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The safety and feasibility of adoptive immunotherapy, using CD19-specific T cells that have been genetically modified to express a chimeric antigen receptor (CAR) and numerically expanded ex vivo, need to be addressed. Second-generation... more
The safety and feasibility of adoptive immunotherapy, using CD19-specific T cells that have been genetically modified to express a chimeric antigen receptor (CAR) and numerically expanded ex vivo, need to be addressed. Second-generation trials are being developed incorporating improvements into the design of the CAR as well as the manufacturing processes. Here we describe a platform for propagating CD19-specific T cells through an artificial antigen presenting cell (aAPC) which co-expresses CD19 and T-cell co-stimulatory molecules to provide a fully-competent T-cell activation signal leading to T-cell proliferation. K562 cells were selected as the platform for the aAPCs since (i) they have previously been used in compliance with current good manufacturing practice (cGMP), (ii) they express the desired endogenous T-cell adhesion molecules, and (iii) they fail to express classical HLA class I/II molecules and thus are not targets for a T-cell mediated allogeneic immune response. There...
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1417 Poster Board I-440 Gene-modified cellular products (GMCP) hold great promise for the management of numerous disease indications but are considered high-risk biological agents and are derived through extremely complex design and... more
1417 Poster Board I-440 Gene-modified cellular products (GMCP) hold great promise for the management of numerous disease indications but are considered high-risk biological agents and are derived through extremely complex design and manufacturing processes. Thus, a robust Quality Management System (QMS) is essential for safe production of GMCP for clinical investigation. Development of a QMS that ensures compliance with current Good Manufacturing Practices (cGMP) and current Good Tissue Practices (cGTP) is particularly challenging in an academic setting where basic researchers, clinical investigators, regulatory, administrative, facilities and manufacturing personnel are all involved in the realization of a single GMCP. Following an ISO9001-based gap analysis of the Cellular Therapeutics program at the City of Hope, we implemented Quality Management Reports (QMR) as a tool for capturing data related to GMCP manufacturing. The QMR system was used to document and facilitate corrective...
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Research Interests:
Este documento es producto de una investigación de sistematización que sobre desplazamiento forzado y reasentamientos se han realizado en Cali, tratados a través de tesis de grado de estudiantes del departamento de Geografía de la... more
Este documento es producto de una investigación de sistematización que sobre desplazamiento forzado y reasentamientos se han realizado en Cali, tratados a través de tesis de grado de estudiantes del departamento de Geografía de la Universidad del Valle. Mi análisis parte de la Antropología Urbana y la Geografía de Género, en la cual se intenta analizar las trayectorias de vida de desplazados y desplazadas que han ido construyendo ciudad, la manera de cómo se han asentado de hecho y cuáles han sido las estretegias de supervivencia y de apropiación del espacio citadino de manera diferencial por los hombres y las mujeres.Palabras clave: desplazamiento forzado, desterritorialización, reterritorialización, asentamientos de hecho, ciudad, espacio y tiempo. The new urban tribes of Cali. Forced relocation, deterritorialization, and reterritorialization This document is the product of research on forced displacement and the resettlements which have been made in Cali, treated thr...
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Gene therapy for HIV-1 infection is a promising alternative to lifelong combination antiviral drug treatment. Chemokine receptor 5 (CCR5) is the coreceptor required for R5-tropic HIV-1 infection of human cells. Deletion of CCR5 renders... more
Gene therapy for HIV-1 infection is a promising alternative to lifelong combination antiviral drug treatment. Chemokine receptor 5 (CCR5) is the coreceptor required for R5-tropic HIV-1 infection of human cells. Deletion of CCR5 renders cells resistant to R5-tropic HIV-1 infection, and the potential for cure has been shown through allogeneic stem cell transplantation with naturally occurring homozygous deletion of CCR5 in donor hematopoietic stem/progenitor cells (HSPC). The requirement for HLA-matched HSPC bearing homozygous CCR5 deletions prohibits widespread application of this approach. Thus, a strategy to disrupt CCR5 genomic sequences in HSPC using zinc finger nucleases was developed. Following discussions with regulatory agencies, we conducted IND-enabling preclinical in vitro and in vivo testing to demonstrate the feasibility and (preclinical) safety of zinc finger nucleases-based CCR5 disruption in HSPC. We report here the clinical-scale manufacturing process necessary to de...
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Research Interests:
Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long-term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases.... more
Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long-term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases. In some cases, the gene-modified cells have a selective growth advantage over nonmodified cells and eventually are the dominant engrafted population. However, in disease indications for which the gene-modified cells do not have a selective advantage, optimizing transduction of HSPC is paramount to successful stem cell-based gene therapy. We demonstrate here that transduction of adult CD34+ HSPCs with lentiviral vectors in the presence of rapamycin, a widely used mTORC1 inhibitor, results in an approximately threefold increase in stable gene marking with minimal effects on HSPC growth and differentiation. Using this approach, we have demonstrated that we can enhance the frequency of gene-modified HSPCs that give rise to clonogenic progeny in vitro w...
Research Interests: Flow Cytometry, Biology, Stem Cell, Medicine, Hematopoietic Stem Cells, and 13 moreHumans, Genetic Enhancement, Mice, Animals, Polymerase Chain Reaction, Lentivirus, Haematopoiesis, Sirolimus, Clonogenic Assay, Hematopoietic Stem Cell Transplantation, Genetic Therapy, In Vitro Techniques, and Cell culture techniques
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Research Interests: Genetics, Biology, Adolescent, Medicine, Multivariate Analysis, and 15 moreOppositional Defiant Disorder, Humans, Child, Clinical, Clinical Genetics, Hormones, Polymerase Chain Reaction, Conduct Disorder, Gene, Clinical Sciences, Adult, Genetic Polymorphism, Child preschool, Attention deficit disorder with hyperactivity, and Attention deficit hyperactivity disorder
Chimeric antigen receptors (CAR) combine an antigen-binding domain with a CD3-ζ signaling motif to redirect T-cell specificity to clinically important targets. First-generation CAR, such as the CD19-specific CAR (designated CD19R), may... more
Chimeric antigen receptors (CAR) combine an antigen-binding domain with a CD3-ζ signaling motif to redirect T-cell specificity to clinically important targets. First-generation CAR, such as the CD19-specific CAR (designated CD19R), may fail to fully engage genetically modified T cells because activation is initiated by antigen-dependent signaling through chimeric CD3-ζ, independent of costimulation through accessory molecules. We show that enforced expression of the full-length costimulatory molecule CD28 in CD8+CD19R+CD28− T cells can restore fully competent antigen-dependent T-cell activation upon binding CD19+ targets expressing CD80/CD86. Thus, to provide costimulation to T cells through a CD19-specific CAR, independent of binding to CD80/CD86, we developed a second-generation CAR (designated CD19RCD28), which includes a modified chimeric CD28 signaling domain fused to chimeric CD3-ζ. CD19R+ and CD19RCD28+ CD8+ T cells specifically lyse CD19+ tumor cells. However, the CD19RCD28+...