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Advanced Science (Weinheim,... Dec 2023Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a highly efficacious treatment modality for refractory and relapsed hematopoietic malignancies in recent... (Review)
Review
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a highly efficacious treatment modality for refractory and relapsed hematopoietic malignancies in recent years. Furthermore, CAR technologies for cancer immunotherapy have expanded from CAR-T to CAR-natural killer cell (CAR-NK), CAR-cytokine-induced killer cell (CAR-CIK), and CAR-macrophage (CAR-MΦ) therapy. Nevertheless, the high cost and complex manufacturing processes of ex vivo generation of autologous CAR products have hampered broader application. There is an urgent need to develop an efficient and economical paradigm shift for exploring new sourcing strategies and engineering approaches toward generating CAR-engineered immune cells to benefit cancer patients. Currently, researchers are actively investigating various strategies to optimize the preparation and sourcing of these potent immunotherapeutic agents. In this work, the latest research progress is summarized. Perspectives on the future of CAR-engineered immune cell manufacturing are provided, and the engineering approaches, and diverse sources used for their development are focused upon.
Topics: Humans; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Killer Cells, Natural; Immunotherapy, Adoptive
PubMed: 37906032
DOI: 10.1002/advs.202303215 -
Trends in Immunology Jan 2024In the quest for more precise and effective organ transplantation therapies, chimeric antigen receptor (CAR) regulatory T cell (T) therapies represent a potential... (Review)
Review
In the quest for more precise and effective organ transplantation therapies, chimeric antigen receptor (CAR) regulatory T cell (T) therapies represent a potential cutting-edge advance. This review comprehensively analyses CAR T and how they may address important drawbacks of polyclonal T and conventional immunosuppressants. We examine a growing body of preclinical findings of CAR T therapy in transplantation, discuss CAR T design specifics, and explore established and attractive new targets in transplantation. In addition, we explore present impediments where future studies will be necessary to determine the efficacy of CAR T in reshaping alloimmune responses and transplant microenvironments to reduce reliance on chemical immunosuppressants. Overall, ongoing studies and trials are crucial for understanding the full scope of CAR T therapy in transplantation.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Organ Transplantation; Immunosuppressive Agents; T-Lymphocytes, Regulatory; Receptors, Antigen, T-Cell
PubMed: 38123369
DOI: 10.1016/j.it.2023.11.005 -
Medical Oncology (Northwood, London,... Oct 2023Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their... (Review)
Review
Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Neoplasms; Immunotherapy, Adoptive; Immunotherapy; T-Lymphocytes; Tumor Microenvironment
PubMed: 37779152
DOI: 10.1007/s12032-023-02191-7 -
Blood Mar 2024Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor...
Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.
Topics: Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; T-Lymphocytes; Chronic Disease; Lymphoma, T-Cell; Antigens, CD19
PubMed: 38145560
DOI: 10.1182/blood.2023022204 -
Nature Biotechnology Dec 2023Chimeric antigen receptor (CAR) T cells are changing the therapeutic landscape for hematological malignancies. To date, all six CAR T cell products approved by the US... (Review)
Review
Chimeric antigen receptor (CAR) T cells are changing the therapeutic landscape for hematological malignancies. To date, all six CAR T cell products approved by the US Food and Drug Administration (FDA) are autologous and centrally manufactured. As the numbers of approved products and indications continue to grow, new strategies to increase cell-manufacturing capacity are urgently needed to ensure patient access. Distributed manufacturing at the point of care or at other local manufacturing sites would go a long way toward meeting the rising demand. To ensure successful implementation, it is imperative to harness novel technologies to achieve uniform product quality across geographically dispersed facilities. This includes the use of automated cell-production systems, in-line sensors and process simulation for enhanced quality control and efficient supply chain management. A comprehensive effort to understand the critical quality attributes of CAR T cells would enable better definition of widely attainable release criteria. To supplement oversight by national regulatory agencies, we recommend expansion of the role of accreditation bodies. Moreover, regulatory standards may need to be amended to accommodate the unique characteristics of distributed manufacturing models.
Topics: Humans; Immunotherapy, Adoptive; Hematologic Neoplasms
PubMed: 37884746
DOI: 10.1038/s41587-023-01981-8 -
Viruses Jul 2023This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics... (Review)
Review
This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics and vaccines, plasma immunoglobulin therapy from whole blood donation can still play a key role. These treatments provide passive transfer of high-titer antibodies that either reduces the risk or the severity of the infection and offer immediate but short-term protection against specific diseases. Antibody preparations derived from immunized human donors are commonly used for the prophylaxis and treatment of rabies, hepatitis A and B viruses, varicella-zoster virus, and pneumonia caused by respiratory syncytial virus, , . The use of hyperimmune globulin therapy is a promising challenge, especially for the treatment of emerging viral infections for which there are no specific therapies or licensed vaccines.
Topics: Humans; Immunoglobulins; Globulins; Immunization, Passive; Vaccines; Communicable Diseases; Antibodies, Viral
PubMed: 37515229
DOI: 10.3390/v15071543 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Trends in Molecular Medicine Aug 2023Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past... (Review)
Review
Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past decade, cell-based immunomodulation therapies saw clinical success in the treatment of cancer and autoimmune diseases. In this review, we describe recent advances in engineering solutions for the development of localized immunomodulation techniques focusing on cellular and organoid transplantation. We begin by describing cell transplantation and highlighting notable clinical successes, particularly in the areas of stem cell therapy, chimeric antigen receptor (CAR)-T cell therapy, and islet transplantation. Next, we detail recent preclinical studies centered on genome editing and biomaterials to enhance localized immunomodulation. We close by discussing future opportunities to improve clinical and commercial success using these approaches to facilitate long-term immunomodulation technologies.
Topics: Humans; Immunomodulation; Immunotherapy, Adoptive; Gene Editing; Organoids; Stem Cell Transplantation
PubMed: 37301656
DOI: 10.1016/j.molmed.2023.05.008 -
Biomedicine & Pharmacotherapy =... Dec 2023The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell... (Review)
Review
The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell products have been granted marketing authorization. All of these approved products are generated from autologous sources, but this strategy faces several challenges such as time-consuming and expensive manufacturing process and reduced anti-tumor potency of patients' T cells due to the disease or previous therapies. The use of an allogeneic source can overcome these issues and provide an industrial, scalable, and standardized manufacturing process that reduces costs and provides faster treatment for patients. Nevertheless, for using allogeneic CAR-T cells, we are faced with the challenge of overcoming two formidable impediments: severe life-threatening graft-versus-host-disease (GvHD) caused by allogeneic CAR-T cells, and allorejection of allogeneic CAR-T cells by host immune cells which is called "host versus graft" (HvG). In this study, we reviewed recent registered clinical trials of allogeneic CAR-T cell therapy to analyze different approaches to achieve a safe and efficacious "off-the-shelf" source for chimeric antigen receptor (CAR) based immunotherapy.
Topics: Humans; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Clinical Trials as Topic
PubMed: 37979380
DOI: 10.1016/j.biopha.2023.115888 -
Advances in Experimental Medicine and... 2024The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were... (Review)
Review
The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins.
Topics: Smallpox; Humans; Antiviral Agents; Smallpox Vaccine; Mpox (monkeypox); Vaccination; Variola virus; Animals; Cytosine; Monkeypox virus; Immunization, Passive; Organophosphonates; Isoindoles; Cidofovir; Immunoglobulins, Intravenous; Benzamides; Phthalimides
PubMed: 38801586
DOI: 10.1007/978-3-031-57165-7_19