A Novel Approach to the Immunotherapy of B Cell Malignancy

在最初的资助期间，SPORE支持的研究表明， 免疫刺激性CpG ODN和IL-21在诱导慢性胰腺炎细胞凋亡能力方面具有协同作用， 淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL）细胞。其中一个机制是 细胞凋亡是恶性B细胞产生颗粒酶B-这是一个令人惊讶的发现，因为B细胞具有 以前未显示产生粒酶B。IL-21加抗B细胞受体抗体（抗BCR）还 诱导CLL细胞和其它B细胞群体产生颗粒酶B。的识别 潜在的强大的抗肿瘤活性的新机制开辟了许多新的途径， 调查建议进行研究以探索颗粒酶B的诱导机制 通过B细胞的产生，以这种方式处理的细胞如何介导抗肿瘤活性，以及这种细胞如何介导抗肿瘤活性。 活性可用于治疗。特别是，IL-21、CpG ODN和抗BCR单独和联合应用的作用， 将确定恶性和良性B细胞的组合，以确定诱导的分子变化 并将这些变化与治疗对恶性B细胞活力和表型的影响相关联。 自溶、非定向细胞毒性和抗体定向细胞毒性（ADCC）的相对重要性 将测定用这些试剂处理的恶性B细胞的凋亡。研究将评估如何 恶性B细胞对B细胞活化剂的其它组合有反应。在临床上，相关研究 将与正在进行的CpG ODN治疗CLL的I期试验联合进行，以评估体内 用CpG ODN治疗诱导CLL细胞的变化类似于在体外观察到的那些。将进行研究 评估CpG ODN临床治疗如何影响CLL细胞对IL-21的应答，以及其他 体外生物制剂。在CLL或其他疾病中的生物活性剂组合的其他临床试验 将根据初始临床前和临床结果检测B细胞恶性肿瘤。这些研究将 广泛利用所有的SPORE共享资源，将提供有关如何 出乎意料的免疫学发现，B细胞可以产生功能性颗粒酶B，可以应用于 治疗淋巴瘤和其它B细胞恶性肿瘤。

Studies supported by the SPORE during the initial funding period demonstrated that immunostimulatory CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells. One of the mechanisms responsible for this apoptosis is production of Granzyme B by the malignant B cells - a surprising finding given that B cells have not previously been shown to produce Granzyme B. IL-21 plus anti-B cell receptor antibody (Anti-BCR) also induce Granzyme B production by both CLL cells and other B cell populations. The identification of a potentially powerful new mechanism of anti-tumor activity opens up a number of new avenues for investigation. Studies are proposed to explore the mechanisms responsible for induction of Granzyme B production by the B cells, how cells treated in such a manner mediate anti-tumor activity, and how such activity can be utilized therapeutically. Specifically, the effects of IL-21, CpG ODN, and anti-BCR, alone and in combination, on malignant and benign B cells will be determined to define the molecular changes induced by therapy and correlate these changes with the effect of therapy on malignant B cell viability and phenotype. The relative importance of autolysis, undirected cytotoxicity and antibody directed cellular cytotoxicity (ADCC) in the apoptosis of malignant B cells treated with these agents will be determined. Studies will assess how malignant B cells respond to other combinations of B cell activating agents. In the clinic, correlative studies will be done in conjunction with an ongoing phase I trial of CpG ODN in CLL to assess whether in vivo therapy with CpG ODN induces changes in CLL cells similar to those observed in vitro. Studies will be done to evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and other biological agents in vitro. Additional clinical trials of combinations of biologically active agents in CLL or other B cell malignancies will be tested based on the initial preclinical and clinical results. These studies, which will make extensive use of all of the SPORE shared resources, will provide valuable information on how the unexpected immunologic finding that B cells can produce functional Granzyme B, can be applied to the treatment of Lymphoma and other B cell malignancies.