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

用于实体瘤转化的新型 IL-12 基因递送载体

• 批准号: 10542389
• 负责人: Seth M Pollack
• 金额: $ 48.16万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542389
• 关键词: Adaptive Immune System; Adoptive Cell Transfers; Aftercare; Alphavirus; Animal Hospitals; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Biological Assay; Biology; Biotechnology; Blood; CD209 gene; CD4 Positive T Lymphocytes; Cancer Patient; Cancerous; Canis familiaris; Categories; Cells; Cellular Immunity; Clinic; Clinical; Clinical Trials; Collaborations; Companions; Dangerousness; Dendritic Cells; Disease; Disease remission; Disease-Free Survival; Dose; Elements; Endothelial Cells; Engineering; Experimental Models; Flow Cytometry; Formulation; Gene Delivery; Human; Immune; Immune checkpoint inhibitor; Immunity; Immunohistochemistry; Immunotherapy; Impairment; Infiltration; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin-12; Interleukin-12 Gene; Investments; Kinetics; Lentivirus; Malignant Neoplasms; Methods; Modeling; Movement; Necrosis; Neoadjuvant Therapy; Oncology; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Production; Quality of life; RNA; RNA delivery; RNA replication; Regulatory T-Lymphocyte; Sampling; Serum; Soft Tissue Neoplasms; Soft tissue sarcoma; Solid Neoplasm; Sorting; Specificity; Specimen; System; T cell infiltration; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Up-Regulation; Veterinarians; Viral; Virus; cancer immunotherapy; cancer therapy; cellular transduction; clinical development; companion animal; cytokine; delivery vehicle; design; immune checkpoint; improved outcome; industry partner; intravenous administration; mouse model; neoplastic cell; novel; novel therapeutics; prevent; primary endpoint; recruit; single-cell RNA sequencing; synergism; targeted delivery; therapeutically effective; transcriptome sequencing; tumor; tumor immunology; tumor microenvironment; vector

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?

项目摘要/摘要 免疫疗法正在彻底改变肿瘤学，使许多患有侵略性疾病的癌症患者 享受持久的生活质量的持久弥补。但是，这些疗法通常对 “冷”实体瘤的患者的浸润细胞很少，抗原表现较低。 IL-12是 高度炎性细胞因子，具有转化癌症免疫疗法的潜力。它可以使“冷” 肿瘤“热”，驱动消除肿瘤作为单一药物，并与检查点抑制剂协同作用 多种实验模型中的养细胞疗法。尽管进行了多次IL-12的临床试验，但使用直接 静脉内给药或各种配方和车辆，找到一种最佳输送方法 仍然是其广泛临床使用的关键障碍。肿瘤内（IT）IL-12基因输送车辆是 目前正在临床上进行测试；但是，每个都有主要的缺点，可以阻止一般 执行。我们的小组一直在与位于西雅图的生物技术公司合作，Immune 设计，用于测试两个单独的新型且高度有希望的IL-12产生载体，用于基因递送。一个人使用 通过肿瘤的高水平IL-12产生的有效自我复制RNA输送系统。 另一个使用具有专门针对树突状细胞的包膜的慢病毒。 尽管两个实验矢量都可以消除肿瘤并防止在鼠模型中重新挑战，但 临床级病毒生产所需的大量投资损害了他们迅速进入 诊所。使用大型动物模型在自发癌中证明抗肿瘤功效将催化 生产临床级产品，因此在此提案中，我们将在自发的高度测试这两个矢量 伴侣动物中的软组织肉瘤。如果两个向量方法都是有效的，则分析 这里描述的将有助于确定哪个向量应朝着人类的测试迈进（使用人IL-12-- 包含构造）。此外，我们对这两个代理的比较将回答一个基本问题 癌症免疫学；即，尽管 较少的转导细胞和IL-12产生的总体水平较低？