Mechanisms of Serotherapy of B-Cell Malignancies

B 细胞恶性肿瘤血清疗法的机制

• 批准号: 7728849
• 负责人: MYRON S CZUCZMAN
• 金额: $ 23万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728849
• 关键词: Address; Adverse effects; Alternative Splicing; Animal Model; Antibodies; Antigens; Antisense Oligonucleotides; Apoptosis; Apoptosis Regulator; Apoptotic; Applications Grants; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Beds; Biological; Biopsy; CD20 Antigens; CSF2 gene; Cancer Center; Cell Adhesion Molecules; Cell Line; Cells; Clinical; Clinical Trials; Clone Cells; Collaborations; Combined Modality Therapy; Complement; Data; Development; Development, Other; Disease Resistance; Down-Regulation; Effector Cell; Fox Chase Cancer Center; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hand; Human; In Vitro; Indolent; Investigation; Lead; Lymphoma; MS4A1 gene; Malignant Neoplasms; Mediating; Membrane Microdomains; Monoclonal Antibodies; Mononuclear; NK Cell Activation; Non-Hodgkin' s Lymphoma; Northern Blotting; Numbers; Pathway interactions; Patients; Pharmaceutical Preparations; Positioning Attribute; Process; Proteasome Inhibition; Proteins; Protocols documentation; Raji Cell; Rate; Regulation; Relapse; Research; Research Ethics Committees; Research Personnel; Resistance; Resistance development; SCID Mice; Sampling; Serotherapies; Signal Pathway; Signal Transduction; Specimen; Structure; System; Testing; Therapeutic; Time; Toxic effect; Transcriptional Activation; Tumor Antigens; Ubiquitin; Up-Regulation; Validation; antibody-dependent cell cytotoxicity; base; cancer therapy; chemotherapy; cytokine; cytotoxicity; design; improved; insight; interest; mouse model; multicatalytic endopeptidase complex; neutrophil; programs; receptor; response; rituximab; success; survivin; trafficking; tumor

Serotherapy of non-Hodgkin's lymphoma (NHL) using rituximab has revolutionized the use of naked antibodies in the treatment of cancer. Yet even with this success, there are still many questions about its mechanism of action that, if more were known, could aid in the improvement of or the development of similar relatively non-toxic approaches for treating this and other B-cell malignancies with rituximab or other antibodies. In this regard, we hypothesize that the anti-tumor activity of target-specific naked MAbs can be enhanced by one or more of the following means: (a) Stimulation of mononuclear cells and neutrophils using G-GSF or GM-CSF; (b) Natural killer (NK) cell activation via the concomitant use of immunomodulatory drugs (DvliDs); (c) Inhibition of the proteasome-ubiquitin system by PS341 (bortezimib); (d) Decreasing expression of Bcl-2 anti-apoptotic protein using antisense oligonucleotides (ASO). In addition, we hypothesize that the acquirement of resistant to rituximab is associated with: a) common gene expression profile changes between different rituximab-resistant cell lines and on primary lymphoma cells from patients demonstrating clinical rituximabresistance; b) structural changes in CD20 structure leads to abnormalities in CD20 antigen redistribution into lipid rafts and downstream signaling. These hypotheses serve as a basis for this project. An investigation of the mechanism of action of rituximab will be aided in part by the development of several rituximab-resistant cell lines. This undertaking is possible primarily because of the cooperation and collaboration of several investigators within this Program Project, including Roswell Park Cancer Center and at Fox Chase Cancer Center. Thus, this project is uniquely positioned to evaluate all of these issues with the intent to ultimately use the insights gained in this research to develop better treatment strategies that can be tested clinically, and which could lead to important changes in the way B-cell malignancies will be treated in the future.

利妥昔单抗血清疗法治疗非霍奇金淋巴瘤(NHL)彻底改变了裸露抗体在非霍奇金淋巴瘤(NHL)中的应用 癌症的治疗。然而，即使取得了这样的成功，它的行动机制仍然存在许多问题，如果更多 可以帮助改进或开发类似的相对无毒的治疗方法 以及其他带有利妥昔单抗或其他抗体的B细胞恶性肿瘤。在这方面，我们假设抗肿瘤活性 可通过以下一种或多种手段增强靶向特定的裸露单抗的能力：(A)刺激单核细胞 使用G-GSF或GM-CSF的细胞和中性粒细胞；(B)自然杀伤(NK)细胞通过同时使用 免疫调节药物(Dvlids)；(C)PS341对蛋白酶体-泛素系统的抑制；(D) 应用反义寡核苷酸(ASO)降低Bcl2抗凋亡蛋白的表达。此外，我们假设 获得对利妥昔单抗的抗药性与：a)共同的基因表达谱在 不同的利妥昔单抗耐药细胞系和临床表现为利妥昔单抗耐药的患者的原发淋巴瘤细胞； B)CD20结构的结构变化导致CD20抗原重新分布到脂筏和 下行信令。这些假设是这个项目的基础。黄连素作用机理的研究 利妥昔单抗将从几个耐利妥昔单抗细胞系的发展中得到部分帮助。这项承诺是可能的 主要是因为该计划项目内的几个调查人员的合作和协作，包括 罗斯威尔公园癌症中心和福克斯·蔡斯癌症中心。因此，该项目具有独特的定位，可以评估所有 这些问题的目的是最终利用在这项研究中获得的见解来开发更好的治疗策略， 经过临床测试，这可能会导致未来治疗B细胞恶性肿瘤的方式发生重大变化。