Predictors of clinical outcome after therapeutic vaccination in follicular lympho

描述（由申请人提供）：特异性抗肿瘤免疫效应物（抗体和T细胞）的产生是癌症疫苗临床有效性的必要条件;然而，这些效应物的有效性，甚至可能是通过疫苗接种产生的效应物，可能会受到在肿瘤微环境和癌症患者外周血中发现的几种免疫抑制机制中的任何一种的抑制。在最近完成的一项随机、双盲、对照、多中心III期临床试验中，患者特异性肿瘤衍生独特型（Id）蛋白与载体蛋白结合（匙孔-血蓝蛋白，KLH）并与佐剂一起施用（粒细胞-巨噬细胞集落刺激因子，GM-CSF）的晚期，以前未经治疗的滤泡性淋巴瘤（FL）的患者，在标准诱导化疗后完全缓解。与接受非特异性免疫刺激剂（KLHCSF）的对照组相比，Id-KLHCSF疫苗接种显著延长了无病生存期（DFS）。本提案的目的是确定FL患者治疗性独特型疫苗接种后临床结局的预测因素，并利用它们来确定影响疫苗疗效的机制。将通过将DFS与冻存疫苗接种前和疫苗接种后血清和外周血单核细胞的免疫学和基因组研究结果以及初次诊断时获得的活肿瘤活检样本（可从本试验两组的所有治疗患者中获得）相关联来发现预测因子。我们提出四个具体目标：1）确定FL中抗肿瘤体液和/或细胞免疫应答的诱导是否与独特型疫苗接种后的临床结果有利地相关，2）确定疫苗接种前免疫系统的状态和肿瘤微环境中的细胞成分是否影响FL中Id疫苗接种后抗肿瘤免疫应答的诱导和临床结果，3）确定诊断时肿瘤微环境中肿瘤和/或非肿瘤细胞的基因表达谱是否预测FL中独特型疫苗接种后的临床结果，和4）确定免疫应答相关基因多态性是否预测FL中独特型疫苗接种后的临床结果。 公共卫生相关性：该项目的总体目标是更深入地了解免疫系统和癌细胞之间的相互作用，并提出潜在的靶点，以改善未来癌症疫苗试验的结果。拟议的研究可能会对癌症疫苗领域的发展产生重大影响，特别是淋巴瘤疫苗。

DESCRIPTION (provided by applicant): The generation of specific anti-tumor immune effectors (antibodies and T-cells) is a necessary condition for clinical efficacy of cancer vaccines; however, the efficacy of these effectors, and perhaps even their generation by vaccination, may be opposed by any of several immunosuppressive mechanisms that have been found in tumor microenvironments and in the peripheral blood of cancer patients. In a recently completed randomized, double-blind, controlled, multicenter phase III clinical trial, patient-specific tumor-derived idiotype (Id) protein was conjugated with a carrier protein (keyhole-limpet hemocyanin, KLH) and administered together with an adjuvant (granulocyte-macrophage colony stimulating factor, GM-CSF) to patients with advanced stage, previously untreated follicular lymphoma (FL), in complete remission following standard induction chemotherapy. Vaccination with Id-KLHCSF significantly prolonged disease-free survival (DFS), compared with the control group that received a non-specific immune stimulant (KLHCSF). The objective of this proposal is to identify predictors of clinical outcome after therapeutic idiotype vaccination in patients with FL, and use them to identify mechanisms affecting vaccine efficacy. Predictors will be found by correlating DFS with the results of immunologic and genomic studies on cryopreserved pre- and post vaccine serum and peripheral blood mononuclear cells, and viable tumor biopsy samples obtained at initial diagnosis, available from all treated patients from both arms of this trial. We propose four Specific Aims: 1) determine whether the induction of antitumor humoral and/or cellular immune responses correlates favorably with clinical outcome following idiotype vaccination in FL, 2) determine whether the state of the immune system prior to vaccination and the cellular elements in the tumor microenvironment affect the induction of antitumor immune responses and clinical outcome following Id vaccination in FL, 3) determine whether the gene expression profiles of neoplastic and/or non-neoplastic cells in the tumor microenvironment at diagnosis predict clinical outcome following idiotype vaccination in FL, and 4) determine whether immune-response related gene polymorphisms predict clinical outcome following idiotype vaccination in FL. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to provide a deeper understanding of the interaction between the immune system and cancer cells, and suggest potential targets to improve results in future cancer vaccine trials. The proposed studies are likely to have substantial impact on the development of the cancer vaccine field in general and lymphoma vaccines in particular.