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

基本信息

批准号：
10599944
负责人：
M.G. Finn
金额：
$ 54.86万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599944
关键词：
Abscopal effect Agammaglobulinaemia tyrosine kinase Agonist Animal Model Animals Antigen-Presenting Cells Apoptosis B-Cell Lymphomas B-Lymphocytes Bolus Infusion Cell Death Induction Cells Chemistry Combination immunotherapy Cytotoxic agent Diagnosis Disease Dose Drug Delivery Systems Drug Formulations Drug Targeting EZH2 gene Engineering Ensure Fluorescence Follicular Lymphoma Formulation Human Immune Immuno-Chemotherapy Immunocompetent Immunotherapeutic agent Immunotherapy Indolent Infusion procedures Ligands Link Lymph Lymphatic Lymphocyte Lymphoid Tissue Lymphoma Modeling Monitor Monoclonal Antibodies Mus Nature Non-Hodgkin&apos s Lymphoma Non-Malignant Outcome Penetration Pharmaceutical Preparations Phenotype Population Population Dynamics Pre-Clinical Model Radiation Radiation therapy Research Research Project Grants Risk Site Stimulator of Interferon Genes System Systemic Therapy TLR3 gene Techniques Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Toxic effect Tumor Burden Tumor Immunity Tyrosine Kinase Inhibitor Work adaptive immune response anti-CD20 biomaterial compatibility burden of illness chemotherapeutic agent chemotherapy clinical translation controlled release curative treatments cytotoxic cytotoxicity design draining lymph node human disease immune stimulatory agent immunogenic cell death immunogenicity immunoregulation improved in vivo innovation insight lymph nodes mouse model nanocarrier nanoparticle nanoparticle delivery neoplastic cell novel therapeutic intervention particle pre-clinical programs radiation risk research clinical testing small molecule synergism targeted treatment tumor

项目摘要

PROJECT SUMMARY Follicular lymphoma (FL) is an indolent form of non-Hodgkin’s lymphoma, that arises from B lymphocytes and accounts for ~25% of NHL cases that is presently considered an incurable disease. Intratumoral application [to within diseased lymph nodes (LNs)] of immunotherapy drugs when used in combination with radiation therapy potently induces the abscopal effect, which is an attractive approach given the systemic nature of FL. However, given the toxicity risks of radiation therapy and invasive nature of intratumoral drug administration, new therapeutic approaches are crucially needed. The objective of this R01 program is to develop and validate a temporally controlled, two-stage drug delivery technology targeting lymphoma-bearing LNs for FL therapy. This will be tested in a rigorous preclinical model of Bcl6 and EZH2-driven lymphoma which is an animal model that most closely resembles human disease. Three aims are proposed: Aim 1: LN delivery and effects of immune stimulatory agents. Aim 2: LN delivery and effects of drugs inducing immunogenic cell death (ICD). Aim 3: Combined delivery of immune stimulatory and ICD-inducing agents in the Bcl6-EZH2 lymphoma model. This project is expected to yield several outcomes. First, these studies will define parameters for enhancing the efficacy of FL therapy via LN drug targeting. Second, the potential for LN-targeted therapy to improve the abscopal effect in the treatment of FL will be established. Therapeutic agents already in human clinical testing or approved for human use will be investigated in this work to ensure the highest potential for rapid clinical translation.

项目概要滤泡性淋巴瘤 (FL) 是一种惰性形式的非霍奇金淋巴瘤，源自 B 淋巴细胞，约占 NHL 病例的 25%，目前被认为是不治之症。免疫治疗药物的瘤内应用[在患病淋巴结 (LN) 内] 与放射治疗相结合可有效诱导远隔效应，这是一种有吸引力的方法然而，考虑到 FL 的全身性，放射治疗和侵入性治疗的毒性风险。由于瘤内给药的性质，迫切需要新的治疗方法。该 R01 计划的目标是开发和验证时间控制的两阶段药物输送针对携带淋巴瘤的 LN 进行 FL 治疗的技术将在严格的临床前测试中进行测试。 Bcl6 和 EZH2 驱动的淋巴瘤模型，这是最相似的动物模型提出了三个目标：目标 1：液氮输送和免疫刺激剂的作用。目标 2：液氮输送和药物诱导免疫原性细胞死亡 (ICD) 的作用。目标 3：在 Bcl6-EZH2 中联合递送免疫刺激剂和 ICD 诱导剂淋巴瘤模型。该项目预计将产生几个成果，首先，这些研究将定义参数。通过 LN 药物靶向增强 FL 治疗的疗效其次，LN 靶向的潜力。将建立改善 FL 治疗中远隔效应的治疗方法。已经进行人体临床测试或批准用于人类使用的将在这项工作中进行调查，以确保快速临床转化的最大潜力。