Interplay Between Cancer and Immune Cells on Targeted Therapy

靶向治疗中癌症与免疫细胞之间的相互作用

基本信息

批准号：
7742983
负责人：
Peter Poon-Hang Lee
金额：
$ 44.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742983
关键词：
Address Affect Allogenic Antibody Formation Antigens Autologous B-Lymphocytes BCR/ABL fusion gene Behavior Biological Biological Assay Biological Response Modifier Therapy Biology Blood specimen Bone Marrow CD4 Positive T Lymphocytes CD8B1 gene Cancer Control Cancer Vaccines Cells Chromosomal Rearrangement Chromosomes, Human, Pair 9 Chronic Myeloid Leukemia Chronic Phase Clinical Complex Computer Simulation Correlation Studies Cytogenetics Dasatinib Data Data Analyses Data Set Dependence Detection Development Disease remission Experimental Models Flow Cytometry Goals Hematopoietic Neoplasms Hematopoietic stem cells Imatinib Immune Immune response Immune system Immunologic Techniques Immunosuppressive Agents Immunotherapy In Vitro Institution Interruption Lead Leukemic Cell Leukocytes Link Maintenance Malignant Neoplasms Measures Medical Modeling Molecular Target Mutate Mutation Natural Killer Cells Nature Oncogenic Outcome Patients Pattern Philadelphia Chromosome Population Population Decreases Principal Investigator Production Property Protein Tyrosine Kinase Reciprocal Translocation Relapse Relative (related person)Research Research Personnel Residual Cancers Residual state Resolution Role Sampling Series Stem cell transplant Stem cells Structure T cell response T-Lymphocyte Testing Time Translations Transplantation Tumor Burden Tyrosine Kinase Inhibitor Vaccination Vaccines Validation Work base cancer cell cancer therapy cell growth regulation cell type chemotherapy cytokine disorder control effective therapy enzyme linked immunospot assay granzyme B immune function immunogenic insight leukemia mathematical model novel novel therapeutics prevent programs research study response simulation stem success tool treatment strategy tumor vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): The role of the host immune response in relation to current therapies in controlling cancer remains unclear. We hypothesize that novel molecular targeted therapies, such as imatinib for chronic myelogenous leukemia (CML), may render leukemic cells immunogenic as patients enter remission. This relates to the relative selectivity of imatinib over standard chemotherapy for leukemic cells, thus sparing normal immune cells. In addition, cancer has potent immunosuppressive activity. As leukemic cell population decreases with imatinib, immune function may be restored while cancer antigens are still present at significant levels, thus leading to an endogenous anti-tumor immune response. Such an immune response may synergize with imatinib to maintain disease control (remission), and may be further expanded to eliminate residual leukemic cells for a durable cure. In preliminary studies, we used a novel combined experimental and modeling approach to address the immune response to leukemia. We showed that the majority of CML patients develop robust anti-leukemia T cell responses upon remission on imatinib. Intriguingly, CD4+ T cells producing TNF-a J represent the dominant response, with levels reaching 40% in one patient. Analysis of IFN-y production by CD8+ T cells alone, as commonly done today, would not reveal the entire anti-leukemia T cell response. We studied the dynamics of these responses and showed that they peak around the time patients enter cytogenetic remission, but wane to undetectable levels shortly thereafter. We utilized mathematical modeling to gain insights into the dynamics of leukemia and the immune response, and the complex interplay between these populations. Our results suggest that anti-leukemia T cell responses may contribute to the maintenance of remission under imatinib therapy. The goal of this proposal is to expand on these findings by conducting and integrating additional experiments and mathematical modeling. We will analyze in detail 10 patients per year over 5 years, for a total of 50 patients using an array of novel immunological techniques (Aim 1). We will develop new mathematical models of the interplay between leukemia and immune cells. These models will extend our preliminary findings to independently consider CD4 T cells, CDST cells, NK cells, B cell response (antibodies), and different cytokine patterns (Aim 2). We will use the new experimental data for evaluating patient-dependent model parameters, and study whether the magnitude, timing, and dynamics of the immune response can be correlated with the clinical outcome. Lastly, we will develop novel therapeutic strategies in silico (Aim 3). Using our mathematical models and real patient parameters, we will study cancer vaccines, structured treatment interruptions, and mini-transplants. If successful, this work will provide important insights into the role of the host immune response in CML under targeted therapy, and may lead to novel treatment strategies combining targeted therapy with immunotherapv.

描述（由申请人提供）：宿主免疫反应相对于当前控制癌症的疗法的作用仍不清楚。我们假设新型分子靶向疗法，例如治疗慢性粒细胞白血病（CML）的伊马替尼，可能会在患者进入缓解期时使白血病细胞产生免疫原性。这与伊马替尼相对于标准化疗对白血病细胞的相对选择性有关，从而保护了正常免疫细胞。此外，癌症具有强大的免疫抑制活性。随着伊马替尼治疗后白血病细胞数量减少，免疫功能可能会恢复，而癌症抗原仍以显着水平存在，从而导致内源性抗肿瘤免疫反应。这种免疫反应可以与伊马替尼协同作用以维持疾病控制（缓解），并且可以进一步扩大以消除残留的白血病细胞以获得持久治愈。在初步研究中，我们使用了一种新颖的实验和建模相结合的方法来解决对白血病的免疫反应。我们发现大多数 CML 患者在伊马替尼缓解后会产生强烈的抗白血病 T 细胞反应。有趣的是，产生 TNF-a J 的 CD4+ T 细胞代表了主要反应，一名患者的水平达到 40%。单独分析 CD8+ T 细胞产生的 IFN-γ（如当今常用的那样）并不能揭示整个抗白血病 T 细胞反应。我们研究了这些反应的动态，结果表明它们在患者进入细胞遗传学缓解时达到峰值，但此后不久就减弱至不可检测的水平。我们利用数学模型来深入了解白血病和免疫反应的动态，以及这些人群之间复杂的相互作用。我们的结果表明，抗白血病 T 细胞反应可能有助于维持伊马替尼治疗下的缓解。该提案的目标是通过进行和整合额外的实验和数学建模来扩展这些发现。我们将在 5 年内每年详细分析 10 名患者，使用一系列新型免疫学技术（目标 1）对总共 50 名患者进行分析。我们将开发白血病和免疫细胞之间相互作用的新数学模型。这些模型将扩展我们的初步研究结果，以独立考虑 CD4 T 细胞、CDST 细胞、NK 细胞、B 细胞反应（抗体）和不同的细胞因子模式（目标 2）。我们将使用新的实验数据来评估患者依赖性模型参数，并研究免疫反应的幅度、时间和动态是否可以与临床结果相关。最后，我们将在计算机中开发新的治疗策略（目标 3）。使用我们的数学模型和真实的患者参数，我们将研究癌症疫苗、结构化治疗中断和小型移植。如果成功，这项工作将为了解靶向治疗下 CML 中宿主免疫反应的作用提供重要见解，并可能导致靶向治疗与免疫治疗相结合的新治疗策略。