P1 - A Novel Approach to the Immunotherapy of B Cell Malignancy

P1 - B 细胞恶性肿瘤免疫治疗的新方法

• 批准号: 8076888
• 负责人: George J. Weiner
• 金额: $ 22.23万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076888
• 关键词: Address; Antibodies; Antibody Therapy; Apoptosis; Autolysis; B lymphoid malignancy; B-Lymphocytes; Benign; Biological Products; Biological Response Modifier Therapy; Biology; Cell Survival; Cell-Mediated Cytolysis; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Correlative Study; Dose; Effector Cell; Funding; Immunologics; Immunotherapy; In Vitro; Investigation; Lymphoma; Malignant - descriptor; Mediating; Molecular; Natural Killer Cells; Phase; Phase I Clinical Trials; Phenotype; Population; Production; Receptors, Antigen, B-Cell; Relative (related person); Reproduction spores; Resource Sharing; Route; Small-Cell Lymphoma; Testing; Therapeutic; base; cytotoxicity; granzyme B; in vivo; novel strategies; pre-clinical; response; tumor

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.

SPORE 在初始资助期间支持的研究表明 免疫刺激性 CpG ODN 和 IL-21 在诱导慢性细胞凋亡方面具有协同作用 淋巴细胞白血病/小淋巴细胞淋巴瘤 (CLL) 细胞。对此负责的机制之一 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 之前并未显示可产生粒酶 B。IL-21 加上抗 B 细胞受体抗体（抗 BCR）也可 诱导 CLL 细胞和其他 B 细胞群产生粒酶 B。识别一个 潜在强大的抗肿瘤活性新机制开辟了许多新途径 调查。拟开展研究探索颗粒酶 B 诱导机制 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​​如何 活性可用于治疗。具体而言，单独使用 IL-21、CpG ODN 和抗 BCR 的效果以及 结合起来，恶性和良性 B 细胞将被确定，以定义诱导的分子变化 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 细胞激活剂的其他组合有反应。在临床上，相关研究 将与正在进行的 CpG ODN 在 CLL 中的 I 期试验一起进行，以评估体内是否 CpG ODN 治疗可诱导 CLL 细胞发生类似于体外观察到的变化。将进行研究 评估 CpG ODN 的临床治疗如何影响 CLL 细胞对 IL-21 和其他细胞的反应 体外生物制剂。生物活性药物组合治疗 CLL 或其他疾病的其他临床试验 B细胞恶性肿瘤将根据最初的临床前和临床结果进行测试。这些研究将 广泛利用所有 SPORE 共享资源，将提供有关如何 意想不到的免疫学发现，B 细胞可以产生功能性颗粒酶 B，可应用于 淋巴瘤和其他 B 细胞恶性肿瘤的治疗。