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Indian Journal of Pharmacology 2022During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an... (Review)
Review
During present decade, targeted drug therapy has been the epitome for treatment of cancer. Drugs like Imatinib, a tyrosine kinase receptor inhibitor and Trastuzumab, an human epidermal growth factor receptor-2/neu inhibitor, has been developed and accepted widely for management of chronic myeloid leukaemia and breast cancer respectively. Recent development among the various immunotherapies is adoptive cell transfer (ACT). Research on development of various types of ACT immunotherapy is going on, but so far, Chimeric antigen receptors T cell therapy (CAR-T) has achieved the maximum advancement in terms of clinical development. CARs are the modified receptors that integrates specificity and responsiveness onto immune cells to enhance the recognition of cancer cells. For the CAR-T, the T cells are sequestered from a blood of a participant via apheresis. DNA of particular antigen is injected into harvested T cells to generate CARs on cell surface. Following surface manifestation of receptors, multiplication is carried out in enriched media followed by infusion into patient. After infusion, CAR-T cells targeted and exterminate the cancer cells. Initially, only two drugs targeting CD19 as genetically modified autologous immunotherapy has been approved in CAR-T therapy i.e., Tisagenlecleucel and Axicabtagene Ciloleucel, which are discussed in detail in current review. Recently two more drugs got approval i.e., brexucabtagene ciloleucel and lisocabtagene maraleucel, both are directed against CD19, similar to tisagenlecleucel. CAR-T cell therapy is approved for management of Acute Lymphoblastic Leukaemia, Chronic Lymphocytic Leukaemia and lymphoma. CAR-T cell persistence responsible for effectiveness and safety concerns are barriers for their wide application among patients. Growth factor receptors and cluster of differentiation are new drugs targets that are being explored as effective immunotherapy against cancers.
Topics: Antigens, CD19; Humans; Immunotherapy; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35848695
DOI: 10.4103/ijp.ijp_531_20 -
International Journal of Molecular... May 2021CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having... (Review)
Review
CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor-patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.
Topics: Animals; Antigens, Neoplasm; Cell Culture Techniques; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Engineering; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 34072732
DOI: 10.3390/ijms22115899 -
Immunity Oct 2023Synthetic immunity to cancer has been pioneered by the application of chimeric antigen receptor (CAR) engineering into autologous T cells. CAR T cell therapy is highly... (Review)
Review
Synthetic immunity to cancer has been pioneered by the application of chimeric antigen receptor (CAR) engineering into autologous T cells. CAR T cell therapy is highly amenable to molecular engineering to bypass barriers of the cancer immunity cycle, such as endogenous antigen presentation, immune priming, and natural checkpoints that constrain immune responses. Here, we review CAR T cell design and the mechanisms that drive sustained CAR T cell effector activity and anti-tumor function. We discuss engineering approaches aimed at improving anti-tumor function through a variety of mechanistic interventions for both hematologic and solid tumors. The ability to engineer T cells in such a variety of ways, including by modifying their trafficking, antigen recognition, costimulation, and addition of synthetic genes, circuits, knockouts and base edits to finely tune complex functions, is arguably the most powerful way to manipulate the cancer immunity cycle in patients.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Neoplasms; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 37820585
DOI: 10.1016/j.immuni.2023.09.010 -
Nature Dec 2022The B cell antigen receptor (BCR) is composed of a membrane-bound class M, D, G, E or A immunoglobulin for antigen recognition and a disulfide-linked Igα (also known as...
The B cell antigen receptor (BCR) is composed of a membrane-bound class M, D, G, E or A immunoglobulin for antigen recognition and a disulfide-linked Igα (also known as CD79A) and Igβ (also known as CD79B) heterodimer (Igα/β) that functions as the signalling entity through intracellular immunoreceptor tyrosine-based activation motifs (ITAMs). The organizing principle of the BCR remains unknown. Here we report cryo-electron microscopy structures of mouse full-length IgM BCR and its Fab-deleted form. At the ectodomain (ECD), the Igα/β heterodimer mainly uses Igα to associate with Cµ3 and Cµ4 domains of one heavy chain (µHC) while leaving the other heavy chain (µHC') unbound. The transmembrane domain (TMD) helices of µHC and µHC' interact with those of the Igα/β heterodimer to form a tight four-helix bundle. The asymmetry at the TMD prevents the recruitment of two Igα/β heterodimers. Notably, the connecting peptide between the ECD and TMD of µHC intervenes in between those of Igα and Igβ to guide TMD assembly through charge complementarity. Weaker but distinct density for the Igβ ITAM nestles next to the TMD, suggesting potential autoinhibition of ITAM phosphorylation. Interfacial analyses suggest that all BCR classes utilize a general organizational architecture. Our studies provide a structural platform for understanding B cell signalling and designing rational therapies against BCR-mediated diseases.
Topics: Animals; Mice; B-Lymphocytes; Cryoelectron Microscopy; Receptors, Antigen, B-Cell; Signal Transduction; Immunoglobulin Fab Fragments; Protein Domains; Phosphorylation
PubMed: 36228656
DOI: 10.1038/s41586-022-05412-7 -
Frontiers in Immunology 2023Adoptive cell therapy (ACT) has seen a steep rise of new therapeutic approaches in its immune-oncology pipeline over the last years. This is in great part due to the... (Review)
Review
Adoptive cell therapy (ACT) has seen a steep rise of new therapeutic approaches in its immune-oncology pipeline over the last years. This is in great part due to the recent approvals of chimeric antigen receptor (CAR)-T cell therapies and their remarkable efficacy in certain soluble tumors. A big focus of ACT lies on T cells and how to genetically modify them to target and kill tumor cells. Genetically modified T cells that are currently utilized are either equipped with an engineered CAR or a T cell receptor (TCR) for this purpose. Both strategies have their advantages and limitations. While CAR-T cell therapies are already used in the clinic, these therapies face challenges when it comes to the treatment of solid tumors. New designs of next-generation CAR-T cells might be able to overcome these hurdles. Moreover, CARs are restricted to surface antigens. Genetically engineered TCR-T cells targeting intracellular antigens might provide necessary qualities for the treatment of solid tumors. In this review, we will summarize the major advancements of the CAR-T and TCR-T cell technology. Moreover, we will cover ongoing clinical trials, discuss current challenges, and provide an assessment of future directions within the field.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 36949949
DOI: 10.3389/fimmu.2023.1121030 -
The New England Journal of Medicine Feb 2024
Topics: Humans; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Neoplasms, Second Primary; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 38265704
DOI: 10.1056/NEJMp2400209 -
Methods in Cell Biology 2022The generation of chimeric antigen receptor (CAR) T cells requires the transfer of the CAR gene into primary T cells. Among various gene transfer strategies,...
The generation of chimeric antigen receptor (CAR) T cells requires the transfer of the CAR gene into primary T cells. Among various gene transfer strategies, gammaretroviral vectors have been widely used to generate CAR T cells for both preclinical and clinical settings. Here we describe the detailed method of generating CAR T cells utilizing gammaretroviral vectors. This approach consists of two parallel parts: (1) production of the gammaretroviral particles and (2) gammaretroviral transduction of activated T cells. The gammaretroviral particles are produced by co-transfecting the gammaretroviral vector with packaging plasmids into 293T cells. The manufactured viral particles then efficiently infect activated T cells where the CAR transgene is integrated into host genomic DNA, resulting in stable expression of the CAR molecule on the surface of T cells.
Topics: Genetic Vectors; Plasmids; Receptors, Antigen, T-Cell; T-Lymphocytes; Transgenes
PubMed: 35152995
DOI: 10.1016/bs.mcb.2021.06.014 -
Advances in Experimental Medicine and... 2023Chimeric antigen receptor (CAR) T-cells are considered "living drugs" and offer a compelling alternative to conventional anticancer therapies. Briefly, T-cells are...
Chimeric antigen receptor (CAR) T-cells are considered "living drugs" and offer a compelling alternative to conventional anticancer therapies. Briefly, T-cells are redirected, using gene engineering technology, toward a specific cancer cell surface target antigen via a synthetic chimeric antigen receptor (CAR) protein. CARs have a modular design comprising four main structures: an antigen-binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains for T-cell activation. A major challenge in the CAR T-cell manufacturing field is balancing product quality with scalability and cost-effectiveness, especially when transitioning from an academic clinical trial into a marketed product, to be implemented across many collection, manufacturing, and treatment sites. Achieving product consistency while circumnavigating the intrinsic variability associated with autologous products is an additional barrier. To overcome these limitations, a robust understanding of the product and its biological actions is crucial to establish a target product profile with a defined list of critical quality attributes to be assessed for each batch prior to product certification. Additional challenges arise as the field progresses, such as new safety considerations associated with the use of allogenic T-cells and genome editing tools. In this chapter, we will discuss the release and potency assays required for CAR T-cell manufacturing, covering their relevance, current challenges, and future perspectives.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Neoplasms; Gene Editing; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell
PubMed: 37258787
DOI: 10.1007/978-3-031-30040-0_8 -
International Journal of Biological... 2022Breast cancer rises as the most commonly diagnosed cancer in 2020. Among women, breast cancer ranks first in both cancer incidence rate and mortality. Treatment... (Review)
Review
Breast cancer rises as the most commonly diagnosed cancer in 2020. Among women, breast cancer ranks first in both cancer incidence rate and mortality. Treatment resistance developed from the current clinical therapies limits the efficacy of therapeutic outcomes, thus new treatment approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a type of immunotherapy developed from adoptive T cell transfer, which typically uses patients' own immune cells to combat cancer. CAR-T cells are armed with specific antibodies to recognize antigens in self-tumor cells thus eliciting cytotoxic effects. In recent years, CAR-T cell therapy has achieved remarkable successes in treating hematologic malignancies; however, the therapeutic effects in solid tumors are not up to expectations including breast cancer. This review aims to discuss the development of CAR-T cell therapy in breast cancer from preclinical studies to ongoing clinical trials. Specifically, we summarize tumor-associated antigens in breast cancer, ongoing clinical trials, obstacles interfering with the therapeutic effects of CAR-T cell therapy, and discuss potential strategies to improve treatment efficacy. Overall, we hope our review provides a landscape view of recent progress for CAR-T cell therapy in breast cancer and ignites interest for further research directions.
Topics: Breast Neoplasms; Cell- and Tissue-Based Therapy; Female; Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 35414783
DOI: 10.7150/ijbs.70120 -
Proceedings of the National Academy of... Apr 2023Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can...
Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. To "benchmark" exhaustion in human Tregs, we used a method known to induce exhaustion in conventional T cells: expression of a tonic-signaling chimeric antigen receptor (TS-CAR). We found that TS-CAR-expressing Tregs rapidly acquired a phenotype that resembled exhaustion and had major changes in their transcriptome, metabolism, and epigenome. Similar to conventional T cells, TS-CAR Tregs upregulated expression of inhibitory receptors and transcription factors such as PD-1, TIM3, TOX and BLIMP1, and displayed a global increase in chromatin accessibility-enriched AP-1 family transcription factor binding sites. However, they also displayed Treg-specific changes such as high expression of 4-1BB, LAP, and GARP. DNA methylation analysis and comparison to a CD8 T cell-based multipotency index showed that Tregs naturally exist in a relatively differentiated state, with further TS-CAR-induced changes. Functionally, TS-CAR Tregs remained stable and suppressive in vitro but were nonfunctional in vivo, as tested in a model of xenogeneic graft-versus-host disease. These data are the first comprehensive investigation of exhaustion in Tregs and reveal key similarities and differences with exhausted conventional T cells. The finding that human Tregs are susceptible to chronic stimulation-driven dysfunction has important implications for the design of CAR Treg adoptive immunotherapy strategies.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes, Regulatory; T-Cell Exhaustion; Immunotherapy, Adoptive; Graft vs Host Disease; Receptors, Antigen, T-Cell
PubMed: 36972454
DOI: 10.1073/pnas.2219086120