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

项目总结/摘要 免疫疗法正在彻底改变肿瘤学，使许多患有侵袭性疾病的癌症患者能够 享受持久的缓解和卓越的生活质量。然而，这些疗法通常对以下患者无效： 患有“冷”实体瘤的患者，这些肿瘤具有很少的浸润性T细胞和低水平的抗原呈递。il-12是 一种具有改变癌症免疫疗法潜力的高度炎症性细胞因子。它可以使"冷" 肿瘤“热”，作为单一药物驱动肿瘤消除，并与检查点抑制剂协同作用， 多个实验模型中的过继性细胞治疗。尽管对IL-12进行了多项临床试验，但使用直接 静脉内给药或各种制剂和载体，找到最佳的递送方法 仍然是其广泛临床应用的关键障碍。几种肿瘤内（IT）IL-12基因递送载体是 目前正在临床上进行测试;然而，这些方法中的每一种都有可能阻止一般的 实施.我们的团队一直在与西雅图的生物技术公司Immune合作， 设计，以测试两个独立的，新的和非常有前途的IL-12生产载体的基因传递。一个是用a 有效的自我复制RNA递送系统，以通过肿瘤递送高水平的IL-12产生。 另一种是使用一种慢病毒，它的包膜可以特异性地靶向树突细胞。 虽然两种实验载体都可以消除肿瘤并防止鼠模型中的再攻击，但 临床级病毒生产所需的大量投资阻碍了它们迅速进入 诊所使用大型动物模型来证明自发性癌症中的抗肿瘤功效将催化 临床级产品的生产，因此在本提案中，我们将在自发性高血压中测试这两种载体。 分级软组织肉瘤的伴侣动物。如果两种矢量方法都有效，则分析 本文所述的方法将有助于确定哪种载体应该用于人体试验（使用人IL-12 - 1， 包含构建体）。此外，我们对这两种药物的比较将回答一个基本问题， 癌症免疫学;即，IL-12向DC的精确递送能否实现上级抗肿瘤免疫， 更少的转导细胞和更低的IL-12产生的总体水平？

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?