Dendritic Cell Vaccination During Lymphoid Reconstitution

描述（由申请人提供）：树突状细胞（DC）是一种有效的抗原呈递细胞，已经在早期临床试验中测试了它们启动和扩增肿瘤抗原特异性T细胞反应的能力。迄今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，我们希望利用淋巴细胞耗损后诱导的免疫稳态来放大dc诱导的免疫反应，并通过抗原特异性T细胞实现免疫重建。将进行一项剂量范围研究，在不给药或增加剂量的氟达拉滨之后，结内输注肽脉冲DC和自体淋巴细胞输注（ALI），静脉注射给化疗初期转移性黑色素瘤患者。我们将在每个队列中确定毒性，对定义的黑色素瘤抗原的免疫反应以及对T淋巴细胞重建的影响。我们的假设是，与单独接种DC相比，在淋巴稳态重建期间接种DC会导致抗原特异性免疫反应的幅度和持续时间更大。经细胞因子混合物处理成熟的DC体外最适合T细胞刺激，并以多种I类和ll类限制性肿瘤抗原肽脉冲，将以静脉注射ALI作为“参考”臂注入腹股沟淋巴结，或在增加氟达拉滨剂量诱导淋巴减少后，将ALI注入DC结内。根据我们的临床前工作，DC将在淋巴细胞恢复时输注，然后在1、3、5周后输注。I期研究的目标是确定DC和ALI的氟达拉滨耐受剂量，该剂量可以在免疫分析中显示诱导最大的抗原特异性I类和I类限制性T细胞反应。在这个I期研究中，主要终点将是肿瘤抗原特异性免疫反应的水平和寿命。毒性和临床反应将是次要终点。最佳免疫应答水平的队列将在未来的研究中向前推进。

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.