Generation of Anti-Melanoma T Cells Derived from Human Embryonic Stem Cells

源自人胚胎干细胞的抗黑色素瘤 T 细胞的产生

• 批准号: 7782232
• 负责人: Jerome A. Zack
• 金额: $ 31.83万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782232
• 关键词: Antigens; Biological Models; Cell Lineage; Cells; Cellular biology; Clinical; Clinical Treatment; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Development; Embryo; Embryonic Development; Fibroblasts; Generations; Genes; Genetic Materials; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Human; Immune response; Immune system; In Vitro; Individual; Investigation; Knowledge; Life; Malignant Neoplasms; Molecular; Organ; Patients; Publishing; Research; Series; Signal Transduction; Stem cells; System; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Totipotent Stem Cells; Transgenes; Transplantation; abstracting; base; cell type; combat; gene therapy; genetic manipulation; human embryonic stem cell; human embryonic stem cell line; improved; in vivo; in vivo Model; induced pluripotent stem cell; killings; melanoma; neoplastic cell; pre-clinical; preclinical study; programs; receptor; receptor expression; stem; theories; therapeutic vaccine; treatment strategy

Project 4; Generation of Anti-Melanoma T cells Derived From Human Embryonic Stem Cells Abstract Genetic manipulation of the human immune system is a powerful approach to combating infectious diseases and cancers. Clinically, the most common cell based therapeutic approach currently used is hematopoietic stem cell (HSC) transplantation. The possibility of stably introducing specific T cell receptors (TCRs) into stem cells to generate T lymphocytes targeting specific antigens of choice opens doors to new and exciting life-long vaccine and therapeutic strategies. Human embryonic stem cells (hESC) and the recently-described induced pluripotent stem (IPS) cells, have the potential to revolutionize transplant technology. The theoretical ability of these cells to differentiate into any cell type in the body opens the possibility of improved cell replacement, organ replacement or genetic therapies. Induced pluripotent stem cells have a particular attraction, in that they can theorefically be derived from individual patients and will thus express idenfical HLA molecules, so they would not be rejected by the patient's immune response. We have demonstrated that hESC can be induced to differentiate into cells of the T lineage, and that IPS cells also have hematopoietic potential. New genetic material introduced into these cells can be expressed throughout hematopoietic differenfiafion. Thus the potential for adaptation of these stem cells to clinical use is especially true in regards to genetic manipulation of the immune system. The possibility of using these totipotent stem cells has many advantages over the use of HSC, including ability to culture extensively and ease of genefic manipulafion, however there are many gaps in our knowledge regarding control of differentiation into specialized mature cell types. Development of model systems to optimize and study hESC and IPS generation into funcfional T cells could be very helpful for advancing our ability to genetically manipulate immune responses. This proposal will focus on pre-clinical studies optimizing the generation, from totipotent stem cells, of human T lymphocytes directed to target human melanoma, by virtue of expression of TCRs specific for melanoma anfigens. These studies will interact with other components in this Program Project to provide poof-of-principle that hESC and/or IPS can be used to manipulate the immune system to specifically target cancer by pursuing the following specific aims: 1) Develop melanoma-specific cytotoxic T cells from human embryonic and induced pluripotent stem cells ; 2) Determine how expression of MART-1 TCR influences thymopoietic potential of hESC and IPS cells; 3) Develop T-cell specific expression systems to opfimize distribution of TCR expression in progeny of hESC and IPS. We hope that together with the other components of this Program Project we will provide important pre-clinical informafion that cancer-specific T cells can be generated from these versatile stem cells, and that this approach may have potential for treating melanoma.

项目4：从人胚胎干细胞产生抗黑素瘤T细胞 摘要人类免疫系统的基因操作是对抗传染病和癌症的有力手段。临床上，目前使用的最常见的基于细胞的治疗方法是造血干细胞（HSC）移植。将特异性T细胞受体（TCR）稳定引入干细胞以产生靶向所选特异性抗原的T淋巴细胞的可能性为新的和令人兴奋的终身疫苗和治疗策略打开了大门。人类胚胎干细胞（hESC）和最近描述的诱导多能干细胞（IPS）具有彻底改变移植技术的潜力。这些细胞在体内分化成任何细胞类型的理论能力为改善细胞替代，器官替代或遗传疗法提供了可能性。诱导性多能干细胞具有特殊的吸引力，因为它们理论上可以来自个体患者，因此将表达生物学HLA分子，因此它们不会被患者的免疫反应排斥。我们已经证明，hESC可以被诱导分化为T细胞系，IPS细胞也具有造血潜能。导入这些细胞的新遗传物质可在整个造血分化过程中表达。因此，这些干细胞适应临床应用的潜力在免疫系统的遗传操作方面尤其如此。使用这些全能干细胞的可能性与使用HSC相比具有许多优点，包括广泛培养的能力和易于遗传操作，然而在我们的知识中关于控制分化成专门的成熟细胞类型存在许多差距。开发模型系统来优化和研究hESC和IPS生成功能性T细胞可能对提高我们遗传操纵免疫应答的能力非常有帮助。该提案将集中于临床前研究，通过表达对黑色素瘤抗原特异性的TCR，优化从全能干细胞产生定向靶向人黑色素瘤的人T淋巴细胞。这些研究将与本计划项目中的其他组成部分相互作用，以提供原理性证明，hESC和/或IPS可用于操纵免疫系统，通过追求以下特定目标来特异性靶向癌症：1）从人胚胎干细胞和诱导多能干细胞开发黑素瘤特异性细胞毒性T细胞; 2）确定MART-1 TCR的表达如何影响hESC和IPS细胞的胸腺生成潜力; 3）开发T细胞特异性表达系统，优化hESC和IPS后代中TCR表达的分布。我们希望 与本计划项目的其他组成部分一起，我们将提供重要的临床前 癌症特异性T细胞可以从这些多功能干细胞中产生，并且这种方法可能具有治疗黑色素瘤的潜力。