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1.
Cytotherapy ; 2020 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-33262073

RESUMO

BACKGROUND: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. AIMS: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. METHODS: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 106 IN PKH-labeled huMSCs were administered. RESULTS: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. CONCLUSIONS: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 106 cells/kg total dose) based on more rapid aEEG recovery, improved 31P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h.

2.
Stem Cell Res Ther ; 11(1): 256, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32586403

RESUMO

BACKGROUND: MSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate 89Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma. METHODS: MSCTRAIL were radiolabelled with 89Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of 89Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo. RESULTS: MSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was amount- and time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections. CONCLUSIONS: 89Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.

3.
Stem Cells Transl Med ; 9(9): 974-984, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32416056

RESUMO

Adoptive cell therapy (ACT) is an approach to cancer treatment that involves the use of antitumor immune cells to target residual disease in patients after completion of chemo/radiotherapy. ACT has several advantages compared with other approaches in cancer immunotherapy, including the ability to specifically expand effector cells in vitro before selection for adoptive transfer, as well as the opportunity for host manipulation in order to enhance the ability of transferred cells to recognize and kill established tumors. One of the main challenges to the success of ACT in cancer clinical trials is the identification and generation of antitumor effector cells with high avidity for tumor recognition. Natural killer (NK) cells, cytokine-induced killers and natural killer T cells are key innate or innate-like effector cells in cancer immunosurveillance that act at the interface between innate and adaptive immunity, to have a greater influence over immune responses to cancer. In this review, we discuss recent studies that highlight their potential in cancer therapy and summarize clinical trials using these effector immune cells in adoptive cellular therapy for the treatment of cancer.

4.
Regen Med ; 15(3): 1463-1491, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32342730

RESUMO

Dimethyl sulfoxide (DMSO) is the cryoprotectant of choice for most animal cell systems since the early history of cryopreservation. It has been used for decades in many thousands of cell transplants. These treatments would not have taken place without suitable sources of DMSO that enabled stable and safe storage of bone marrow and blood cells until needed for transfusion. Nevertheless, its effects on cell biology and apparent toxicity in patients have been an ongoing topic of debate, driving the search for less cytotoxic cryoprotectants. This review seeks to place the toxicity of DMSO in context of its effectiveness. It will also consider means of reducing its toxic effects, the alternatives to its use and their readiness for active use in clinical settings.

5.
Aesthet Surg J ; 40(7): 784-799, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31406975

RESUMO

There is growing interest in the regenerative potential of adipose-derived stem cells (ADSCs) for wound healing applications. ADSCs have been shown to promote revascularization, activate local stem cell niches, reduce oxidative stress, and modulate immune responses. Combined with the fact that they can be harvested in large numbers with minimal donor site morbidity, ADSC products represent promising regenerative cell therapies. This article provides a detailed description of the defining characteristics and therapeutic potential of ADSCs, with a focus on understanding how ADSCs promote tissue regeneration and repair. It summarizes the current regulatory environment governing the use of ADSC products across Europe and the United States and examines how various adipose-derived products conform to the current UK legislative framework. Advice is given to clinicians and researchers on how novel ADSC therapeutics may be developed in accordance with regulatory guidelines.

6.
Haematologica ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753926

RESUMO

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover.

7.
Cytotherapy ; 21(10): 1007-1018, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31540804

RESUMO

The human umbilical cord has recently emerged as an attractive potential source of mesenchymal stromal cells (MSCs) to be adopted for use in regenerative medicine. Umbilical cord MSCs (UC-MSCs) not only share the same features of all MSCs such as multi-lineage differentiation, paracrine functions and immunomodulatory properties, they also have additional advantages, such as no need for bone marrow aspiration and higher self-renewal capacities. They can be isolated from various compartments of the umbilical cord (UC) and can be used for autologous or allogeneic purposes. In the past decade, they have been adopted in cardiovascular disease and have shown promising results mainly due to their pro-angiogenic and anti-inflammatory properties. This review offers an overview of the biological properties of UC-MSCs describing available pre-clinical and clinical data with respect to their potential therapeutic use in cardiovascular regeneration, with current challenges and future directions discussed.


Assuntos
Doenças Cardiovasculares/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Animais , Medula Óssea/fisiologia , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Transplante de Medula Óssea/métodos , Doenças Cardiovasculares/epidemiologia , Diferenciação Celular , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/fisiologia
8.
PLoS One ; 14(6): e0218674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242243

RESUMO

An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation, or "priming," of NK cells by exposure to pro-inflammatory cytokines, such as interleukin (IL)-2, has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions have not been thoroughly characterized. We investigated the consequences of co-incubation with K562, CTV-1, Daudi RPMI-8226, and MCF-7 tumor cell lines on the phenotype, cytokine expression profile, and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1, and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we reveal the upregulation of NK cell activation markers, such as CD69 and CD25; secretion of pro-inflammatory cytokines, including macrophage inflammatory proteins (MIP-1) α /ß and IL-1ß/6/8; and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions, such as FAS, TNFSF10, MAPK11, TNF, and IFNG. Thus, it appears that tumor-mediated ligation of receptors on NK cells may induce a primed state which may or may not lead to full triggering of the lytic or cytokine secreting machinery. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounters with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition toward harnessing the therapeutic potential of NK cells in cancer.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/imunologia , Citotoxicidade Imunológica , Redes Reguladoras de Genes , Humanos , Imunoterapia , Mediadores da Inflamação/metabolismo , Células K562 , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Células MCF-7 , Neoplasias/genética , Neoplasias/terapia , Fenótipo , Transcriptoma
9.
Leuk Lymphoma ; 60(10): 2457-2463, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30947589

RESUMO

The aim of the present study was to identify biomarkers predictive of the outcome of patients with high-risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (AZA). We prospectively examined the association between NK-cytotoxic activity, myeloid-derived suppressor cells (MDSCs), and T-regulatory cells (Tregs) on the overall survival (OS) of patients. Patients with NK-cytotoxicity above a critical threshold had a longer duration of response and survived longer than patients with severe impairment of NK-cytotoxicity. The numbers of MDSCs, and Tregs in the PB of patients after a short exposure to AZA were not different from normal donors. In conclusion, the results of our study suggest that the therapeutic activity of AZA is at least partly mediated by an immunomodulatory effect. To our knowledge, this is the first study reported so far, that shows a positive correlation between NK cytotoxicity and OS of AZA-treated patients.


Assuntos
Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Prognóstico , Curva ROC
11.
Cytotherapy ; 21(3): 367-375, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30890307

RESUMO

Translation of cell and gene therapies from pre-clinical experiments to clinical trials and final drug licensing brings requires the development, verification and even validation of the assays essential for the definition of the drug product. The technical and scientific challenges in doing this are far greater than they seem at first and are compounded by a lack of approved standards for assays used to support (c)GMP manufacture. This paper highlights some of those challenges and proposes solutions based on the experience of our colleagues using similar assay platforms in regulated pathology laboratories.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Aprovação de Drogas/métodos , Terapia Genética/métodos , Imunoterapia Adotiva/métodos , Cooperação Internacional , Controle de Qualidade , Bioensaio/normas , Instabilidade Cromossômica/genética , Impressões Digitais de DNA/normas , Citometria de Fluxo/normas , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/terapia , Testes Hematológicos/normas , Teste de Histocompatibilidade/normas , Humanos , Laboratórios/normas , Terminologia como Assunto , Transplante Homólogo
12.
Cytotherapy ; 21(3): 315-326, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30910383

RESUMO

As a part of the innate immune system, natural killer (NK) cells are cytotoxic lymphocytes that can exert cytotoxic activity against infected or transformed cells. Furthermore, due to their expression of a functional Fc receptor, they have also been eluded as a major effector fraction in antibody-dependent cellular cytotoxicity. These characteristics have led to multiple efforts to use them for adoptive immunotherapy against various malignancies.  There are now at least 70 clinical trials testing the safety and efficacy of NK cell products around the world in early-phase clinical trials. NK cells are also being tested in the context of tumor retargeting via chimeric antigen receptors, other genetic modification strategies, as well as tumor-specific activation strategies such as bispecific engagers with or without cytokine stimulations. One advantage of the use of NK cells for adoptive immunotherapy is their potential to overcome HLA barriers. This has led to a plethora of sources, such as cord blood hematopoietic stem cells and induced pluripotent stem cells, which can generate comparatively high cytotoxic NK cells to peripheral blood counterparts. However, the variety of the sources has led to a heterogeneity in the characterization of the final infusion product. Therefore, in this review, we will discuss a comparative assessment strategy, from characterization of NK cells at collection to final product release by various phenotypic and functional assays, in an effort to predict potency of the cellular product.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Animais , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Testes Imunológicos de Citotoxicidade/métodos , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Resultado do Tratamento
13.
Cytotherapy ; 21(3): 327-340, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30685216

RESUMO

Clinical trials of adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have delivered unprecedented responses in patients with relapsed refractory B-cell malignancy. These results have prompted Food and Drug Administration (FDA) approval of two CAR T-cell products in this high-risk patient population. The widening range of indications for CAR T-cell therapy and increasing patient numbers present a significant logistical challenge to manufacturers aiming for reproducible delivery systems for high-quality clinical CAR T-cell products. This review discusses current and novel CAR T-cell processing methodologies and the quality control systems needed to meet the increasing clinical demand for these exciting new therapies.


Assuntos
Imunoterapia Adotiva/métodos , Instalações Industriais e de Manufatura/normas , Neoplasias/terapia , Controle de Qualidade , Receptores de Antígenos Quiméricos , Antígenos CD19/imunologia , Remoção de Componentes Sanguíneos/métodos , Sobrevivência Celular , Criopreservação/métodos , Endotoxinas/análise , Humanos , Imunoterapia Adotiva/efeitos adversos , Ativação Linfocitária , Mycoplasma , Linfócitos T/imunologia , Transdução Genética/métodos
14.
Tissue Eng Part C Methods ; 25(2): 93-102, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30648458

RESUMO

IMPACT STATEMENT: This article describes a method for engrafting epithelial progenitor cells to a revascularized scaffold in a protective and supportive collagen-rich environment. This method has the potential to overcome two key limitations of existing grafting techniques as epithelial cells are protected from mechanical shear and the relatively hypoxic phase that occurs while grafts revascularize, offering the opportunity to provide epithelial cells to decellularized allografts at the point of implantation. Advances in this area will improve the safety and efficacy of bioengineered organ transplantation.


Assuntos
Colágeno/metabolismo , Fibroblastos/citologia , Pulmão/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Engenharia Tecidual , Traqueia/fisiologia , Animais , Sobrevivência Celular , Galinhas , Membrana Corioalantoide/metabolismo , Células Epiteliais/citologia , Masculino , Coelhos , Tecidos Suporte
15.
Cytotherapy ; 21(3): 341-357, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30655164

RESUMO

Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically modified T-cell receptors (TCRs) can be used to produce T-lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although major histocompatibility complex (MHC)-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high-affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimizing adverse events. This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of adoptive cell transfer (ACT), basic manufacturing procedures and characterization protocols and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice, beyond early-phase clinical trials.


Assuntos
Transferência Adotiva/métodos , Genes Codificadores dos Receptores de Linfócitos T/genética , Terapia Genética/métodos , Engenharia de Proteínas/métodos , Receptores de Antígenos de Linfócitos T/genética , Sobrevivência Celular , Edição de Genes/métodos , Vetores Genéticos , Humanos , Lentivirus/genética , Neoplasias/terapia , Linfócitos T/imunologia , Transdução Genética
16.
Nat Commun ; 9(1): 4286, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327457

RESUMO

A tissue engineered oesophagus could overcome limitations associated with oesophageal substitution. Combining decellularized scaffolds with patient-derived cells shows promise for regeneration of tissue defects. In this proof-of-principle study, a two-stage approach for generation of a bio-artificial oesophageal graft addresses some major challenges in organ engineering, namely: (i) development of multi-strata tubular structures, (ii) appropriate re-population/maturation of constructs before transplantation, (iii) cryopreservation of bio-engineered organs and (iv) in vivo pre-vascularization. The graft comprises decellularized rat oesophagus homogeneously re-populated with mesoangioblasts and fibroblasts for the muscle layer. The oesophageal muscle reaches organised maturation after dynamic culture in a bioreactor and functional integration with neural crest stem cells. Grafts are pre-vascularised in vivo in the omentum prior to mucosa reconstitution with expanded epithelial progenitors. Overall, our optimised two-stage approach produces a fully re-populated, structurally organized and pre-vascularized oesophageal substitute, which could become an alternative to current oesophageal substitutes.


Assuntos
Esôfago/citologia , Esôfago/fisiologia , Músculo Esquelético/citologia , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Criança , Pré-Escolar , Criopreservação/métodos , Células Epiteliais , Matriz Extracelular/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Crista Neural/transplante , Ratos Sprague-Dawley
17.
Mater Sci Eng C Mater Biol Appl ; 92: 565-574, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184783

RESUMO

Cancer, disease and trauma to the larynx and their treatment can lead to permanent loss of structures critical to voice, breathing and swallowing. Engineered partial or total laryngeal replacements would need to match the ambitious specifications of replicating functionality, outer biocompatibility, and permissiveness for an inner mucosal lining. Here we present porous polyhedral oligomeric silsesquioxane-poly(carbonate urea) urethane (POSS-PCUU) as a potential scaffold for engineering laryngeal tissue. Specifically, we employ a precipitation and porogen leaching technique for manufacturing the polymer. The polymer is chemically consistent across all sample types and produces a foam-like scaffold with two distinct topographies and an internal structure composed of nano- and micro-pores. While the highly porous internal structure of the scaffold contributes to the complex tensile behaviour of the polymer, the surface of the scaffold remains largely non-porous. The low number of pores minimise access for cells, although primary fibroblasts and epithelial cells do attach and proliferate on the polymer surface. Our data show that with a change in manufacturing protocol to produce porous polymer surfaces, POSS-PCUU may be a potential candidate for overcoming some of the limitations associated with laryngeal reconstruction and regeneration.


Assuntos
Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Laringe , Compostos de Organossilício/química , Poliuretanos/química , Engenharia Tecidual , Tecidos Suporte/química , Animais , Células Cultivadas , Células Epiteliais/citologia , Fibroblastos/citologia , Suínos
18.
Biol Blood Marrow Transplant ; 24(8): 1581-1589, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29597002

RESUMO

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/terapia , Adulto , Idoso , Contagem de Células , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prevenção Secundária , Doadores de Tecidos , Transplante Haploidêntico , Resultado do Tratamento
19.
Cytotherapy ; 20(1): 1-20, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28988692

RESUMO

BACKGROUND AIMS: With the support of five established scientific organizations, this report, the seventh of its kind, describes activity in Europe for the years 2014 and 2015 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis. METHODS: In 2015 [respectively 2014], 205 [276] teams from 32 countries responded to the cellular and tissue-engineered therapy survey; 178 [126] teams reported treating 3686 [2665] patients. RESULTS: Indications were musculoskeletal/rheumatological disorders (32% [33%]), cardiovascular disorders (12% [21%]), hematology/oncology (predominantly prevention or treatment of graft versus host disease and HSC graft enhancement; 20% [20%]), neurological disorders (4% [6%]), gastrointestinal disorders (<1% [1%]) and other indications (31% [20%]). The majority of autologous cells (60% [73%]) were used to treat musculoskeletal/rheumatological (44% [36%]) disorders, whereas allogeneic cells were used mainly for hematology/oncology (61% [68%]). The reported cell types were mesenchymal stromal cells (40% [49%]), chondrocytes (13% [6%]), hematopoietic stem cells (12% [23%]), dermal fibroblasts (8% [3%]), dendritic cells (2% [2%]), keratinocytes (1% [2%]) and others (24% [15%]). Cells were expanded in vitro in 63% [40%] of the treatments, sorted in 16% [6%] of the cases and rarely transduced (<1%). Cells were delivered predominantly as suspension 43% [51%], intravenously or intra-arterially (30% [30%]), or using a membrane/scaffold (25% [19%]). DISCUSSION: The data are compared with those from previous years to identify trends in a still unpredictably evolving field. Perspectives of representatives from plastic surgery practitioners, Iran and ISCT are presented (contributing authors D.A. Barbara, B. Hossein and W.L. Mark, respectively).


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/estatística & dados numéricos , Inquéritos e Questionários , Engenharia Tecidual/métodos , Engenharia Tecidual/estatística & dados numéricos , Ensaios Clínicos como Assunto , Europa (Continente) , Transplante de Células-Tronco Hematopoéticas , Humanos , Células-Tronco Mesenquimais/metabolismo , Medicina de Precisão
20.
Curr Stem Cell Rep ; 3(4): 279-289, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29177132

RESUMO

Purpose of Review: There is no consensus on the best technology to be employed for tracheal replacement. One particularly promising approach is based upon tissue engineering and involves applying autologous cells to transplantable scaffolds. Here, we present the reported pre-clinical and clinical data exploring the various options for achieving such seeding. Recent Findings: Various cell combinations, delivery strategies, and outcome measures are described. Mesenchymal stem cells (MSCs) are the most widely employed cell type in tracheal bioengineering. Airway epithelial cell luminal seeding is also widely employed, alone or in combination with other cell types. Combinations have thus far shown the greatest promise. Chondrocytes may improve mechanical outcomes in pre-clinical models, but have not been clinically tested. Rapid or pre-vascularization of scaffolds is an important consideration. Overall, there are few published objective measures of post-seeding cell viability, survival, or overall efficacy. Summary: There is no clear consensus on the optimal cell-scaffold combination and mechanisms for seeding. Systematic in vivo work is required to assess differences between tracheal grafts seeded with combinations of clinically deliverable cell types using objective outcome measures, including those for functionality and host immune response.

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