SLC/6Ckine Immunotherapy for Cancer

SLC/6Ckine 癌症免疫疗法

• 批准号: 6896197
• 负责人: SHERVEN SHARMA
• 金额: $ 14.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-13 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896197
• 关键词: T lymphocyte; cell migration; chemokine; cytokine; dendritic cells; immunologic memory; laboratory mouse; lung neoplasms; lymphatic tissue; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; tumor antigens; tumor infiltrating lymphocyte

DESCRIPTION (provided by applicant): Lung cancer is the number one cause of cancer death in the United States. Lung cancers express tumor antigens but are ineffective as antigen presenting cells. We will utilize secondary lymphoid chemokine (SLC) to localize DC at the tumor site where they can function to present an array of antigenic epitopes. This approach to stimulate specific T cell immune responses would not exclude patients on the basis of HLA phenotype or because of lack of expression of a particular tumor antigen. Thus, this therapy would be available to all lung cancer patients in the appropriate clinical setting. We hypothesize that SLC therapy will lead to co-localization of dendritic cells (DC) and Th1 cytokine-expressing lymphocytes. We anticipate that DC will traffick to the tumor site where they will be positioned to process and present autologous tumor antigen (Ag) thus providing access to the entire repertoire of available antigens in situ, both increasing the likelihood of a response and reducing the potential for phenotypic modulation. The overall goal of this proposal is to use murine models to determine the mechanisms of SLC-mediated restoration of anti-tumor immune responses. Utilizing transplantable murine lung cancer models, different modes of SLC delivery will be evaluated that ultimately may have clinical relevance. The following modes of intratumoral SLC delivery will be assessed: 1) injection of recombinant SLC, 2) injection of irradiated SLC transduced tumor cells, and 3) injection of adenovirus vector expressing SLC. A spontaneous murine lung cancer model will be utilized to evaluate the antitumor efficacy of these modes of SLC delivery by intradermal, axillary lymph node region and systemic i.p. injections. Each of these systems will be evaluated because each has potential advantages in the development of immune based therapy for lung cancer. Specific Aims: 1. To identify the mechanisms of anti-tumor responses in secondary lymphoid chemokine (SLC) therapy. (A) The capacity of SLC to enhance the generation of tumor-specific CTL will be investigated. Tumor infiltrating lymphocytes (TIL), splenic T cells and lymph node derived lymphocytes (LNDL) will be evaluated for cytolytic activity and cytokine release against specific and non-specific tumor targets. (B) The importance of cytokines IFN gamma, IL-10, GM-CSF, IL-12, MIG and IP10 in SLC- mediated anti-tumor responses will be assessed. 2. To identify the T cell subsets and cytokines important for the memory phenotype following SLC mediated tumor eradication. (A) Mice having rejected their tumors following SLC therapy will be treated with anti-CD3, anti-CD4, anti-CD8 antibodies before rechallenge with 3LL parental tumors, T cell subsets from mice having rejected their tumors following SLC therapy will be transferred to naive mice before challenge with 3LL parental tumors. (B) The importance of cytokines IFN gamma, IL-10, GM-CSF and IL-12 will be assessed in the memory phenotype after SLC mediated tumor eradication. 3. To evaluate the efficacy of different modes and routes of SLC therapy in a spontaneous murine lung cancer model. Dr. Sharma, has the requisite attributes that predict successful academic independence. He is in an excellent scientific environment and will spend 100 percent effort to this endeavor. Work resulting in this environment will prepare Dr. Sharma for a successful independent career in basic cancer research.

描述（由申请人提供）：肺癌是 美国的癌症死亡。 肺癌表达肿瘤抗原，但 作为抗原呈现细胞无效。 我们将利用次要 淋巴趋化因子（SLC）将直流定位在肿瘤部位 呈现一系列抗原表位的功能。 这种方法 刺激特定的T细胞免疫反应不会排除患者 HLA表型的基础或由于缺乏特定肿瘤的表达 抗原。 因此，该疗法将适用于所有肺癌患者 适当的临床环境。 我们假设SLC疗法将领导 为树突状细胞（DC）和Th1细胞因子表达的共定位 淋巴细胞。 我们预计DC会贩运他们 将定位以处理并呈现自体肿瘤抗原（Ag） 提供对原位可用抗原的整个曲目的访问 增加响应的可能性并降低了潜力 表型调制。 该提议的总体目标是使用鼠 确定SLC介导的抗肿瘤恢复机制的模型 免疫反应。 利用可移植的鼠肺癌模型， 将评估不同模式的SLC交付方式，最终可能有 临床相关性。 肿瘤内SLC的以下模式将是 评估：1）注射重组SLC，2）注射辐射的SLC 转导的肿瘤细胞，3）注射表达SLC的腺病毒载体。 将使用自发的鼠肺癌模型来评估 这些SLC递送模式的抗肿瘤功效通过皮内腋生 淋巴结区域和全身性i.p.注射。 这些系统中的每一个都将是 评估是因为每个人在免疫的发展中都有潜在的优势 基于肺癌的疗法。 具体目的：1。确定机制 继发性淋巴趋化因子（SLC）疗法中的抗肿瘤反应。 （a） SLC增强肿瘤特异性CTL产生的能力将是 调查。 肿瘤浸润淋巴细胞（TIL），脾T细胞和淋巴 淋巴结衍生的淋巴细胞（LNDL）将评估细胞溶解活性和 细胞因子针对特异性和非特异性肿瘤靶标的释放。 （b） slc-中细胞因子IFN伽马，IL-10，GM-CSF，IL-12，MIG和IP10的重要性 将评估介导的抗肿瘤反应。 2。识别T细胞 SLC之后的记忆表型重要的子集和细胞因子很重要 介导的消除肿瘤。 （a）拒绝其肿瘤后的小鼠 SLC治疗将用抗CD3，抗CD4，抗CD8抗体治疗 在患有3LL亲本肿瘤的重新检查之前，来自具有的小鼠的T细胞子集 SLC治疗后拒绝其肿瘤将转移到天真小鼠 在挑战3LL父母肿瘤之前。 （b）细胞因子的重要性 IFN伽马，IL-10，GM-CSF和IL-12将在记忆表型中进行评估 SLC介导的根除后。 3。评估 自发鼠肺癌中SLC治疗的不同模式和途径 模型。 Sharma博士具有预测成功的必要属性 学术独立性。 他处于一个极好的科学环境中，会 花100％的努力来努力。 导致这种环境的工作 将为Sharma博士做好准备，以成功地从事基本癌症的独立职业 研究。