAR-T) cell therapy has drawn increasing attention over the last few decades given its remarkable effectiveness and breakthroughs in... (Review)
Review
Chimeric antigen receptor T (CAR-T) cell therapy has drawn increasing attention over the last few decades given its remarkable effectiveness and breakthroughs in treating B cell hematological malignancies. Even though CAR-T cell therapy has outstanding clinical successes, most treated patients still relapse after infusion. CARs are derived from the T cell receptor (TCR) complex and co-stimulatory molecules associated with T cell activation; however, the similarities and differences between CARs and endogenous TCRs regarding their sensitivity, signaling pathway, killing mechanisms, and performance are still not fully understood. In this review, we discuss the parallel comparisons between CARs and TCRs from various aspects and how these current findings might provide novel insights and contribute to improvement of CAR-T cell therapy efficacy.
Topics: Humans; T-Lymphocytes; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive
PubMed: 37626090
DOI: 10.1038/s41375-023-01976-z -
Nature Methods May 2024Single-cell T cell and B cell antigen receptor-sequencing data analysis can potentially perform in-depth assessments of adaptive immune cells that inform on... (Review)
Review
Single-cell T cell and B cell antigen receptor-sequencing data analysis can potentially perform in-depth assessments of adaptive immune cells that inform on understanding immune cell development to tracking clonal expansion in disease and therapy. However, it has been extremely challenging to analyze and interpret T cells and B cells and their adaptive immune receptor repertoires at the single-cell level due to not only the complexity of the data but also the underlying biology. In this Review, we delve into the computational breakthroughs that have transformed the analysis of single-cell T cell and B cell antigen receptor-sequencing data.
Topics: Single-Cell Analysis; Humans; Receptors, Antigen, B-Cell; T-Lymphocytes; B-Lymphocytes; Receptors, Antigen, T-Cell; Animals; Computational Biology
PubMed: 38637691
DOI: 10.1038/s41592-024-02243-4 -
Cancer Research Feb 2023Chimeric antigen receptor (CAR) T-cell therapy can lead to dramatic clinical responses in B-cell malignancies. However, early clinical trials with CAR T-cell therapy in...
UNLABELLED
Chimeric antigen receptor (CAR) T-cell therapy can lead to dramatic clinical responses in B-cell malignancies. However, early clinical trials with CAR T-cell therapy in non-B-cell malignancies have been disappointing to date, suggesting that tumor-intrinsic features contribute to resistance. To investigate tumor-intrinsic modes of resistance, we performed genome scale CRISPR-Cas9 screens in mesothelin (MSLN)-expressing pancreatic cancer cells. Co-culture with MSLN-targeting CAR T cells identified both antigen-dependent and antigen-independent modes of resistance. In particular, loss of the majority of the genes involved in the pathway responsible for GPI-anchor biosynthesis and attachment abrogated the ability of CAR T cells to target pancreatic cancer cells, suggesting that disruption of this pathway may permit MSLN CAR T-cell evasion in the clinic. Antigen-independent mediators of CAR T-cell response included members of the death receptor pathway as well as genes that regulate tumor transcriptional responses, including TFAP4 and INTS12. TFAP4-mediated CAR T resistance depended on the NFκB transcription factor p65, indicating that tumor resistance to CAR T-cell therapy likely involves alterations in tumor-intrinsic states. Overall, this study uncovers multiple antigen-dependent and -independent mechanisms of CAR T-cell evasion by pancreatic cancer, paving the way for overcoming resistance in this disease that is notoriously refractory to immunotherapy.
SIGNIFICANCE
The identification and validation of key determinants of CAR T-cell response in pancreatic cancer provide insights into the landscape of tumor cell intrinsic resistance mechanisms and into approaches to improve therapeutic efficacy.
Topics: Humans; Cell Line, Tumor; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Pancreatic Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 36548402
DOI: 10.1158/0008-5472.CAN-22-2245 -
Cancer Journal (Sudbury, Mass.)The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This... (Review)
Review
The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This includes different antigen-binding domains such as antigen-ligand binding partners and variable lymphocyte receptors. Another recent advancement in CAR design is Boolean logic gates that can minimize on-target, off-tumor toxicities. Recent studies on the optimization of costimulatory signaling have also shown how CAR design can impact function. By using specific signaling pathways and transcription factors, CARs can impact T-cell gene expression to enhance function. By using these techniques, the promise of CAR T-cell therapies for solid tumors can be fulfilled.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 33750067
DOI: 10.1097/PPO.0000000000000514 -
Cells Jul 2023Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median... (Review)
Review
Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.
Topics: Humans; Receptors, Chimeric Antigen; Glioblastoma; Receptors, Antigen, T-Cell; Neoplasm Recurrence, Local; T-Lymphocytes; Tumor Microenvironment
PubMed: 37443804
DOI: 10.3390/cells12131770 -
Hematology/oncology Clinics of North... Dec 2023As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory... (Review)
Review
As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory toxicities will be vital to success. Early experiences with CD19-targeted CAR T-cell therapy identified cytokine release syndrome and neurotoxicity as key acute toxicities and led to unified initiatives to mitigate the influence of these complications. In this section, we provide an update on the current state of CAR T-cell-related toxicities, with an emphasis on emerging acute toxicities affecting additional organ systems and considerations for delayed toxicities and late effects.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; T-Lymphocytes; Neoplasms
PubMed: 37349152
DOI: 10.1016/j.hoc.2023.05.010