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 滤泡性淋巴瘤（FL）起源于B淋巴细胞，约占非霍奇金淋巴瘤的25% 淋巴瘤病例。由于没有现有的治愈性治疗方法，只有~2.6%的病例消退，FL是 目前被认为是不治之症。治疗FL的新的治疗方法是 因此非常需要。导致缺乏有效治疗的原因是， 继发性FL病例可发生在皮肤中。皮肤病变似乎表现出独特的免疫抵抗力 机制，使他们成为一个具有挑战性的淋巴瘤介绍治疗。 然而，通过皮肤FL损伤的免疫应答受到现有FL模型的限制。公 接受大多数FL肿瘤产生和传播的免疫微环境- 淋巴组织-与皮肤有很大的不同。该领域开发新技术的能力存在重大差距， 有效对抗皮肤FL的免疫疗法是测试合适肿瘤模型的差距 免疫疗法在其皮肤呈现的背景下。本项目旨在通过以下方式克服这一障碍： 设计诱导可靠和一致的肿瘤形成的细胞基质载体，以及 可编程免疫渗透，增强一致性和与待测试人类疾病的相关性 对皮肤FL的免疫功效。父母补助金将利用纳米颗粒， 生物结合技术，当一起使用时，将分子药物递送到淋巴结内， 提高其治疗生物活性。本补编下的拟议工作旨在使 评价淋巴结靶向纳米制剂如何对淋巴瘤引起远位效应 皮肤肿瘤的局部免疫微环境改变了皮肤中形成的病变， 工程化基质载体支架，其能够实现一致的皮肤肿瘤形成。这个的目标 建议将逐步完成。首先，我们将分析矩阵车辆的影响 本发明提供了一种组合物对由以下形成的皮肤肿瘤的形成速率、潜伏期和免疫微环境的影响： 来自Bcl 6-EZH 2淋巴瘤模型的恶性淋巴细胞。第二，我们将评估淋巴如何 皮肤淋巴瘤的淋巴结与非靶向化学免疫治疗控制因局部 免疫微环境这项工作的成功结果将具有广泛的意义和影响 通过建立与人类淋巴瘤相关的免疫治疗测试模型系统， 作为确定淋巴结靶向治疗对引起针对淋巴结转移的稳健的远位效应的作用， 皮肤肿瘤