Predictors of clinical outcome after therapeutic vaccination in follicular lympho

描述（由申请人提供）：产生特异性抗肿瘤免疫效应器（抗体和t细胞）是癌症疫苗临床有效的必要条件；然而，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可能会反对这些效应物的功效，甚至可能通过疫苗产生这些效应物。在最近完成的一项随机、双盲、对照、多中心III期临床试验中，将患者特异性肿瘤来源的独特型（Id）蛋白与载体蛋白（keyholes -limpet hemocyanin， KLH）结合，并与佐剂（粒细胞-巨噬细胞集落刺激因子，gmcsf）一起给药给晚期、未经治疗的滤泡性淋巴瘤（FL）患者，这些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，接种Id-KLHCSF可显著延长无病生存期（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果的预测因素，并利用它们确定影响疫苗疗效的机制。通过将DFS与免疫和基因组研究结果（冷冻保存的疫苗前和疫苗后血清和外周血单个核细胞）以及在初始诊断时获得的活的肿瘤活检样本)相关联，可以发现预测因素，这些样本来自本试验两组所有接受治疗的患者。我们提出四个具体目标：1)确定特异性疫苗接种后抗肿瘤体液和/或细胞免疫应答的诱导是否与临床结果有利相关；2)确定疫苗接种前免疫系统状态和肿瘤微环境中的细胞因子是否影响特异性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能预测独特型FL疫苗接种后的临床结果；4)确定免疫反应相关基因多态性是否能预测独特型FL疫苗接种后的临床结果。

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.