Predictive Mathematical Models for Rational Design of Chemoimmunotherapy of Leuke

描述(由申请人提供)：本申请涉及广泛的挑战领域(10)用于处理研究的医疗保健数据的信息技术“和特定的挑战主题10-CA-102正常和癌症过程的预测数学模型。这项提议将开发数学模型来研究FDA批准的三种药物与供者淋巴细胞输注相互作用的影响，在采用由人类bcr-abl突变驱动的新型急性白血病模型的MHC相合异基因移植小鼠模型中。这项研究的长期目标是发展数学方法，以指导合理设计控制异基因移植后残留白血病的多模式治疗。急性白血病复发是异基因移植后治疗失败的最常见原因。与慢性粒细胞白血病等血液系统恶性肿瘤不同，移植后复发的急性白血病不能通过异基因供者淋巴细胞输注或其他免疫疗法有效地治疗。这一失败的机制尚未完全阐明。这些机制研究的结果表明，白血病细胞和同种异体T细胞增殖的相对动力学，而不是固有的免疫缺陷是供者淋巴细胞输注治疗急性白血病无效的主要机制。体内白血病的动力学和T细胞群体动力学的定量模拟是现有免疫和药物治疗合理组合的必要的第一步，这将显著增加控制残留ALL的可能性。目的1：建立一个基于微分方程式的模型，用于描述异基因供者淋巴细胞输注后白血病和同种异体反应性T细胞的体内动力学。这些参数将从体外实验中得出，然后在体内进行验证。然后将进行模拟，以预测目标2中提议的干预措施的潜在结果，并设计统计分析所需的实验采样频率。目的：验证数学模型指导给药可显著提高异基因供者淋巴细胞输注控制残留急性淋巴细胞白血病的疗效的假说。我们将测试FDA批准的三种不同作用机制的药物：(A)伊马替尼(一种BCR-ABL融合蛋白的酪氨酸激酶抑制剂)；(B)脉冲式甲氨蝶呤(一种抗代谢药物)；以及(C)抗CD20单抗。如果这些研究表明残留急性白血病的免疫控制可以通过 这样的操作，将机械性的洞察力快速转化为临床试验是可以预见的。 公共卫生相关性白血病是一种血癌，许多患者死于白血病，因为即使在接受了骨髓移植的强化治疗后，白血病也会复发。该项目将开发数学技术，帮助医生以新的方式将化疗和免疫治疗结合起来，防止白血病在骨髓移植后复发。

DESCRIPTION (provided by applicant): This application addresses broad challenge area (10) Information Technology for Processing Health Care Data for Research" and specific challenge topic 10-CA-102 Predictive Mathematical Models of Normal and Cancer Processes. This proposal will develop mathematical models to study the impact of three FDA approved drugs for interactions with donor lymphocyte infusion in a murine model of MHC-matched allogeneic transplantation that employs novel acute leukemia models driven by the human bcr-abl mutation. The long range goal of this research is to develop mathematical methods that can guide rational design of multimodality therapies for control of residual leukemia present after allogeneic transplantation. Relapse of acute leukemia is the most common cause of treatment failure after allogeneic transplantation. Unlike some hematological malignancies such as chronic myelogenous leukemia, relapse of acute leukemia after transplant is not effectively treated with allogeneic donor lymphocyte infusion or other immune therapies. The mechanism of this failure is not yet fully elucidated. The results of these prior mechanistic studies suggest the hypothesis that the relative kinetics of leukemia cell and allogeneic T cell proliferation rather than intrinsic deficiency in immunity is the major mechanism for the lack of efficacy of donor lymphocyte infusion in acute leukemia. Quantitative modeling of the kinetics of leukemia and T cell population dynamics in vivo is a necessary first step in the rational combination of existing immunological and pharmacological therapies that will substantially increase the probability of control of residual ALL. Aim 1: Construct a differential equation based model to mechanistically describe leukemia and alloreactive T cell population kinetics in vivo following allogeneic donor lymphocyte infusion. Parameters will be derived from in vitro experiments and then verified in vivo. Simulations will then be performed to predict the potential outcomes of the interventions proposed in Aim 2, as well as to design the experimental sampling frequencies needed for statistical analysis. Aim 2: To test the hypothesis that mathematical model directed administration of currently available drugs can substantially improve the efficacy of allogeneic donor lymphocyte infusion in controlling residual acute lymphoblastic leukemia. We will test three FDA approved drugs with different mechanisms of action: (a) imatinib (a tyrosine kinase inhibitor of the bcr-abl fusion protein); (b) pulsatile methotrexate (an antimetabolite); and (c) anti-CD20 monoclonal antibody. If these studies demonstrate that immune control of residual acute leukemia can be enhanced by such maneuvers, rapid translation of the mechanistic insights into clinical trials is envisioned. Public Health Relevance Many patients with leukemia, a blood cancer, die because the leukemia comes back even after intensive treatment with bone marrow transplantation. This project will develop mathematical techniques that will help doctors combine chemotherapy and immunological therapy in new ways that will keep leukemia from coming back after bone marrow transplantation.