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):

我们将检验以下假设：DC和其他与肿瘤相关细胞产生不同集的能力 趋化因子（CK）和吸引功能上不同的免疫细胞亚群，在肿瘤中确定 通过不同的炎症介体的特定方式。此外，我们假设药理 肿瘤CK环境的调节可用于选择性促进疫苗接种的肿瘤进入 诱导1型效应T细胞（Jeff：TH1和CTL）具有CK受体的定义表达，但没有Treg。 我们的目标是开发具有药理剂肿瘤匹配组合的可靠治疗方法 有选择地增强肿瘤病变中提高TEFF的CK的产生，以促进 癌症免疫疗法的临床功效。根据我们的初步数据，我们希望我们能够 确定具有双重选择性的组合处理：a）选择性增强Jeff-的产生 吸引CK而不增强Treg吸引CK的CK； b）优先在肿瘤病变中有效 比健康的组织。对比的黑色素瘤和结直肠癌，肿瘤转移至相同 器官（肝脏），我们将确定肿瘤组织学类型的各自作用与其部位 在确定局部CK产生时植入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的不同CK产生以及 此类组织对特定CK调节剂的差异反应性。 在特定目标1中，我们将确定哪些肿瘤特异性炎症因子有选择地与 黑色素瘤或CRC，在体外确定与肿瘤相关细胞的CK产生，并决定 募集免疫细胞功能差异的子集。我们将分析此类因素对 分离的DC和其他与肿瘤相关的细胞类型产生Jeff吸引人与Treg-的能力 吸引CK，并优先吸引TE/Fv。Treg细胞。在特定的AIM2中，我们将确定 CRC，黑色素瘤和健康组织中CK调节差异的机制，并将发展 纠正黑色素瘤和CRC肿瘤中TE/FV吸引CK之间平衡的方法， 使用肿瘤外植体培养物的人体离体模型和小鼠在原发性和转移性的体内模型中 肿瘤。在特定目标3中，我们将进行临床前小鼠研究测试癌症的协同作用 疫苗和趋化因子调节方案针对原发性和转移性癌症，然后是相位 基于直流疫苗的选定疗法的临床试验以及优先的肿瘤选择性CK- 调节肝脏中转移性CRC患者和过境中黑色素瘤患者的治疗方案。 相关性（请参阅说明）：