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Engineered Vaccines for Neoantigen Targeted Cancer Immunotherapy

用于新抗原靶向癌症免疫治疗的工程疫苗

基本信息

批准号：
10522928
负责人：
John Tanner Wilson
金额：
$ 63.82万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522928
关键词：
Address Adjuvant Agonist Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Artificial nanoparticles Blood Circulation CD8-Positive T-Lymphocytes Cancer Vaccines Cell Maturation Cellular Immunity Characteristics Charge Clinical Clinical Treatment Data Dendritic Cells Development Dinucleoside Phosphates Drug Delivery Systems Endosomes Engineering Formulation Goals Homing Hydrophobicity Immune response Immunologics Immunosuppression Immunotherapy Infiltration Inflammatory Response Interferon Type I Investigation Length Libraries Link Lipids Malignant Neoplasms Mediating Minority Modeling Morphology Mutation Myeloid Cells N-terminal Natural Immunity Patients Peptides Periodicity Pharmacologic Substance Pharmacology Polymers Property Publishing Readiness Regimen Research Resistance Science Shapes Signal Transduction Solid Neoplasm Stimulator of Interferon Genes T cell response T-Cell Activation T-Lymphocyte TLR4 gene Technology Testing Tumor Immunity Tumor-Derived Tumor-infiltrating immune cells Vaccination Vaccine Adjuvant Vaccine Therapy Vaccines Vesicle adaptive immunity base cancer immunotherapy cancer therapy clinical translation combinatorial cytotoxic cytotoxic CD8 T cells design immune checkpoint blockade immunoengineering immunogenicity improved improved outcome insight lipophilicity lymph nodes multidisciplinary nano nanoparticle nanoscale neoantigen vaccine neoantigens novel novel strategies novel therapeutics particle personalized immunotherapy protein aminoacid sequence recruit response success synchronous delivery synergism therapeutic vaccine therapy outcome treatment response tumor tumor immunology tumor microenvironment vaccine delivery vaccine efficacy vaccine platform virtual

项目摘要

PROJECT SUMMARY Immune checkpoint blockade (ICB) is an immunotherapy that is revolutionizing cancer treatment, but is effective in a minority of patients. Across many solid tumor types, this can largely be ascribed to an insufficient number, diversity, and/or function of endogenously generated, pre-existing T cells that recognize tumor neoantigens and infiltrate tumors. Therefore, there is a critical need for new strategies to bolster the magnitude, breadth, and quality of neoantigen-specific T cells, to recruit cytotoxic CD8+ T cells to tumors, and to amplify their expansion, effector function, and persistence. Towards this goal, we propose a new strategy for neoantigen-targeted cancer immunotherapy. Our approach leverages a STING-activating nanoparticle vaccine (STAN-V) that we have designed to overcome several critical immunopharmacological barriers that limit cancer vaccine efficacy. The STAN-V platform is based on polymer nanoparticles engineered to enhance intracellular co-delivery of peptide neoantigen and agonists of stimulator of interferon genes (STING), a design that we have demonstrated stimulates potent neoantigen-specific CD8+ T cells and increases response to ICB. Our objective in this R01 application is to advance and mature STAN-V as a universal platform for neoantigen- targeted cancer vaccines. We will accomplish this through the following Specific Aims. First, we will develop and optimize a facile strategy for rapid fabrication of STAN-Vs based on spontaneous and efficient loading of neoantigenic peptides designed with optimized lipophilic domains. We will evaluate the capacity of this approach to increase the magnitude and breadth of neoantigen-specific T cell responses to physicochemically diverse neoantigens. As such, we expect these studies to advance the translational-readiness of STAN-Vs as a personalized vaccine technology. Second, we will leverage the unique morphology and properties of STAN- Vs to develop and optimize a novel adjuvant combination based on coordinated co-packaging and co-delivery of STING and TLR agonists. We will systematically explore the effect of combinatorial adjuvant delivery on innate and adaptive immunity, studies that we expect will yield an optimized adjuvant combination for stimulating antitumor cellular immunity. Third, we will devise and test a new approach for enhancing tumor homing and infiltration of T cells elicited via vaccination. This strategy will leverage systemic administration of a nanoparticle STING agonist that reshapes the tumor milieu to enhance T cell infiltration, proliferation, and function. Overall, these studies will advance STAN-Vs as an enabling and versatile technology for stimulating robust neoantigen-specific T cell responses and improving outcomes of immunotherapy across many cancers.

项目总结