RESUMEN
Preclinical studies have suggested that purified populations of CD1c (BDCA-1) blood-derived dendritic cells (BDC) loaded with tumor-specific peptides may be a feasible option for prostate cancer immunotherapy. We performed an open-label dose-finding Phase I study to evaluate the safe use of CD1c BDC in patients with advanced metastatic hormone refractory prostate cancer. HLA-A*0201-positive patients with advanced metastatic prostate cancer were recruited and consented. The vaccine was manufactured by pulsing autologous CD1c BDC, prepared by magnetic bead immunoselection from apheresed peripheral blood mononuclear cells, with a cocktail of HLA-A*0201-restricted peptides (prostate-specific antigen, prostate acid phosphatase, prostate specific membrane antigen, and control influenza peptide) and keyhole limpet hemocyanin. The vaccine was administered intradermally or intravenously and peripheral blood was taken at predetermined intervals for clinical and immunologic monitoring. The vaccine was manufactured with a median purity of 82% CD1c BDC and administered successfully to 12 patients. Each patient received between 1 and 5 × 10 fresh CD1c BDC on day 0, followed by cryopreserved product in the same dose on days 28 and 56. The vaccine was well tolerated in all patients, with the most frequent adverse events being grade 1-2 fever, pain, or injection-site reactions. Vaccination with CD1c BDC is therefore feasible, safe, and well tolerated in patients with advanced-stage metastatic prostate cancer.
Asunto(s)
Vacunas contra el Cáncer , Células Dendríticas/inmunología , Antígeno HLA-A2/metabolismo , Inmunoterapia Adoptiva , Fragmentos de Péptidos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/terapia , Fosfatasa Ácida/inmunología , Fosfatasa Ácida/metabolismo , Administración Intravenosa , Anciano , Antígenos CD1/metabolismo , Células Dendríticas/trasplante , Estudios de Factibilidad , Glicoproteínas/metabolismo , Humanos , Inyecciones Intradérmicas , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Especificidad de Órganos , Antígeno Prostático Específico/inmunología , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/inmunologíaRESUMEN
Clinical grade human mesenchymal stem cells (MSC) are manufactured and used in clinical trials for a range of regenerative and inflammatory diseases. Human MSC have now been derived from tissues other than bone marrow, such as placenta, as described in this laboratory protocol. It provides instructions for clinical grade MSC manufacturing according to the Code of Good Manufacturing Practice (cGMP) principles and according to policies and procedures of our internal Quality Management System (QMS), which is based on the International Organization for Standardization (ISO) standard requirements. Relevant organizational structure and QMS elements are presented.
Asunto(s)
Materiales Manufacturados/normas , Células Madre Mesenquimatosas/citología , Células Madre Multipotentes/citología , Placenta/citología , Animales , Técnicas de Cultivo de Célula , Núcleo Celular/metabolismo , Separación Celular , Criopreservación , Femenino , Citometría de Flujo , Humanos , Fenotipo , Embarazo , Etiquetado de Productos , EsterilizaciónRESUMEN
Mesenchymal stem cells (MSC) are being used increasingly in clinical trials for a range of regenerative and inflammatory diseases. Bone marrow is the traditional source but is relatively inaccessible in large volume. MSC have now been derived from tissues other than bone marrow including placenta and adipose tissue. We have used placenta obtained after delivery as a source of MSC and have been unable to detect any marked differences from marrow-derived MSC in terms of cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability. This report described our manufacturing process for isolating and expanding placenta-derived human MSC and their safe infusion into the first patient in a clinical trial program of human placenta-derived MSC.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Placenta/citología , Células de la Médula Ósea/citología , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Separación Celular/métodos , Criopreservación/métodos , Resultado Fatal , Femenino , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/terapia , Masculino , Células Madre Mesenquimatosas/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
SUMMARY: Therapeutic applications of cells are likely to increase greatly in the future. Cell and cell-based gene therapy manufacturing facilities need to be purpose-designed and accredited by their national medicinal regulatory body. Production scientists need to work in close tandem with quality assurance and ethics committees to absolutely ensure the safety of new cellular products. In this review, we consider the need for preclinical safety and efficacy data, tissue source for manufacture of clinical grade human mesenchymal stem cells, aseptic tissue processing, indemnification, and the role of the national medicinal regulatory body in appropriate clinical trial design.