Dendritic Cell Vaccination During Lymphoid Reconstitution

淋巴重建期间的树突状细胞疫苗接种

• 批准号: 6929470
• 负责人: Jeffrey S Weber
• 金额: $ 53.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929470
• 关键词: autotransfusion; clinical research; clinical trial phase I; combination cancer therapy; dendritic cells; fludarabine; human subject; human therapy evaluation; immune response; leukocyte transfusion; melanoma; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; tumor antigens; vaccine evaluation

DESCRIPTION (provided by applicant): Dendritic cells (DC) are potent antigen-presenting cells that have been tested in early phase clinical trials for their ability to prime and amplify tumor antigen-specific T cell responses. The modest results achieved so far suggest that new approaches to DC vaccination are needed. In this proposal, we wish to take advantage of immune homeostasis induced after lymphoid depletion to amplify DC-induced immune responses and achieve immune reconstitution with antigen-specific T cells. A dose ranging study will be performed in which either no, or escalating doses of fludarabine will be followed by intranodally infused peptide-pulsed DC and autologous lymphocyte infusion (ALI) given intravenously to patients with chemotherapy-naive metastatic melanoma. We will determine the toxicities, the immune responses seen to defined melanoma antigens and the impact upon T lymphoid reconstitution in each cohort. Our hypothesis is that DC immunization during lymphoid homeostatic reconstitution will result in greater amplitude and duration of antigen-specific immune responses than DC vaccination alone. DC matured with a cocktail of cytokines shown in vitro to be optimal for T cell stimulation and pulsed with multiple class I and class ll-restricted tumor antigen peptides will be infused into a groin lymph node with intravenous ALI as a "reference" arm, or DC will be given intranodally with ALI after escalating doses of fludarabine given to induce lymphopenia. DC will be infused during lymphoid recovery based on our pre-clinical work, then 1, 3 and 5 weeks later. The goal of the phase I study is to define a tolerable dose of fludarabine with DC and ALI that can be shown to induce maximal antigen-specific class I and ll-restricted T cell responses in immunologic assays. In this phase I study the principal endpoint will be the level and longevity of tumor antigen-specific immune response achieved. Toxicity as well as clinical response will be secondary endpoints. The cohort with the optimal level of immune response will be taken forward in future studies.

描述（由申请人提供）：树突状细胞（DC）是有效的抗原呈递细胞，已在早期临床试验中测试了其引发和扩增肿瘤抗原特异性T细胞应答的能力。迄今为止取得的适度结果表明，需要新的DC疫苗接种方法。在这个提议中，我们希望利用淋巴耗竭后诱导的免疫稳态来放大DC诱导的免疫应答，并利用抗原特异性T细胞实现免疫重建。将进行一项剂量范围研究，其中没有氟达拉滨或氟达拉滨剂量递增，随后将向未经化疗的转移性黑色素瘤患者静脉内给予结内输注肽脉冲DC和自体淋巴细胞输注（ALI）。我们将确定毒性、对确定的黑色素瘤抗原的免疫应答以及对每个队列中T淋巴重建的影响。我们的假设是，DC免疫在淋巴稳态重建将导致更大的幅度和持续时间的抗原特异性免疫反应比DC单独接种。用体外显示对T细胞刺激最佳的细胞因子混合物成熟的DC和用多种I类和II类限制性肿瘤抗原肽脉冲的DC将被输注到腹股沟淋巴结中，静脉内ALI作为“参考”臂，或者DC将在给予递增剂量的氟达拉滨以诱导淋巴细胞减少症后与ALI一起被结内给予。根据我们的临床前工作，DC将在淋巴恢复期间输注，然后在1、3和5周后输注。I期研究的目的是定义氟达拉滨与DC和ALI的耐受剂量，其可以在免疫学测定中显示诱导最大抗原特异性I类和II类限制性T细胞应答。在这项I期研究中，主要终点将是所达到的肿瘤抗原特异性免疫应答的水平和寿命。毒性和临床应答将是次要终点。具有最佳免疫应答水平的队列将在未来的研究中继续进行。