TRANSLATIONAL THERAPEUTIC STRATEGIES FOR LOW GRADE LYMPHOMA

很少（如果有的话）晚期滤泡性低度NHL（FL）患者 用传统的治疗方法治愈 复发后， 这些患者中的大多数仍然对重新开始治疗有反应， 然而，大多数人最终将死于他们的疾病。 过去10 多年来，我们和其他人一直试图治愈复发和新诊断的 使用ABMT的FL患者。 尽管这些患者中的一个亚组明显 受益于这种方法，很大比例的患者复发 和/或经历该过程的并发症。 的目的 建议是试图研究滤泡性淋巴瘤的生物学， 尝试将这些观察结果转化为临床结果，以改善结局 同时将毒性降至最低。 目前尚不清楚哪种生物 参数控制FL细胞亚群对以下的敏感性： 治疗 临床上，我们观察到关于 疾病表现、肿瘤进展率和 对治疗的反应 我们建议研究两个主要范畴， 第二，在分子水平上理解， FL细胞的亚群对体外治疗具有抗性， 可能在体内。 因此，本项目的主要目标是 以确定哪些信号调节滤泡性淋巴瘤的生长， 抵抗治疗。 为此，我们提出三个具体目标。 首先，我们计划继续我们正在进行的治疗方案，重点是 清髓性治疗和抗B细胞mAb治疗自体的用途 造血干细胞支持与微量残留免疫毒素治疗 疾病 此外，我们计划试行新的翻译战略，包括 强化诱导和消融治疗，免疫毒素的协同作用 与化疗，并治疗微小残留疾病， 免疫毒素、细胞因子和基于免疫的治疗策略。 第二，我们计划开发和优化系统，以生长FL细胞， 培养以研究该肿瘤的异质性。 一旦技术 优化后，我们计划确定哪些微环境影响影响FL 细胞生长和存活，以及哪些分子信号调节这些 观察. 第三，我们计划检查存活基因的表达， FL，并确定这些分子是否负责 观察阻力。 同样，调节这些通路的尝试可能 提供翻译策略以改变治疗。 的成功 项目高度依赖于确定哪些患者具有最小 骨髓或患者体内的残留疾病以及治疗方法 微小残留病

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.