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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 -
Transfusion and Apheresis Science :... Oct 2023The success of genetically engineered adoptive cell therapies in haematological malignancy in the second decade of the 21st century has surprised both immunologists and... (Review)
Review
The success of genetically engineered adoptive cell therapies in haematological malignancy in the second decade of the 21st century has surprised both immunologists and oncologists. It challenges much of our understanding of the role of personalised medicine, the divide between cell products and pharmaceutical drugs and the limitations of the immune system to clear cancer. Furthermore, many challenges remain, the therapy is both expensive, hazardous and largely restricted to lymphoproliferative disease.
Topics: Humans; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Cell- and Tissue-Based Therapy; Pharmaceutical Preparations; Receptors, Antigen, T-Cell
PubMed: 37423868
DOI: 10.1016/j.transci.2023.103754 -
Medical Oncology (Northwood, London,... Dec 2023Immunotherapies using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapy have achieved successful results against several types of... (Review)
Review
Immunotherapies using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapy have achieved successful results against several types of human tumors, particularly hematological malignancies. However, their clinical results for the treatment of solid tumors remain poor and unsatisfactory. The immunosuppressive tumor microenvironment (TME) plays an important role by interfering with intratumoral T-cell infiltration, promoting effector T-cell exhaustion, upregulating inhibitory molecules, inducing hypoxia, and so on. Oncolytic viruses are an encouraging biocarrier that could be used in both natural and genetically engineered platforms to induce oncolysis in a targeted manner. Oncolytic virotherapy (OV) contributes to the reprogramming of the TME, thus synergizing the functional effects of current ICIs and CAR T-cell therapy to overcome resistant barriers in solid tumors. Here, we summarize the TME-related inhibitory factors affecting the therapeutic outcomes of ICIs and CAR T cells and discuss the potential of OV-based approaches to alleviate these barriers and improve future therapies for advanced solid tumors.
Topics: Humans; Oncolytic Viruses; Receptors, Chimeric Antigen; Tumor Microenvironment; Immunotherapy, Adoptive; Immunotherapy; Neoplasms; Oncolytic Virotherapy
PubMed: 38062315
DOI: 10.1007/s12032-023-02233-0 -
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 -
International Journal of Cancer Nov 2023The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne... (Review)
Review
The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell; Neurotoxicity Syndromes; Immunotherapy, Adoptive; Neoplasms; Hematologic Neoplasms
PubMed: 37350095
DOI: 10.1002/ijc.34635 -
Haematologica Aug 2023Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising form of adoptive T-cell immunotherapy for selected hematologic malignancies including leukemia,... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising form of adoptive T-cell immunotherapy for selected hematologic malignancies including leukemia, lymphoma and multiple myeloma. China has become the country with the largest number of registered CAR T-cell trials. Despite the remarkable clinical outcomes achieved with CAR Tcell therapy, challenges such as disease relapse, the process of manufacturing the CAR T cells and safety have limited the therapeutic efficacy of CAR T cells in hematologic malignancies. In this period of innovation, several clinical trials have reported the design of CAR directed at new targets in hematologic malignancies. In this review, we comprehensively summarize the contemporary landscape and clinical development of CAR T-cell therapy in China. In addition, we present strategies for further improving the clinical utility of CAR T-cell therapy, such as increasing the efficacy and response duration, in hematologic malignancies.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Hematologic Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 36794504
DOI: 10.3324/haematol.2022.282316 -
Biotechnology Letters Feb 2024Rapid advancements in the field of immunotherapy have significantly improved cancer treatments. Specifically, an individualized cell-based modality which involves the... (Review)
Review
Rapid advancements in the field of immunotherapy have significantly improved cancer treatments. Specifically, an individualized cell-based modality which involves the removal of some of the patient's own white blood cells, including T cells, has revolutionized research in this field. This study focuses on the recent advances and current challenges of Chimeric Antigen Receptor- T (CAR-T) cell therapy and its regulations in the United States (US) and European Union (EU). Understanding the regulatory regimes of CAR-T cell therapy is critical for researchers and manufacturers as they navigate the hurdles of bringing CAR-T cell therapy to the global market. Benefits of CAR-T cell therapy include high response rates and the potential of long-term remissions in some haematological malignancies. However, the drawbacks are still evident including high costs, adverse reactions, and limited efficacy to solid tumours. CAR-T cell therapy is rapidly advancing, with 1231 clinical trials launched globally according to www.clinicalTrial.gov . The future of CAR-T cell therapy holds enormous promise but improving its safety, effectiveness, and availability are still barriers to its successful implementation.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 38150098
DOI: 10.1007/s10529-023-03461-0 -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T therapies are being developed for acute myeloid leukemia (AML) on the basis of the results obtained for other haematological... (Review)
Review
Chimeric antigen receptor (CAR) T therapies are being developed for acute myeloid leukemia (AML) on the basis of the results obtained for other haematological malignancies and the need of new treatments for relapsed and refractory AML. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy haematopoietic stem cells (HSC). The concomitant expression of the target antigen on both tumour and HSC may lead to on-target/off-tumour toxicity. In this review, we guide researchers to design, develop, and translate to the clinic CART therapies for the treatment of AML. Specifically, we describe what issues have to be considered to design these therapies; what and assays can be used to prove their efficacy and safety; and what expertise and facilities are needed to treat and manage patients at the hospital.
Topics: Humans; T-Lymphocytes; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive; Hematopoietic Stem Cells
PubMed: 38098489
DOI: 10.3389/fimmu.2023.1260470 -
Cancer Immunology Research Sep 2023Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of...
Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T-cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilizing nonnative dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilizing the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimicked the cytokine receptor heterodimerization, with transcriptomic signatures like those obtained by activation of the native IL2 receptor. Moreover, we found that this dimerization structure was agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs coexpressed with a clinically relevant solid tumor-specific GD2-specific chimeric antigen receptor (CAR). Based on this characterization, we suggest that the coexpression of either the common β-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T-cell expansion, engraftment, and efficacy. Our results demonstrate how Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T-cell therapies, as well as therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T-cell therapies.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Cytokine; Receptors, Chimeric Antigen; Neoplasms; Cytokines
PubMed: 37352396
DOI: 10.1158/2326-6066.CIR-22-0640 -
Chinese Medical Journal Oct 2023Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell... (Review)
Review
Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Hematologic Neoplasms; Multiple Myeloma; Cell- and Tissue-Based Therapy
PubMed: 37358555
DOI: 10.1097/CM9.0000000000002549