Reprogramming Cancer Cells into Antigen Presenting Cells: Cancer Vaccination with mRNA Enabled by Charge-Altering Releasable Transporters

将癌细胞重编程为抗原呈递细胞：通过改变电荷的可释放转运蛋白实现 mRNA 的癌症疫苗接种

• 批准号: 10153927
• 负责人: Blaine McCarthy
• 金额: $ 6.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-16 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10153927
• 关键词: Active Immunotherapy; Address; Affect; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biodistribution; Biological Sciences; CCAAT-Enhancer-Binding Protein-alpha; CD86 gene; Cancer Vaccine Related Development; Cancer Vaccines; Cations; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Charge; Chemistry; Clinic; Collaborations; Development; Disease; Exhibits; FDA approved; Fellowship; Future; Gene Delivery; Genes; Genetic; Genetic Vectors; Genome; Goals; Health; Human; Immune; Immune Targeting; Immune response; Immune system; Immunologic Memory; Immunologist; Immunooncology; Immunotherapy; Institution; Investigation; Knowledge; Learning; MHC Class I Genes; Malignant Neoplasms; Mediating; Medicine; Mentors; Messenger RNA; Methods; Mission; Modeling; Modification; Myelogenous; Nucleic Acids; Oncogenes; Organism; Patients; Proteins; RNA vaccine; Research; Research Personnel; Signal Pathway; Signal Transduction; Structure; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Techniques; Technology; Therapeutic; Tumor-infiltrating immune cells; United States National Institutes of Health; Vaccination; Vaccines; Work; base; cancer cell; cancer immunotherapy; cancer therapy; cancer vaccination; career; design; effector T cell; immune activation; improved; in vivo; innovation; insight; interdisciplinary collaboration; lipophilicity; macrophage; neoplastic cell; novel; patient population; personalized therapeutic; post-doctoral training; professor; protein expression; stem; therapeutic gene; transcription factor; treatment effect; treatment strategy; tumor; vaccination strategy; vaccine delivery; vaccine development; vaccine efficacy; vector

Cancer vaccines have the potential to provide potent and personalized therapeutics with long-lasting effects for treatment of the ~100 million people worldwide currently affected by this disease. While recent advances have led to the first FDA-approved cancer vaccines, treatments that are broadly effective across patient populations remain elusive. As such, there is a critical need to develop cancer vaccines that operate via fundamentally new mechanisms that enable greater potency. The overall goal of this work is to leverage recent advances in gene delivery and cell reprogramming to develop a cancer vaccine that directly reprograms cancer cells into anti-tumor immune cells. The proposed work will be executed in the lab of Prof. Robert Waymouth (chemistry) at Stanford and in close collaboration with Prof. Paul Wender (chemistry), Prof. Ravindra Majeti (medicine), and Prof. Ronald Levy (medicine). Through this interdisciplinary collaboration of chemists and cancer immunologists, vaccines that operate by a unique cell reprogramming mechanism will be developed and the efficacy of these vaccines will be evaluated in cell lines and vertebrate models. One critical barrier that hinders the potency of current cancer vaccination approaches is insufficient activation of immune cells (T cells) due to inefficient antigen presentation or lack of costimulatory signals. To overcome this barrier, a new cancer vaccination strategy will be developed that directly reprograms cancer cells into immune cells that exhibit cancer-derived antigens and the proper costimulatory molecules for efficient T cell activation. To realize this goal, gene delivery vehicles will be developed for cancer cell reprogramming and relationships between their molecule structure and function (i.e. protein expression and biodistribution) will be elucidated (Aim 1). These gene delivery vehicles will be used to reprogram cancer cells into antigen presenting cells (APCs) using cell lines and vertebrate models (Aim 2). The ability of reprogrammed APCs to elicit a cancer- targeted immune response and establish immunological memory will be investigated (Aim 3). These studies are anticipated to lay the groundwork for future application of this technology in the clinic and add to the growing body of knowledge on gene delivery, cell reprogramming, and cancer vaccine development. In line with the mission of the NIH, the fundamental knowledge and therapeutic technology developed through this work will improve the future of human health by helping to treat cancer, one of the most prevalent and deadly diseases. The candidate will use this postdoctoral training fellowship to grow as an intellectual and researcher in the biological sciences by learning a suite of new experimental techniques and theoretical concepts that compliment her expertise in chemistry. The unique support provided by this fellowship, the chosen sponsor (Prof. Waymouth), key collaborators (Professors Wender, Majeti, and Levy), and research institution (Stanford) will enable the applicant to progress as a researcher and mentor and engage in professional development activities to accelerate the trajectory of her future career towards becoming a professor at an R1 institution.

癌症疫苗有潜力提供有效和个性化的治疗方法， 治疗目前全世界受这种疾病影响的约1亿人的效果。虽然最近 这些进展导致了第一批FDA批准的癌症疫苗，这些治疗方法在各个领域都广泛有效。 患者群体仍然难以捉摸。因此，迫切需要开发通过以下途径起作用的癌症疫苗： 从根本上说，新的机制，使更大的潜力。这项工作的总体目标是利用最近的 基因传递和细胞重编程的进展，以开发直接重编程癌症的癌症疫苗 转化为抗肿瘤免疫细胞。拟议的工作将在罗伯特·韦茅斯教授的实验室执行 （化学）在斯坦福大学，并密切合作，教授保罗温德（化学），教授Ravindra Majeti （医学）和罗纳德利维教授（医学）。通过化学家和癌症的跨学科合作 根据免疫学家的说法，将开发出通过独特的细胞重编程机制运作的疫苗， 将在细胞系和脊椎动物模型中评价这些疫苗的效力。 阻碍当前癌症疫苗接种方法效力的一个关键障碍是活化不足 免疫细胞（T细胞）由于低效的抗原呈递或缺乏共刺激信号。克服 这一屏障，一种新的癌症疫苗接种策略将被开发出来，直接将癌细胞重新编程为 免疫细胞表现出癌源性抗原和适当的共刺激分子， activation.为了实现这一目标，将开发用于癌细胞重编程的基因递送载体， 它们的分子结构和功能（即蛋白质表达和生物分布）之间的关系将是 目的1（Aim 1）这些基因传递载体将用于将癌细胞重编程为抗原呈递 使用细胞系和脊椎动物模型（Aim 2）的APCs。重新编程的APC诱发癌症的能力- 将研究靶向免疫应答和建立免疫记忆（目的3）。这些研究 预计将为这项技术在临床上的未来应用奠定基础，并增加日益增长的 关于基因传递、细胞重编程和癌症疫苗开发的知识体系。为配合 NIH的使命，通过这项工作开发的基础知识和治疗技术将 通过帮助治疗癌症来改善人类健康的未来，癌症是最流行和最致命的疾病之一。 候选人将利用这个博士后培训奖学金成长为知识分子和研究人员， 通过学习一套新的实验技术和理论概念， 她在化学方面的专长。该奖学金提供的独特支持，选定的赞助商（教授。 Waymouth）、主要合作者（Wender、Majeti和Levy教授）和研究机构（斯坦福大学）将 使申请人能够作为研究人员和导师取得进展，并从事专业发展活动 加速她未来职业生涯的轨迹，成为R1机构的教授。

项目成果

An mRNA SARS-CoV-2 Vaccine Employing Charge-Altering Releasable Transporters with a TLR-9 Agonist Induces Neutralizing Antibodies and T Cell Memory.

• DOI: 10.1021/acscentsci.1c00361
• 发表时间: 2021-07-28
• 期刊: ACS central science
• 影响因子: 18.2
• 作者: Haabeth OAW;Lohmeyer JJK;Sallets A;Blake TR;Sagiv-Barfi I;Czerwinski DK;McCarthy B;Powell AE;Wender PA;Waymouth RM;Levy R
• 通讯作者: Levy R