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Frontiers in Immunology 2020T-cells genetically engineered to express a chimeric antigen receptor (CAR) have shown remarkable results in patients with B-cell malignancies, including B-cell acute... (Review)
Review
T-cells genetically engineered to express a chimeric antigen receptor (CAR) have shown remarkable results in patients with B-cell malignancies, including B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma, with some promising efficacy in patients with multiple myeloma. However, the efficacy of CAR T-cell therapy is still hampered by local immunosuppression and significant toxicities, notably cytokine release syndrome (CRS) and neurotoxicity. The tumor microenvironment (TME) has been identified to play a major role in preventing durable responses to immunotherapy in both solid and hematologic malignancies, with this role exaggerated in solid tumors. The TME comprises a diverse set of components, including a heterogeneous population of various cells and acellular elements that collectively contribute towards the interplay of pro-immune and immunosuppressive signaling. In particular, macrophages, myeloid-derived suppressor cells, regulatory T-cells, and cell-free factors such as cytokines are major contributors to local immunosuppression in the TME of patients treated with CAR T-cells. In order to create a more favorable niche for CAR T-cell function, armored CAR T-cells and other combinatorial approaches are being explored for potential improved outcomes compared to conventional CAR T-cell products. While these strategies may potentiate CAR T-cell function and efficacy, they may paradoxically increase the risk of adverse events due to increased pro-inflammatory signaling. Herein, we discuss the mechanisms by which the TME antagonizes CAR T-cells and how innovative immunotherapy strategies are being developed to address this roadblock. Furthermore, we offer perspective on how these novel approaches may affect the risk of adverse events, in order to identify ways to overcome these barriers and expand the clinical benefits of this treatment modality in patients with diverse cancers. Precise immunomodulation to allow for improved tumor control while simultaneously mitigating the toxicities seen with current generation CAR T-cells is integral for the future application of more effective CAR T-cells against other malignancies.
Topics: Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 33643299
DOI: 10.3389/fimmu.2020.618387 -
Current Hematologic Malignancy Reports Dec 2017In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy. (Review)
Review
PURPOSE OF REVIEW
In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy.
RECENT FINDINGS
Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies. As CART19 enters routine clinical use, improving the efficacy of this exciting platform is the next step in broader application. Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells.
Topics: Gene Editing; Humans; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 29039115
DOI: 10.1007/s11899-017-0417-7 -
Virulence Nov 2016The outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) has significantly improved during the last decades. However, opportunistic infections... (Review)
Review
The outcome after allogeneic haematopoietic stem cell transplantation (allo-HSCT) has significantly improved during the last decades. However, opportunistic infections such as viral and mold infections are still a major obstacle for cure. Within this field, adoptive T cell therapy against pathogens is a promising treatment approach. Recently, the techniques to develop T cell products including pathogen-specific T cells have been sophisticated and are now available in accordance to good manufacturing practice (GMP). Here, we aim to summarize current knowledge about adoptive T cell therapy against viral and mold infections.
Topics: Aspergillosis; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Opportunistic Infections; T-Lymphocytes
PubMed: 27385102
DOI: 10.1080/21505594.2016.1207038 -
International Journal of Molecular... Jan 2022Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the... (Review)
Review
Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the well-established cancer surgery, radiotherapy and chemotherapy, immunotherapeutic strategies gain more and more attention, and some of them have already been successfully introduced into the clinic. Among these, immunotherapy based on natural killer (NK) cells is considered as one of the most promising options. In the present review, we will expose the different possibilities NK cells offer in this context, compare data about the theoretical background and mechanism(s) of action, report some results of clinical trials and identify several very recent trends. The pharmaceutical industry is quite interested in NK cell immunotherapy, which will benefit the speed of progress in the field.
Topics: Animals; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Disease Management; Disease Susceptibility; Genetic Engineering; Humans; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Prognosis; Treatment Outcome
PubMed: 35054985
DOI: 10.3390/ijms23020797 -
Journal of Cellular and Molecular... Dec 2023Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies.... (Review)
Review
Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies. In this review, we provide a narrative of PHT occurring in patients following CAR-T-cell therapy; evidence of PHT treatment strategies is also presented, with the aim of contributing to systematic understanding of PHT.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Immunotherapy; Hematologic Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 37702530
DOI: 10.1111/jcmm.17930 -
Frontiers in Immunology 2024Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune... (Review)
Review
Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.
Topics: Humans; Melanoma; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; T-Lymphocytes; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 38550594
DOI: 10.3389/fimmu.2024.1352805 -
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 -
Frontiers in Immunology 2020Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological... (Review)
Review
Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of "off the shelf" products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.
Topics: Allogeneic Cells; Allografts; Animals; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Transplantation, Homologous
PubMed: 33488631
DOI: 10.3389/fimmu.2020.618427 -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval.... (Review)
Review
Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Neoplasms; Antigens, Neoplasm; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 36761757
DOI: 10.3389/fimmu.2023.1045024 -
International Journal of Molecular... Dec 2023Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have... (Review)
Review
Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer-not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects.
Topics: Humans; T-Lymphocytes; Killer Cells, Natural; Immunotherapy; Neoplasms; Immunotherapy, Adoptive; Macrophages
PubMed: 38139461
DOI: 10.3390/ijms242417634