Lymph node-targeted multistage chemoimmunotherapy for lymphoma

项目总结 滤泡性淋巴瘤(FL)是一种慢性非霍奇金淋巴瘤，起源于B细胞。 淋巴细胞，约占目前被认为是不治之症的NHL病例的25%。 免疫治疗药物的瘤内应用[在病变淋巴结(LNS)内] 与放射治疗相结合可以有效地诱导非局部性效应，这是一种有吸引力的方法。 鉴于FL的系统性。然而，鉴于放射治疗和侵入性治疗的毒性风险 由于肿瘤内给药的性质，迫切需要新的治疗方法。这个 该R01计划的目标是开发和验证一种时间控制的两阶段给药方法 用于FL治疗的针对淋巴瘤LNS的技术。这将在严格的临床前测试中进行 Bcl6和EZH2驱动的淋巴瘤模型，这是一种与 人类疾病。提出了三个目标： 目的1：免疫刺激剂对LN的释放及作用。 目的2：LN传递及药物诱导免疫原性细胞死亡(ICD)的作用。 目的3：免疫刺激剂和ICD诱导剂在Bcl6-EZH2中的联合输送 淋巴瘤模型。 预计这一项目将产生几个成果。首先，这些研究将为 通过LN药物靶向提高FL治疗的疗效。第二，LN目标的潜力 在FL的治疗中，将建立改善非局部性效果的治疗方法。治疗剂 在这项工作中，将对已经在人体临床试验中或被批准用于人类的进行调查，以确保 快速临床翻译的最大潜力。

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.