Tumor-Specific Chemokine Modulation in Colorectal Cancer Versus Melanoma

结直肠癌与黑色素瘤的肿瘤特异性趋化因子调节

• 批准号: 8518921
• 负责人: Pawel Kalinski
• 金额: $ 1.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8518921
• 关键词: Cancer Vaccines; Cells; Clinical; Clinical Data; Clinical Trials; Colorectal Cancer; Combined Vaccines; Data; Disseminated Malignant Neoplasm; Environment; Equilibrium; Eragrostis; Goals; Human; Immune; In Vitro; Inflammation Mediators; Inflammatory; Instruction; Lesion; Liver; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Organ; Patients; Phase; Primary Neoplasm; Production; Regimen; Regulation; Regulatory T-Lymphocyte; Role; Site; T-Lymphocyte; Testing; Tissues; Vaccination; Vaccines; base; cancer immunotherapy; cell type; chemokine; chemokine receptor; clinical efficacy; implantation; in vivo Model; melanoma; pre-clinical; response; synergism; tumor

We will test the hypothesis that the ability of DCs and other tumor-associated cells to produce distinct sets of chemokines (CK)and to attract functionally different subsets of immune cells is determined in a tumor- specific manner by distinct inflammatory mediators. Furthermore, we hypothesize that pharmacological modulation of tumor CK environment can be used to selectively promote the tumor entry of the vaccination- induced type-1 effector T cells (Jeff: Th1 and CTL) with defined expression of CK receptors, but not Tregs. Our goal is to develop reliable treatments with tumor-matched combinations of pharmacologic agents to selectively enhance the production of the Teff-attracting CKs within tumor lesions, in order to promote the clinical efficacy of cancer immunotherapies. Based on our Preliminary data, we expect that we will be able to identify the combination treatments with double selectivity: A) selectively enhancing the production of Jeff- attracting CKs without enhancing Treg-attracting CKs; and B) preferentially effective in tumor lesions, rather than healthy tissues. Contrasting melanoma and colorectal cancer, the tumors metastasizing to the same organ (liver), we will determine the respective roles of the histological type of tumor versus the site of its implantation in determining local CK production, will identify the cellular and molecular mechanisms of different CK production between healthy tissues, primary and metastatic cancer, and the mechanisms of the differential responsiveness of such tissues to particular CK-modulating agents. Within Specific Aim 1, we will determine which tumor-specific inflammatory factors, selectively relevant to melanoma or to CRC,determine the CK production by tumor-associated cells in vitro and dictate the recruitment of functionally-different subsets of immune cells. We will analyze the impact of such factors on the ability of isolated DCs and other tumor-associated cell types to produce the Jeff-attracting- versus Treg- attracting CKs, and to preferentially attract Te/f v. Treg cells. Within Specific Aim2, we will determine the mechanisms of differences in CK regulation between CRC, melanoma, and healthy tissues, and will develop the methods to correct the balance between the Te/fv Treg-attracting CKs in melanoma and CRC tumors, using human ex vivo models of tumor explant cultures and mouse in vivo models of primary and metastatic tumors. Within Specific Aim 3, we will perform preclinical mouse studies testing the synergism of cancer vaccines and chemokine-regulatory regimens against primary and metastatic cancers, followed by phase clinical trials of selected therapies with DC-based vaccines combined with the prioritized tumor-selective CK- modulating regimens in patients with liver-metastatic CRC and patients with melanoma in transit. RELEVANCE (See instructions):

我们将检验这样一个假设，即DC和其他肿瘤相关细胞产生不同类型的细胞因子的能力， 趋化因子（CK）和吸引功能上不同的免疫细胞亚群的能力在肿瘤中被确定- 不同炎症介质的特定方式。此外，我们假设药理学 肿瘤CK环境的调节可用于选择性地促进疫苗接种的肿瘤进入。 诱导的1型效应T细胞（Jeff：Th 1和CTL）具有确定的CK受体表达，但不表达TcR。 我们的目标是开发与肿瘤匹配的药物组合的可靠治疗方法， 选择性地增强肿瘤病变内吸引Tef的CK的产生，以促进肿瘤细胞的增殖。 癌症免疫疗法的临床疗效。根据我们的初步数据，我们预计我们将能够 确定具有双重选择性的组合处理：A）选择性地提高Jeff- 吸引CK而不增强Treg吸引CK;和B）优先在肿瘤病变中有效，而不是 比健康的组织。对比黑色素瘤和结直肠癌，肿瘤转移到相同的 器官（肝脏），我们将确定肿瘤的组织学类型与其部位的各自作用 植入在确定当地CK生产，将确定细胞和分子机制， 健康组织、原发性和转移性癌症之间CK产生的差异，以及 这些组织对特定CK调节剂的不同反应性。 在特定目标1中，我们将确定哪些肿瘤特异性炎症因子，选择性地与肿瘤相关。 黑色素瘤或结直肠癌，确定CK生产的肿瘤相关细胞在体外，并规定 募集功能不同的免疫细胞亚群。我们将分析这些因素对 分离的DC和其他肿瘤相关细胞类型产生Jeff-attracting-vs. Treg-的能力， 吸引CK，并优先吸引Te/f v. Treg细胞。在具体目标2中，我们将确定 CRC、黑色素瘤和健康组织之间CK调节差异的机制， 校正黑色素瘤和CRC肿瘤中吸引Te/fv Treg的CK之间平衡的方法， 使用肿瘤外植体培养物的人离体模型和原发性和转移性肿瘤的小鼠体内模型， 肿瘤的在具体目标3中，我们将进行临床前小鼠研究，测试癌症的协同作用， 针对原发性和转移性癌症的疫苗和趋化因子调节方案， 基于DC的疫苗与优先的肿瘤选择性CK相结合的选定疗法的临床试验， 肝转移性CRC患者和转移中的黑色素瘤患者的调节方案。 相关性（参见说明）：