Immune responses to T-cell expansion + PCV immunization

T 细胞扩增 PCV 免疫的免疫反应

• 批准号: 6836149
• 负责人: AARON P RAPOPORT
• 金额: $ 27.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-05 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836149
• 关键词: CD3 molecule; CD38 molecule; Streptococcus pneumoniae vaccine; T lymphocyte; autologous transplantation; cell proliferation; cell transplantation; clinical research; clinical trials; combination therapy; enzyme linked immunosorbent assay; flow cytometry; human subject; human therapy evaluation; immune response; immunomodulators; leukocyte activation /transformation; multiple myeloma; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; passive immunization; patient oriented research; tissue /cell culture; vaccine evaluation; virus antigen

DESCRIPTION (provided by applicant): High-dose chemotherapy followed by autologous stem cell transplantation is considered to be the most effective therapy for multiple myeloma but produces complete remissions in only about a third of patients and very few cures. The long-term objective of our clinical research is to learn how to re-establish anti-myeloma T-cell responses in the setting of autologous stem cell transplantation in order to improve upon the outcomes from this procedure. A key hypothesis behind this work is that ex-vivo costimulation of autologous T-cells using anti-CD3/anti-CD28 - conjugated magnetic beads may help to restore T-cell recognition and responsiveness toward myeloma tumor targets. We have developed and implemented a clinical trial in which patients with myeloma receive infusions of ex-vivo costimulated autologous T-cells after autotransplantation. In this trial, patients are also immunized with the T-cell dependent pneumococcal conjugate vaccine (PCV) in order to provide a reliable "readout" of immune function and to test whether administration of the ex-vivo expanded T-cells will enhance cellular or humoral responses post-transplantation. Using a randomized design, we plan to analyze the specific contributions of the vaccine and the "vaccine-primed" costimulated T-cells to the overall pneumococcal immune responses. Under this application, we specifically plan to i) analyze the phenotypic pattern and mechanism of immune cell reconstitution after infusion of costimulated T-cells; ii) measure the cellular immune responses that are directed against the conjugate vaccine and the protein carrier component of the PCV (CRM-197); iii) measure T-cell responses against VZV, CMV, and EBV antigens. Peripheral blood mononuclear cells will be incubated with PCV-vaccine, CRM-197 carrier protein, or CMV/VZV/EBV viral antigens and interferon gamma secreting T-cell responders will be detected by proliferation or ELISPOT assays. Knowledge gained from these studies will provide a platform on which to base the development of combined immunotherapy strategies for multiple myeloma and other immunoresponsive hematologic neoplasms as well as novel approaches to the immunization of immunocompromised hosts.

描述（由申请人提供）：高剂量化疗后自体干细胞移植被认为是多发性骨髓瘤最有效的治疗方法，但只有约三分之一的患者完全缓解，很少治愈。我们临床研究的长期目标是学习如何在自体干细胞移植的情况下重建抗骨髓瘤t细胞反应，以改善这一过程的结果。这项工作背后的一个关键假设是，使用抗cd3 /抗cd28偶联磁珠体外共刺激自体t细胞可能有助于恢复t细胞对骨髓瘤肿瘤靶点的识别和反应性。我们已经开发并实施了一项临床试验，骨髓瘤患者在自体移植后接受体外共刺激的自体t细胞输注。在这项试验中，患者也接种了t细胞依赖性肺炎球菌结合疫苗（PCV），以提供可靠的免疫功能“读数”，并测试体外扩增t细胞是否会增强移植后的细胞或体液反应。采用随机设计，我们计划分析疫苗和“疫苗启动”共刺激t细胞对整体肺炎球菌免疫反应的具体贡献。在此应用下，我们具体计划i)分析共刺激t细胞输注后免疫细胞重建的表型模式和机制；ii)测量针对结合疫苗和PCV蛋白载体组分的细胞免疫反应（cr -197）；iii)测量t细胞对VZV、CMV和EBV抗原的反应。外周血单核细胞将与pcv疫苗、cr -197载体蛋白或CMV/VZV/EBV病毒抗原孵育，分泌干扰素γ的t细胞应答者将通过增殖或ELISPOT检测。从这些研究中获得的知识将为多发性骨髓瘤和其他免疫反应性血液学肿瘤的联合免疫治疗策略的发展以及免疫功能低下宿主免疫的新方法提供一个平台。