Combination therapies with interleukin-21 in chronic lymphocytic leukemia

描述(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。慢性淋巴细胞性白血病导致严重的免疫抑制，感染是慢性淋巴细胞性白血病患者死亡的主要原因。不幸的是，目前的许多一线治疗方法加剧了这种免疫抑制。迫切需要针对肿瘤的治疗，但也需要维持或增强患者的免疫反应。白介素21(IL-21)是一种具有免疫调节作用的细胞因子，由于其具有免疫刺激作用，但也能直接杀伤CLL肿瘤细胞，因此具有广阔的治疗前景。我们的实验室已经证明，对IL-21的反应与IL-21受体(IL-21R)的表达直接相关，而IL-21R的表达因患者而异。为了改善患者的反应，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。这将通过使用两种临床上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)探讨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、蛋白质诱导和细胞毒性的实验将在原发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相结合，增强IL-21‘S的抗肿瘤和免疫刺激作用，从而改善CLL的治疗。

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.