Predictors of clinical outcome after therapeutic vaccination in follicular lympho

描述(申请人提供)：产生特定的抗肿瘤免疫效应器(抗体和T细胞)是癌症疫苗临床疗效的必要条件；然而，这些效应器的有效性，甚至可能是通过疫苗产生的，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反对。在最近完成的一项随机、双盲、对照、多中心的III期临床试验中，患者特有的肿瘤独特型(ID)蛋白与载体蛋白(Keyhole-limet血蓝蛋白，KLH)结合，并与佐剂(粒细胞-巨噬细胞集落刺激因子，GM-CSF)一起用于标准诱导化疗后完全缓解的晚期滤泡性淋巴瘤(FL)患者。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)。这项建议的目的是确定FL患者在治疗性独特型疫苗接种后的临床结果的预测因素，并使用它们来确定影响疫苗有效性的机制。通过将DFS与对冷冻保存的疫苗前和疫苗后血清和外周血单核细胞以及初步诊断时获得的活肿瘤活检样本的免疫学和基因组研究结果相关联，将找到预测因素。我们提出了四个特定的目标：1)确定FL独特型疫苗接种后抗肿瘤体液和/或细胞免疫反应的诱导是否与临床结果有利相关，2)确定免疫接种前的免疫系统状态和肿瘤微环境中的细胞因素是否影响FL ID疫苗诱导的抗肿瘤免疫反应和临床结果，3)确定确诊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独特型疫苗接种后的临床结果，以及4)确定免疫反应相关基因多态性是否预测FL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，特别是淋巴瘤疫苗的发展产生重大影响。

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.