Lymph node-targeted multistage chemoimmunotherapy for lymphoma

项目总结 滤泡性淋巴瘤起源于B淋巴细胞，约占非霍奇金淋巴瘤的25% 淋巴瘤病例。由于目前还没有根治方法，而且只有2.6%的病例得到解决，FL是 目前被认为是不治之症。治疗FL的新治疗方法是 因此，这是迫切需要的。缺乏有效的治疗方法的原因之一是，初级和初级治疗 继发性FL可发生在皮肤。皮肤损伤似乎表现出独特的免疫抵抗力 这些机制使它们成为一种具有挑战性的淋巴瘤治疗方案。研究：关于 然而，现有的FL模型限制了真皮FL病变的免疫治疗反应。这很好 承认大多数FL肿瘤产生和扩散的免疫微环境- 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的免疫疗法是在合适的肿瘤模型中测试的缺口 免疫疗法在其皮肤介绍的背景下。该项目旨在通过以下方式克服这一障碍 设计一种细胞基质载体，以诱导可靠和一致的肿瘤形成，以及 可编程免疫渗透以增强一致性和与人类疾病的相关性以进行测试 对皮肤FL的免疫治疗效果。母基金将使用纳米颗粒和 生物偶联技术，当一起使用时，将分子药物输送到淋巴结内，从而 提高其治疗生物活性。本补编下的拟议工作旨在使 淋巴结靶向纳米制剂治疗淋巴瘤的疗效评价 皮肤肿瘤的局部免疫微环境通过以下方式改变皮肤中形成的病变 设计一种基质载体支架，使皮肤肿瘤能够持续形成。这样做的目的是 提案将以循序渐进的方式完成。首先，我们将分析矩阵车辆的影响 人皮肤肿瘤的形成速度、潜伏期和免疫微环境的成分 Bcl6-EZH2淋巴瘤模型中的恶性淋巴细胞。第二，我们将评估淋巴 皮肤淋巴瘤的结节和非靶向化学免疫治疗控制因局部而异 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 通过建立与人类淋巴瘤相关的免疫治疗测试的模型系统 作为确定淋巴结靶向治疗在引起强大的非内窥镜效应方面的作用 皮肤肿瘤。

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.