New Materials to Deliver mRNA: Applications in Cancer Immunotherapy

传递 mRNA 的新材料：在癌症免疫治疗中的应用

• 批准号: 10237935
• 负责人: RONALD LEVY
• 金额: $ 52.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10237935
• 关键词: Address; Adoptive Cell Transfers; Amides; Amines; Animals; Antigens; Antitumor Response; Autologous; B-Lymphocytes; Biometry; Blocking Antibodies; Cancer Model; Cancer Vaccines; Catalysis; Cations; Cell Culture Techniques; Cells; Charge; Chemical Structure; Clinic; Clinical Research; Collaborations; Complex; Confocal Microscopy; Cryoelectron Microscopy; Development; Drug Delivery Systems; Effectiveness; Electroporation; Engineering; Evaluation; Family; Formulation; Gene Expression; Genetic Engineering; Goals; Human; Hybrids; Imaging Techniques; Immune response; Immune system; Immunity; Immunoglobulin Idiotypes; Immunologist; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Lactams; Length; Lipids; Lymphocyte; Lymphoma; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Microbiology; Modeling; Molecular Biology; Molecular Immunology; Morbidity - disease rate; Mus; Neomycin resistance gene; Non-Viral Vector; Organ; Patients; Pharmaceutical Chemistry; Pre-Clinical Model; Procedures; Proteins; RNA; Research; Signal Pathway; Specificity; Structure; Synthesis Chemistry; System; T cell response; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toxic effect; Translations; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Variant; Viral Vector; animal imaging; antigen-specific T cells; base; cancer immunotherapy; cancer therapy; cancer vaccination; cell type; chimeric antigen receptor; clinical investigation; clinically relevant; combinatorial; cytotoxicity; density; design; disorder prevention; effective therapy; effectiveness evaluation; effector T cell; gene therapy; immune checkpoint blockade; immunogenicity; improved; in vivo; interdisciplinary approach; iterative design; lipid nanoparticle; mRNA Expression; mRNA delivery; mortality; mouse model; multidisciplinary; neoantigens; neoplastic cell; novel; novel vaccines; patient population; pre-clinical; protein expression; response; tumor; uptake; vaccination strategy; vector; zeta potential

Project Summary: Cancer is a leading global cause of mortality. The goal of this multi-disciplinary project is to pre-clinically advance a novel concept for selective and efficient mRNA delivery that enables a highly promising vaccination strategy for cancer immunotherapy. Given the potential of cancer vaccination to both generate new antigen-specific T cell responses against tumor cells and amplify existing responses, cancer vaccination could be an especially effective therapy on its own or in combination with, e.g., check- point blockade. Through a unique collaboration of chemists, cancer immunologists and biostatisticians we propose to advance just such a method called CART-RNA which in preliminary studies has produced cures of up to 80% in animals with established tumors. The critical technological challenge for mRNA and all gene-based therapies is the development of safe, effective, accessible and selective mRNA delivery vectors. This project exploits a unique class of charge-altering releasable transporters (CARTs) that complex, protect and selectively deliver mRNA to target cells/organs and then release mRNA intracellularly through an unprecedented charge-altering mechanism, mediating exceptionally effective translation to proteins both in cell culture and in live animals. The three interrelated specific aims are directed at the design and evaluation of novel CARTs that deliver mRNA to a variety of cell types, elicit functional protein expression, and induce a therapeutic immunological response. Aim 1 leverages the synthetic expertise of the team and the ease of formulation of CART-RNA vectors to assess the relationship of CART chemical structure, formulation and administration to the efficiency and selectivity of protein expression in culture and in live animals. Aim 2 is directed at the evaluation of CART-RNA vaccination to elicit protective immunological responses in validated mouse models for cancer immunotherapy. Aim 3 focuses on pre-clinical investigations to elicit protective immunity against clinically-relevant antigens (specifically B- and T-cell lymphoma idiotypes) in primary human cells from human patients. This project exploits an interdisciplinary approach that integrates materials design and synthesis, chemistry, microbiology, non-invasive cellular and live animal imaging, immunology and biostatistics to develop, evaluate and refine strategies for the development of novel vaccines based on the new CART- RNA platform. Cellular and live animal imaging techniques will be employed to assess the efficiency of both mRNA delivery and expression as a function of mode of administration in mice. This research will identify and clarify design criteria for engineering effective mRNA delivery systems and the effectiveness of mRNA-based approaches for immunotherapy. This project is directed at new families of superior transfecting agents for mRNA delivery and mRNA vaccination for treating and curing cancer.

项目摘要：癌症是全球主要的死亡原因。这个多学科的目标