TRANSLATIONAL THERAPEUTIC STRATEGIES FOR LOW GRADE LYMPHOMA

晚期滤泡性低级别非霍奇金淋巴瘤(FL)患者很少(如果有的话) 用常规治疗策略治愈。在复发后， 这些患者中的大多数仍然对重新建立治疗机构有反应， 然而，大多数人最终都会死于自己的疾病。在过去10年中 多年来，我们和其他人一直试图治愈复发和新诊断的疾病 FL患者采用ABMT治疗。尽管这些患者中的一小部分显然 受益于这种方法，相当大比例的患者复发 和/或体验到此过程的并发症。这样做的目的是 建议尝试研究滤泡性淋巴瘤的生物学和 尝试将这些观察结果应用于临床以改善结果 同时将毒性降至最低。目前还不清楚是哪种生物 参数控制FL细胞亚群对 治疗。临床上，我们观察到异常的异质性 疾病表现、肿瘤进展率和肿瘤的异质性 对治疗的反应。我们建议就以下两个主要领域进行研究 与FL的生物学有关。其次，要在分子水平上理解为什么 FL细胞亚群在体外对治疗具有耐药性，然后 可能在活体内。因此，该项目的主要目标将是 确定哪些信号调节滤泡性淋巴瘤的生长和 对治疗产生抗药性。为此，我们提出了三个具体目标。 首先，我们计划继续我们正在进行的治疗方案，重点是 应用清髓疗法和抗B细胞单抗治疗自体骨髓瘤 微小残留的造血干细胞支持和免疫毒素治疗 疾病。此外，我们计划试行新的翻译策略，包括 加强诱导和消融治疗，免疫毒素的协同作用 用化疗，和治疗微小残留病 免疫毒素、细胞因子和基于免疫的治疗策略。 其次，我们计划开发和优化培养FL细胞的系统 培养以研究该肿瘤的异质性。一旦技术成为 经过优化，我们计划确定哪些微环境影响FL 细胞的生长和存活，以及哪些分子信号调节这些 观察。第三，我们计划研究生存基因在 FL并确定这些分子是否对 观察到了抗性。同样，尝试调节这些通路可能会 提供转换策略以改变治疗方法。这件事的成功 项目高度依赖于确定哪些患者有最低限度的 骨髓或患者的残留病及其治疗方法 最小的残留疾病。

Few, if any, patients with advanced stage follicular low grade NHL (FL) are cured with conventional treatment strategies. Following relapse the majority of these patients still respond to re-institution of treatment, however most will ultimately succumb to their disease. Over the past 10 years, we and others have attempted to cure relapsed and newly diagnosed patients with FL using ABMT. Although a subgroup of these patients clearly benefit from this approach, a significant percentage of patients relapse and/or experience complications of this procedure. The objective of this proposal is to attempt to study the biology of follicular lymphoma and attempt to translate these observations to the clinic to improve outcome while minimizing toxicity. It is presently unknown which biologic parameters govern the sensitivity of subpopulations of FL cells to treatment. Clinical, we observe extraordinary heterogeneity with regard disease presentation, rate of tumor progression, and heterogeneity of response to treatment. We propose to examine two major areas with regard to the biologic of FL. Second, to understand at a molecular level, why subpopulations of FL cells are resistant to treatment in vitro and then potentially in vivo. Therefore, the primary goal of this Project will be to identify which signals regulate follicular lymphoma growth and resistance to treatment. To this end, we propose three Specific Aims. First, we plan to continue our ongoing treatment protocols which focus ont he use of myeloablative therapy and anti-B cell mAb treated autologous hematopoietic stem cell support and immunotoxin therapy of minimal residual disease. Moreover, we plan to pilot new translational strategies including intensification of induction and ablative therapy, synergy of immunotoxins with chemotherapy, and treatment of minimal residual disease with immunotoxins, cytokines, and immunization based treatment strategies. Second, we plan to develop and optimize systems to growth FL cells in culture to study the heterogeneity of this neoplasm. Once technology is optimized, we plan to determine which microenvironment influences affect FL cell growth and survival, and which molecular signals regulate these observation. Third, we plan to examine the expression of survival genes in FL and to determine whether these molecules are responsible for the observed resistance. Again, attempts to modulate these pathways might provide translational strategies to alter treatment. The success of this Project is highly interdependent on determining which patients have minimal residual disease in the marrow or in the patient and methods to treat minimal residual disease.