Directing Tumor-specific T cells to Tumors

描述（由申请人提供）：我们将评估总体假设，即诱导肿瘤特异性效应T细胞上特定趋化因子受体（CKR）的疫苗与诱导肿瘤内选择性产生相关趋化因子的治疗的联合治疗将通过将肿瘤特异性T细胞导向肿瘤而产生治疗协同作用。我们的建议是基于我们开发的一种新的树突状细胞变体（aDC 1），具有独特的诱导肿瘤特异性T细胞上确定的CKR模式（选择性增强CXCR 3和CCR 5的表达）的能力，以及我们开发的几种互补策略，以选择性增强不同肿瘤组织中相关趋化因子的产生。该计划包括三个研究项目：项目1：结直肠癌与黑色素瘤中的肿瘤特异性趋化因子调节;项目2：CMS肿瘤中的1型抗原呈递细胞：有效抗肿瘤免疫的关键;项目3：肿瘤选择性溶瘤痘苗病毒和aDC 1疫苗作为结直肠癌的联合治疗。我们正在进行的黑色素瘤、结直肠癌和神经胶质瘤的临床试验将为第1-3年的实验室研究提供患者材料。在此期间开发的范例和方法将导致临床引入新的癌症联合疗法（疫苗接种+趋化因子靶向方案），并将在本计划的第4-5年进行临床测试。

DESCRIPTION (provided by applicant): We will evaluate the overall hypothesis that the combined treatment with the vaccines that induce particular chemokine receptors (CKR) on tumor-specific effector T cells with the treatments that induce the production of the relevant chemokines selectively within tumors, will result in therapeutic synergism, by directing tumorspecific T cells to tumors. Our proposal is based on our development of a new dendritic cell variant (aDC1s) with a unique ability of to induce a defined pattern of CKRs on tumor-specific T cells (selectively-enhanced expression of CXCR3 and CCR5), and our development of several complementary strategies to selectively enhance the production of the relevant chemokines in different tumor tissues. This Program involves three Research Projects: Project 1: Tumor-Specific Chemokine Modulation in Colorectal Cancer versus Melanoma; Project 2: Type-1 Antigen Presenting Cells in the CMS Tumors: the Key to Efficient Anti-tumor Immunity; Project 3: Tumor-selective Oncolytic Vaccinia Virus and aDC1-based Vaccine as a Combination Therapy for Colorectal Cancer. Our ongoing clinical trials in melanoma, colorectal cancer, and glioma, will provide the patient material for the laboratory studies proposed in years 1-3. The paradigms and methods developed within this period will result in the clinical introduction of new combination therapies of cancer (vaccination + chemokine-targeting regimen) that will be clinically tested in years 4-5 of this Program.