Cytokine Gene Therapy of Cancer - Preclinical Studies

我们的“癌症细胞因子基因治疗：临床前研究”的统一假设是，将细胞因子基因转移到肿瘤微环境中将促进细胞抗肿瘤免疫的增强招募、多样性、功能和维持。如果应用得当，CGT将有效地促进外周和脑内肿瘤的消退，并导致主要由1型效应T细胞介导的持久的抗肿瘤保护。了解CGT在抗肿瘤反应的传入和传出臂上的疗效的免疫生物学基础将为那些最有希望的CGT应用最终转化为治疗不同形式癌症患者的临床试验提供重要线索。重要的是，我们的研究将应用于两个临床相关的 这些研究包括：1)反映人类疾病的模型系统；1)扩散到肺、肝和脑的自发的皮下黑色素瘤，在疾病晚期患者中通常是致命的；2)模仿人类疾病的颅内黑色素瘤和胶质瘤模型，在这些疾病中致命性很常见，目前几乎没有可用的治疗方案。我们提出了三个临床前项目，将评估单一模式和联合CGT对肿瘤免疫诱导阶段和肿瘤微环境内“临床相关”免疫效应阶段的影响。 以CGT为条件。我们根据细胞因子促进和维持1型免疫、增强白细胞对肿瘤病变的渗透和促进肿瘤抗原特异性交叉压强的能力，选择了特定的细胞因子应用于CGT治疗。联合细胞因子基因治疗方法将根据选定方式(包括树突状细胞疫苗和细胞因子GT)和细胞因子在促进治疗性1型免疫方面的已知或假想的免疫生物学协同作用而被选择进行评估。这一高度整合的努力如果成功，将为开发创新、安全和有效的癌症CGT方法提供基础。我们的3个项目是：项目1.基于DC的 中枢神经系统(CNS)肿瘤的细胞因子基因免疫治疗；项目2.IL-12基因治疗，以激活和重新极化抗肿瘤Th1型T细胞，并增强表位扩散；项目3.IL-18和IL-1 H4基因治疗，以促进固有和特异性肿瘤免疫。

The unifying hypothesis of our "Cytokine Gene Therapy (CGT) of Cancer: Preclinical Studies" PPG is that the transfer of cytokine genes into the tumor microenviroment will promote enhanced recruitment, diversity, function, and maintenance of cellular anti-tumor immunity. When properly applied, CGT will be effective in promoting tumor regression in both the periphery and the brain and result in prolonged anti-tumor protection, principally mediated by Type-1 effector T ceils. The understanding of the immunobiology underlying the efficacy of of CGT on the afferent and efferent arms of the anti-tumor response will provide major cues for the ultimate translation of those most promising CGT applications into clinical trials for the treatment of patients with diverse forms of cancer. Importantly, our studies will be applied to two clinically-relevant model systems that reflect human disease; 1) spontaneously metatasizing subcutaneous melanomas that disseminate to lungs, liver and brain and which are frequently lethal in advanced disease stage patients, and 2) intracranial melanoma and glioma models that mimic human disease where lethality is common and few treatment options are currently available. We propose three pro-clinical projects that will evalute the impact of single-modality and combinational CGT on both the induction phases of tumor immunity and the fortification of the effector phases of "clinically relevant" immunity within the tumor microenvironment conditioned by CGT. We have chosen the specific cytokines for appication in CGT approaches based on their abilities to promote and sustain Type-1 immunity, to enhance leukocyte infiltrate into tumor lesions and to facilitate tumor antigen-specific crosspresentation. Combinational cytokine gene therapy approaches will be selected for evaluation based on the known or hypothesized immunobiologic synergy of the selected modalities (including both dendritic cell-based vaccines and cytokine GT) and cytokines in promoting therapeutic Type-1 immunity. This highly-integrated effort, if successful, will provide the basis for developing innovative, safe and effective CGT approaches for cancer. Our 3 Projects are: Project 1. DC-Based Cytokine Gene Immunotherapy for Central Nervous System (CNS) Tumors; Project 2. IL-12 Gene Therapy to Prime and Repolarize Anti-Tumor Th1-type T cells and enhance Epitope Spreading; Project 3. IL-18 and IL-1 H4 gene therapy to promote innate and specific tumor immunity.