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1.
Stem Cell Res Ther ; 12(1): 578, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34801084

RESUMO

BACKGROUND: Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy. METHODS: We conducted a systematic review and meta-analysis of all available preclinical and clinical studies, with assessment of their quality and risk of bias. RESULTS: A total of 20 articles using diverse cell types were selected for analysis, including six clinical trials and 14 pre-clinical studies in three species. The meta-analysis showed a positive effect of cell-based therapies on relevant disease outcomes (quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis). No significant publication bias was observed. CONCLUSION: Cell-based therapies have the potential to improve secondary lymphedema. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.


Assuntos
Linfedema , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Humanos , Linfedema/etiologia , Linfedema/terapia
2.
Front Immunol ; 12: 664244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841448

RESUMO

A number of immune regulatory cellular therapies, including regulatory T cells and mesenchymal stromal cells, have emerged as novel alternative therapies for the control of transplant alloresponses. Clinical studies have demonstrated their feasibility and safety, however developing our understanding of the impact of cellular therapeutics in vivo requires advanced immune monitoring strategies. To accurately monitor the immune response, a combination of complementary methods is required to measure the cellular and molecular phenotype as well as the function of cells involved. In this review we focus on the current immune monitoring strategies and discuss which methods may be utilized in the future.


Assuntos
Transplante de Células , Terapia Baseada em Transplante de Células e Tecidos , Ensaios Clínicos como Assunto , Monitorização Imunológica/métodos , Animais , Transplante de Células/efeitos adversos , Transplante de Células/métodos , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/normas , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto/normas , Gerenciamento Clínico , Humanos , Monitorização Imunológica/normas , Especificidade de Órgãos , Resultado do Tratamento
3.
Cancer Discov ; 11(3): 560-574, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33563662

RESUMO

Adoptive cell therapy (ACT) for cancer shows tremendous potential; however, several challenges preclude its widespread use. These include poor T-cell function in hostile tumor microenvironments, a lack of tumor-specific target antigens, and the high cost and poor scalability of cell therapy manufacturing. Creative genome-editing strategies are beginning to emerge to address each of these limitations, which has initiated the next generation of cell therapy products now entering clinical trials. CRISPR is at the forefront of this revolution, offering a simple and versatile platform for genetic engineering. This review provides a comprehensive overview of CRISPR applications that have advanced ACT. SIGNIFICANCE: The clinical impact of ACT for cancer can be expanded by implementing specific genetic modifications that enhance the potency, safety, and scalability of cellular products. Here we provide a detailed description of such genetic modifications, highlighting avenues to enhance the therapeutic efficacy and accessibility of ACT for cancer. Furthermore, we review high-throughput CRISPR genetic screens that have unveiled novel targets for cell therapy enhancement.


Assuntos
Sistemas CRISPR-Cas , Terapia Baseada em Transplante de Células e Tecidos/métodos , Edição de Genes/métodos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Terapia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
4.
Stem Cell Res Ther ; 9(1): 19, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29386049

RESUMO

BACKGROUND: The underlying pathophysiology in intellectual disability (ID) involves abnormalities in dendritic branching and connectivity of the neuronal network. This limits the ability of the brain to process information. Conceptually, cellular therapy through its neurorestorative and neuroregenerative properties can counteract these pathogenetic mechanisms and improve neuronal connectivity. This improved networking should exhibit as clinical efficacy in patients with ID. METHODS: To assess the safety and efficacy of cellular therapy in patients with ID, we conducted an open-label proof-of-concept study from October 2011 to December 2015. Patients were divided into two groups: intervention group (n = 29) and rehabilitation group (n = 29). The intervention group underwent cellular transplantation consisting of intrathecal administration of autologous bone marrow mononuclear cells and standard neurorehabilitation. The rehabilitation group underwent only standard neurorehabilitation. The results of the symptomatic outcomes were compared between the two groups. In the intervention group analysis, the outcome measures used were the intelligence quotient (IQ) and the Wee Functional Independence Measure (Wee-FIM). To compare the pre-intervention and post-intervention results, statistical analysis was done using Wilcoxon's matched-pairs test for Wee-FIM scores and McNemar's test for symptomatic improvements and IQ. The effect of age and severity of the disorder were assessed for their impact on the outcome of intervention. Positron emission tomography-computed tomography (PET-CT) brain scan was used as a monitoring tool to study effects of the intervention. Adverse events were monitored for the safety of cellular therapy. RESULTS: On symptomatic analysis, greater improvements were seen in the intervention group as compared to the rehabilitation group. In the intervention group, the symptomatic improvements, IQ and Wee-FIM were statistically significant. A significantly better outcome of the intervention was found in the paediatric age group (<18 years) and patients with milder severity of ID. Repeat PET-CT scan in three patients of the intervention group showed improved metabolism in the frontal, parietal cortex, thalamus, mesial temporal structures and cerebellum. No major adverse events were witnessed. CONCLUSIONS: Cellular transplantation with neurorehabilitation is safe and effective for the treatment of underlying brain deficits in ID. TRIAL REGISTRATION: ClinicalTrials.gov NCT02245724. Registered 12 September 2014.


Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Deficiência Intelectual/reabilitação , Deficiência Intelectual/terapia , Monócitos/transplante , Adolescente , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Cerebelo/fisiologia , Feminino , Humanos , Inteligência/fisiologia , Testes de Inteligência , Masculino , Lobo Parietal/fisiologia , Estudo de Prova de Conceito , Tálamo/fisiologia , Transplante Autólogo/métodos , Resultado do Tratamento
5.
J Autoimmun ; 71: 78-87, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27133597

RESUMO

Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4(+)CD127(lo/-)CD25(+) cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/terapia , Imunoterapia Adotiva , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Ensaios Clínicos Fase I como Assunto , Terapia Combinada , Diabetes Mellitus Tipo 1/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
6.
Artigo em Alemão | MEDLINE | ID: mdl-26431722

RESUMO

For the development of medicinal products animal models are still indispensable to demonstrate efficacy and safety prior to first use in humans. Advanced therapy medicinal products (ATMP), which include cell-based medicinal products (CBMP), differ in their pharmacology and toxicology compared to conventional pharmaceuticals, and thus, require an adapted regime for non-clinical development. Developers are, therefore, challenged to develop particular individual concepts and to reconcile these with regulatory agencies. Guidelines issued by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other sources can provide direction.The published approaches for non-clinical testing of efficacy document that homologous animal models where the therapeutic effect is investigated in a disease-relevant animal model utilizing cells derived from the same species are commonly used. The challenge is that the selected model should reflect the human disease in all critical features and that the cells should be comparable to the investigated human medicinal product in terms of quality and biological activity. This is not achievable in all cases. In these cases, alternative methods may provide supplemental information. To demonstrate the scientific proof-of-concept (PoC), small animal models such as mice or rats are preferred. During the subsequent product development phase, large animal models (i.e. sheep, minipigs, dogs) must be considered, as they may better reflect the anatomical or physiological situation in humans. In addition to efficacy, those models may also be suitable to prove some safety aspects of ATMP (e.g. regarding dose finding, local tolerance, or undesired interactions and effects of the administered cells in the target tissue). In contrast, for evaluation of the two prominent endpoints for characterizing the safety of ATMP (i.e. biodistribution, tumorigenicity) heterologous small animal models, especially immunodeficient mouse strains, are favourable due to their tolerance to the human cell therapy product. The execution of non-clinical studies under the principles of good laboratory practice (GLP) increases the acceptance of the results by authorities and the scientific community.


Assuntos
Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Modelos Animais , Academias e Institutos , Alternativas ao Uso de Animais/legislação & jurisprudência , Alternativas ao Uso de Animais/métodos , Animais , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Alemanha , Humanos
7.
Rev Neurol (Paris) ; 170(12): 779-98, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25459115

RESUMO

Stroke is the second leading cause of death worldwide and the most common cause of severe disability. Neuroprotection and repair mechanisms supporting endogenous brain plasticity are often insufficient to allow complete recovery. While numerous neuroprotective drugs trials have failed to demonstrate benefits for patients, they have provided interesting translational research lessons related to neurorestorative therapy mechanisms in stroke. Stroke damage is not limited to neurons but involve all brain cell type including the extracellular matrix in a "glio-neurovascular niche". Targeting a range of host brain cells, biotherapies such as growth factors and therapeutic cells, currently hold great promise as a regenerative medical strategy for stroke. These techniques can promote both neuroprotection and delayed neural repair through neuro-synaptogenesis, angiogenesis, oligodendrogliogenesis, axonal sprouting and immunomodulatory effects. Their complex mechanisms of action are interdependent and vary according to the particular growth factor or grafted cell type. For example, while "peripheral" stem or stromal cells can provide paracrine trophic support, neural stem/progenitor cells (NSC) or mature neurons can act as more direct neural replacements. With a wide therapeutic time window after stroke, biotherapies could be used to treat many patients. However, guidelines for selecting the optimal time window, and the best delivery routes and doses are still debated and the answers may depend on the chosen product and its expected mechanism including early neuroprotection, delayed neural repair, trophic systemic transient effects or graft survival and integration. Currently, the great variety of growth factors, cell sources and cell therapy products form a therapeutic arsenal that is available for stroke treatment. Their effective clinical use will require prior careful considerations regarding safety (e.g. tumorgenicity, immunogenicity), potential efficacy, cell characterization, delivery route and in vivo biodistribution. Bone marrow-derived cell populations such as mesenchymal stromal/stem cells (MSC) or mononuclear cells (MNC), umbilical cord stem cells and NSC are most investigated notably in clinical trials. Finally, we discuss perspectives concerning potential novel biotherapies such as combinatorial approaches (growth factor combined with cell therapy, in vitro optimization of cell products, or co-transplantation) and the development of biomaterials, which could be used as injectable hydrogel scaffold matrices that could protect a cell graft or selectively deliver drugs and growth factors into the post-stroke cavity at chronic stages. Considering the remaining questions about the best procedure and the safety cautions, we can hope that future translational research about biotherapies will bring more efficient treatments that will decrease post-stroke disability for many patients.


Assuntos
Terapia Biológica/métodos , Acidente Vascular Cerebral/terapia , Animais , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Células-Tronco Neurais/citologia , Células-Tronco Neurais/transplante , Fármacos Neuroprotetores/uso terapêutico , Transplante de Células-Tronco/efeitos adversos , Células-Tronco/citologia , Pesquisa Translacional Biomédica
10.
Fortschr Med ; 112(18): 257-60, 1994 Jun 30.
Artigo em Alemão | MEDLINE | ID: mdl-8088689

RESUMO

The risks of cell therapy as seen by the microbiologist and virologist, are not calculable. Numerous viruses with longterm persistence in the host cells, cannot be detected on the basis of an acute disease in the host. This applies, for example to herpesviruses, lentiviruses, retroviruses, hepatitis C virus, Borna disease virus and the so-called unconventional viruses. There are two reasons why testing of the donor animal ist not possible, the first being the great number of potential pathogens, the second being the fact that for some of these agents there are no signs of a diagnostic approach involving isolation or antibody detection. e.g. scrapie (BSE). Further, so far unknown viruses must be expected.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapias Complementares , Viroses/transmissão , Animais , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Humanos , Fatores de Risco , Latência Viral
11.
Fortschr Med ; 112(18): 261-5, 1994 Jun 30.
Artigo em Alemão | MEDLINE | ID: mdl-8088690

RESUMO

Parenteral administration of fresh cells, frozen cells (snapfrozen cell suspensions) or lyophilized cells (sicca cells), is known as cellular or cell therapy. While the German Health Office (BGA) provisionally banned the use of dried cell preparations in 1987, injection of fresh cells is still allowed. There have been repeated reports of life-threatening, and even fatal, complications of this type of therapy. Since it involves the administration of heterologous biological material, most of the complications that have been observed have been of the allergic/hyperergic type resembling experimental allergic encephalomyelitis (EAE) and experimental allergic neuritis (EAN). When evaluating the risks of this form of alternative-medical treatment, the well-known risks of injection therapy must also be borne in mind. In the case of cell therapy, too, the hoped for effect must be weighed against the risks of the procedure, and our guiding principle must be: nil nocere.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapias Complementares , Encefalomielite Autoimune Experimental/etiologia , Neurite Autoimune Experimental/etiologia , Polirradiculoneuropatia/etiologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Sistema Nervoso/patologia , Neurite Autoimune Experimental/patologia , Polirradiculoneuropatia/patologia , Fatores de Risco
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