Combination therapies with interleukin-21 in chronic lymphocytic leukemia

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是西方世界最常见的成人白血病。CLL导致严重的免疫抑制，感染是CLL患者死亡的主要原因。不幸的是，目前许多一线疗法加剧了这种免疫抑制。目前迫切需要一种既能针对肿瘤又能维持或增强患者免疫反应的治疗方法。白细胞介素-21 （IL-21）是一种具有免疫调节作用的细胞因子，具有令人兴奋的潜在治疗作用，因为它具有免疫刺激特性，但也可以直接杀死CLL肿瘤细胞。我们的实验室已经表明，对IL-21的反应与IL-21受体（IL-21R）的表达直接相关，而IL-21受体在不同患者之间是不同的。为了提高患者的疗效和设计合理的IL-21联合治疗方案，我们建议阐明IL-21R在恶性B细胞中的调节作用。这将通过使用两种临床相关的免疫调节化合物来实现。我们的目标是1)确定这些化合物上调CLL细胞中IL-21R的机制，2)询问IL-21及其受体在这些化合物的免疫调节作用中的作用。评估基因调控、蛋白诱导和细胞毒性的实验将在原代患者细胞和全血以及CLL的Tcl1小鼠模型中进行。我们的长期目标是通过与其他临床相关治疗联合，增强IL-21的抗肿瘤和免疫刺激作用，从而改善CLL治疗。

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. CLL results in profound immune suppression, and infection is a leading cause of mortality in CLL patients. Unfortunately, many current frontline therapies exacerbate this immune suppression. There is an urgent need for treatment that will target the tumor but also sustain or enhance the patient's immune response. Interleukin-21 (IL-21), a cytokine that has immune regulatory effects, presents an exciting potential therapy because it has immune stimulating properties but can also directly kill the CLL tumor cells. Our lab has shown that response to IL-21 directly correlates with the expression of the IL-21 receptor (IL-21R), which varies between patients. In order to improve patient response and design rational combination therapies with IL-21, we propose to elucidate the regulation of IL-21R in malignant B cells. This will be accomplished through the use of two clinically relevant immunomodulatory compounds. Our aims are 1) to determine the mechanism by which these compounds upregulate IL-21R in CLL cells and 2) to interrogate the role of IL-21 and its receptor in the immunomodulatory effects of these compounds. Experiments to assess gene regulation, protein induction, and cytotoxicity will be performed in primary patient cells and whole blood as well as in the Tcl1 mouse model of CLL. Our long-term goal is to improve CLL therapy by enhancing IL-21's anti-tumor and immune stimulating effects through combinations with other clinically relevant treatments.