Local blockade of IL10R on innate immune cells to mediate both innate and adaptive anti-tumor immunity

IL10R 对先天免疫细胞的局部阻断可介导先天和适应性抗肿瘤免疫

• 批准号: 10620165
• 负责人: Danny Khalil
• 金额: $ 26.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620165
• 关键词: Address; Advisory Committees; Affect; Agonist; Animals; Antigen-Presenting Cells; Antitumor Response; Area; Attention; Attenuated; Bilateral; Bioinformatics; Biological Assay; Blocking Antibodies; Cancer Model; Cancer Patient; Cells; Cellular biology; Clinical Research; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Dependence; Development; Disinhibition; Educational workshop; Feedback; Foundations; Funding; Goals; Human; Immune; Immune response; Immunology; Immunotherapy; Impairment; Implant; In Vitro; Innate Immune System; Interleukin-10; Investigation; Laboratories; Laboratory Study; Life; Lipid A; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Memory; Mentors; Methods; Modeling; Monoclonal Antibodies; Natural Immunity; Patient-Focused Outcomes; Patients; Phenotype; Population; Positioning Attribute; Receptor Cell; Records; Regimen; Research; Research Project Grants; Research Training; Resistance; Role; Scientist; Solid; System; T cell response; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; Testing; Training; Translating; Tumor Antigens; Tumor Immunity; Work; adaptive immune response; adaptive immunity; cancer immunotherapy; cancer type; career; cytokine; design; efficacy testing; exhaustion; experimental study; immune checkpoint blockade; improved; improved outcome; in situ cancer vaccination; in situ vaccination; in situ vaccine; in vivo Model; insight; interest; interleukin-10 receptor; knowledge base; meetings; melanoma; neoplastic cell; novel; preclinical study; programs; receptor; response; skills; standard of care; statistics; tenure track; therapeutic vaccine; tumor; tumor specificity; vaccination strategy

PROJECT SUMMARY Immune checkpoint blockade (ICB) has improved outcomes for patients with various malignancies by disinhibiting anti-tumor T cells; however, most cancer patients do not yet benefit from it. In situ vaccination (ISV), which converts tumors into therapeutic vaccines via direct intratumoral treatment, is under investigation as a means of potentiating ICB. ISV often consists of injecting tumors with agents that activate stimulatory receptors on antigen presenting cells (APCs). However, this method of ISV has not yet been translated into standard-of-care treatments for most cancer patients. This may be, in part, because of the secretion of inhibitory cytokines such as IL10 that confer negative feedback in response to ISV, and thus represent a critical barrier to progress in this field. Preliminary data in this proposal suggest that by incorporating an IL10 receptor- blocking antibody (αIL10R) into ISV, tumor control is significantly improved. These data further suggest that αIL10R enhances tumor control by two distinct mechanisms, and support the central hypothesis that αIL10R enhances innate immune cells' ability to control tumors, in various in situ vaccines, by both a direct and an indirect mechanism. The objective of this proposal is to interrogate this central hypothesis through the proposed Specific Aims. This work will provide ideal training for the candidate as he prepares for his long-term career goal of investigating the mechanisms by which innate immune cells can enhance the efficacy of cancer immunotherapy. Memorial Sloan Kettering Cancer Center has a renowned immunology program. Dr. Jedd Wolchok, the candidate's mentor, is a leader in the development of new immunotherapies, and the candidate's co-mentors are experts on distinct aspects of innate immune cell biology. All have strong track records of mentoring independent scientists. Together with the candidate and an interdisciplinary advisory committee, they have formulated a rigorous training plan designed to increase the candidate's knowledge base in (i) innate immunity, (ii) bioinformatics, especially regarding single-cell data, (iii) statistics, and (iv) practical skills related to professional development. Training in these areas will occur through formal coursework, workshops, and meetings with mentors and the advisory committee, who will evaluate the candidate's progress. This research project and training plan will provide the foundation for the candidate to transition to a tenure-track position leading an academic laboratory that is well positioned to compete for R01 funding. The candidate's ultimate aim is to define new ways to enhance immunotherapy through the innate immune system, and thereby extend life for patients with a range of solid cancers.

项目概要 免疫检查点阻断 (ICB) 通过以下方式改善了各种恶性肿瘤患者的预后 抑制抗肿瘤 T 细胞；然而，大多数癌症患者尚未受益于原位疫苗接种。 （ISV），通过直接瘤内治疗将肿瘤转化为治疗性疫苗，正在研究中 作为增强 ICB 的一种手段，通常包括向肿瘤注射激活刺激剂。 然而，ISV的这种方法尚未转化为抗原呈递细胞（APC）上的受体。 大多数癌症患者的标准护理治疗可能部分是由于分泌的。 抑制性细胞因子，例如 IL10，对 ISV 产生负反馈，因此代表了一个关键的细胞因子 该提案中的初步数据表明，通过纳入 IL10 受体 - 阻断抗体（αIL10R）进入ISV，肿瘤控制得到显着改善。 αIL10R 通过两种不同的机制增强肿瘤控制，并支持 αIL10R 的中心假设 在各种原位疫苗中，通过直接和间接增强先天免疫细胞控制肿瘤的能力 该提案的目的是通过间接机制质疑这一中心假设。 提出的具体目标。 这项工作将为候选人提供理想的培训，帮助他为自己的长期职业目标做准备 研究先天免疫细胞增强癌症功效的机制 纪念斯隆凯特琳癌症中心拥有著名的杰德博士免疫学项目。 候选人的导师 Wolchok 是新免疫疗法开发领域的领导者，而候选人的 共同导师都是先天免疫细胞生物学不同方面的专家，他们都拥有丰富的跟踪记录。 与候选人和跨学科咨询委员会一起指导独立科学家， 他们制定了严格的培训计划，旨在增加候选人在以下方面的知识基础：(i) 与生俱来的 免疫，（ii）生物信息学，特别是单细胞数据，（iii）统计学，以及（iv）相关实用技能 这些领域的培训将通过正式课程、研讨会和 与导师和咨询委员会举行会议，他们将评估候选人的研究进展。 项目和培训计划将为候选人过渡到终身职位提供基础 领导一个学术实验室，该实验室处于竞争 R01 资金的有利地位。 目的是确定通过先天免疫系统增强免疫治疗的新方法，从而扩展 患有一系列实体癌症的患者的生活。