Lymph node-targeted multistage chemoimmunotherapy for lymphoma

淋巴瘤的淋巴结靶向多阶段化学免疫治疗

• 批准号: 10532591
• 负责人: M.G. Finn
• 金额: $ 8.28万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532591
• 关键词: Abscopal effect; Activation Analysis; Agammaglobulinaemia tyrosine kinase; Animals; B-Lymphocytes; Biocompatible Materials; Biological Models; Blood; C57BL/6 Mouse; Cell Density; Cell Maturation; Cells; Cutaneous Lymphoma; Dendritic Cells; Dermal; Development; Diagnosis; Disease; Disease Progression; EZH2 gene; Engineering; Evaluation; Exhibits; Follicular Lymphoma; Formulation; Frequencies; Gel; Goals; Granzyme; Histology; Human; Hydrogels; IL2RA gene; Immune; Immuno-Chemotherapy; Immunocompetent; Immunologics; Immunotherapeutic agent; Immunotherapy; Implant; Infiltration; Injections; Interferon Type II; Lesion; Ligands; Lymphocyte; Lymphoid; Lymphoid Tissue; Lymphoma; Measurement; Measures; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Non-Hodgkin' s Lymphoma; Outcome; Peptides; Pharmaceutical Preparations; Phenotype; Polymers; Randomized; Saline; Site; Skin; Skin Neoplasms; System; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutic; Time; Tumor Burden; Tumor Volume; Tumor stage; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; Ursidae Family; Variant; Weight; Work; anti-CD20; anti-PD-L1; base; cohort; curative treatments; cytokine; design; efficacious treatment; human disease; humane endpoint; immune activation; immune resistance; implantation; improved; in vivo; intradermal injection; lymph nodes; malignant lymphocyte; matrigel; nanoformulation; nanoparticle; novel therapeutic intervention; parent grant; programs; resistance mechanism; response; scaffold; skin lesion; targeted treatment; therapeutic evaluation; tumor; tumor growth; tumor-immune system interactions

PROJECT SUMMARY Follicular lymphoma (FL) arises from B lymphocytes and accounts for ~25% of non-Hodgkin’s lymphoma cases. With no existing curative treatments and only ~2.6% of cases resolving, FL is presently considered an incurable disease. New therapeutic approaches to therapeutically treat FL are thus critically needed. Contributing to the lack of efficacious therapies is the fact that both primary and secondary FL cases can arise in skin. Dermal lesions appear to exhibit unique immune resistance mechanisms making them a challenging lymphoma presentation to treat. Studies on immunotherapeutic response by dermal FL lesions are limited however by existing FL models. It is well accepted that the immune microenvironments in which most FL tumors arise and disseminate to – lymphoid tissues – are vastly different from the skin. A major gap in the field’s ability to develop new immunotherapies effective against skin FL is the gap in appropriate tumor models to test immunotherapies in the context their skin presentation. This project seeks to overcome this hurdle by designing a cell matrix vehicle that induces reliable and consistent tumor formation, as well as programmable immune infiltration for enhanced consistency and relevance to human disease to test immunotherapeutic efficacy against skin FL. The parent grant will utilize nanoparticle and bioconjugation technologies that when used together deliver molecular drugs to within lymph nodes to improve their therapeutic bioactivity. The proposed work under this supplement seeks to enable the evaluation of how abscopal effects elicited by the lymph node-targeted nanoformulation on lymphoma lesions that form in skin are altered by the local immune microenvironment of the skin tumor by engineering a matrix vehicle scaffold that enables consistent skin tumor formation. The goals of this proposal will be accomplished in a stepwise fashion. First, we will analyze effects of matrix vehicle composition on the formation rate, latency, and immune microenvironments of skin tumors formed from malignant lymphocytes from the Bcl6-EZH2 lymphoma model. Second, we will evaluate how lymph node- versus non-targeted chemoimmunotherapy control of skin lymphomas varies by the local immune microenvironment. Successful outcomes in this work will have broad significance and impact by establishing both a model system for immunotherapy testing relevant to human lymphoma as well as determining the effects of lymph node targeted therapies on eliciting robust abscopal effects against skin tumors.

项目摘要 卵泡淋巴瘤（FL）来自B淋巴细胞，占非霍奇金的约25％ 淋巴瘤病例。没有现有的治疗方法，只有约2.6％的案件解决，佛罗里达州是 目前认为是一种无法治愈的疾病。治疗治疗的新治疗方法是 因此需要至关重要。导致缺乏有效疗法的原因是主要和 次要FL病例可能在皮肤中出现。真皮病变似乎表现出独特的免疫抗性 机制使其成为治疗的挑战淋巴瘤表现。研究 然而，现有的FL模型受到了真皮FL病变的免疫治疗反应受到限制。很好 接受大多数FL肿瘤的免疫微环境并传播到 - 淋巴组织 - 与皮肤大不相同。该领域发展新的能力的主要差距 对皮肤有效的免疫疗法是适当的肿瘤模型中的差距 在其皮肤表现的情况下，免疫疗法。这个项目旨在克服这个障碍 设计一种诱导可靠且一致的肿瘤形成的细胞基质车辆以及 可编程的免疫浸润，以提高一致性和与人类疾病的相关性 对皮肤FL的免疫治疗效率。父母赠款将利用纳米颗粒和 生物偶联技术一起使用，当一起使用分子药物在淋巴结内部 改善其治疗性生物活性。该补品下的拟议工作旨在使 评估淋巴结靶标对淋巴瘤引起的潜线作用如何引起的 皮肤中形成的病变会因皮肤肿瘤的局部免疫微环境而改变 工程矩阵车辆脚手架，可以使皮肤肿瘤形成一致。目标的目标 提案将以逐步的方式完成。首先，我们将分析矩阵车辆的效果 由皮肤肿瘤形成的形成率，潜伏期和免疫微环境的组成 来自BCL6-EZH2淋巴瘤模型的恶性淋巴细胞。其次，我们将评估淋巴 淋巴结与非靶向性化学免疫疗法控制皮肤淋巴瘤的控制因局部而异 免疫微环境。这项工作的成功成果将具有广泛的意义和影响 通过建立与人淋巴瘤相关的免疫疗法测试模型系统 确定淋巴结靶向疗法对引起强大的脱节作用的影响 皮肤肿瘤。