权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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?

项目总结/文摘