Novel IL-12 Gene Delivery Vehicles for Transformation of Solid Tumors

项目摘要/摘要 免疫疗法正在给肿瘤学带来革命性的变化，使许多患有侵袭性疾病的癌症患者 享受持久的缓解和卓越的生活质量。然而，这些疗法通常对 患有“冷”实体瘤的患者，其浸润性T细胞很少，抗原提呈水平较低。IL-12是 一种高度炎症的细胞因子，有可能改变癌症免疫治疗。它能让人“冷”起来 肿瘤热，作为单一药物推动肿瘤消除，并与检查点抑制剂和 多种实验模型中的过继细胞治疗。尽管对IL-12进行了多项临床试验，但直接使用 静脉给药或多种制剂和载体，寻找最佳给药方法 仍然是其广泛临床应用的关键障碍。几种肿瘤内(IT)IL-12基因传递载体是 目前正在进行临床测试；然而，每种方法都有重大缺陷，可能会阻止一般情况 实施。我们的团队一直在与总部位于西雅图的生物技术公司免疫 设计，以测试两个独立的，新颖的和非常有希望的IL-12生产载体的基因传递。一种是使用 强大的自我复制RNA递送系统，通过肿瘤递送高水平的IL-12。 另一种使用的是带有包膜的慢病毒，该病毒专门针对树突状细胞。 虽然这两种实验载体都可以在小鼠模型中消除肿瘤并防止再次挑战，但 生产临床级病毒所需的大量投资阻碍了它们迅速进入 诊所。在自发性癌症中使用大型动物模型来证明抗肿瘤效果将催化 生产临床级别的产品，因此在本方案中，我们将在自发高电压下测试这两个载体 对同伴动物软组织肉瘤进行分级。如果这两种向量方法都有效，那么分析 这里描述的将有助于确定哪个载体应该进入人体试验(使用人IL-12- 包含构造物)。此外，我们对这两个代理的比较将回答一个基本的问题 癌症免疫学；即，精确地将IL-12输送到DC是否能够获得卓越的抗肿瘤免疫能力 更少的转导细胞和更低水平的IL-12产生？

Project Summary/Abstract Immunotherapies are revolutionizing oncology allowing many cancer patients with aggressive disease to enjoy durable remissions with excellent quality of life. However, these therapies are generally not effective for patients with "cold" solid tumors that have few infiltrating T cells and low levels of antigen presentation. IL-12 is a highly inflammatory cytokine with the potential to transform cancer immunotherapy. It can make "cold" tumors "hot", drive elimination of tumors as a single agent and synergize with checkpoint inhibitors and adoptive cellular therapy in multiple experimental models. Despite multiple clinical trials of IL-12, using direct intravenous administration or a variety of formulations and vehicles, finding an optimal delivery method remains a critical barrier to its widespread clinical use. Several intra-tumor (IT) IL-12 gene delivery vehicles are currently being tested clinically; however each of these has major drawbacks that could prevent general implementation. Our group has been collaborating with the Seattle-based biotechnology company, Immune Design, to test two separate, novel and highly promising IL-12-producing vectors for gene delivery. One uses a potent self-replicating RNA delivery system to delivery high levels of IL-12 production through out the tumor. The other uses a lentivirus with an envelope that specifically targets dendritic cells. While both experimental vectors can eliminate tumors and prevent re-challenge in murine models, the significant investment required for clinical-grade virus production has impaired their swift movement into the clinic. Using a large animal model to demonstrate anti-tumor efficacy in a spontaneous cancer will catalyze the production of a clinical-grade product, thus in this proposal we will test both these vectors in spontaneous high grade soft tissue sarcomas in companion animals. If both vector approaches are efficacious, the analysis described here will help identify which vector should move towards testing in humans (using a human IL-12- containing construct). Furthermore, our comparison of these two agents will answer a fundamental question in cancer immunology; i.e., can precise delivery of IL-12 to DCs achieve superior anti-tumor immunity despite fewer transduced cells and a lower overall level of IL-12 production?