Detection, prevention and treatment of acute myeloid leukemia (AML) relapse.

急性髓系白血病（AML）复发的检测、预防和治疗。

• 批准号: 8746707
• 负责人: Christopher Hourigan
• 金额: $ 80.81万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746707
• 关键词: Active Immunization; Activities of Daily Living; Acute Myelocytic Leukemia; Acute leukemia; Adopted; Adult Acute Myeloblastic Leukemia; Aftercare; Allogenic; American; American Society of Clinical Oncology; Antibodies; Antigen Targeting; Antigens; Autoimmunity; B-Lymphocytes; Benchmarking; Biological Markers; Biology; Bone Marrow; Cancer Center; Cell Therapy; Cell physiology; Cells; Characteristics; Chronic Myeloid Leukemia; Clinical; Clinical Data; Clinical Protocols; Clinical Trials; Collaborations; Color; Comorbidity; Complete Blood Count; Comprehensive Cancer Center; Consensus; Custom; Data; Detection; Development; Diagnosis; Disease; Disease remission; Dysmyelopoietic Syndromes; Elderly; Eligibility Determination; Employee; Enrollment; Epitopes; Flow Cytometry; Future; Gene Expression; Generic Drugs; Genetic Variation; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune; Immune response; Immune system; Immunization; Immunobiology; Immunology; Immunoprecipitation; Immunotherapy; In complete remission; Inflammation; Influenza; Influenza vaccination; Institutional Review Boards; Intervention; K-562; Laboratories; Malignant Neoplasms; Manuscripts; Massachusetts; Measurement; Medical; Messenger RNA; Molecular; Molecular Profiling; Monitor; Myeloproliferative disease; National Comprehensive Cancer Network; Newly Diagnosed; Normal tissue morphology; Organ; Patients; Population; Populations at Risk; Preparation; Prevention; Proteomics; Protocols documentation; Publications; Publishing; RNA; Relapse; Reporting; Research; Residual Neoplasm; Reverse Transcriptase Polymerase Chain Reaction; Risk; Route; Sampling; Stem cell transplant; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Translational Research; United States National Institutes of Health; Vaccination; Vaccines; Work; alemtuzumab; base; burden of illness; cancer immunotherapy; chemotherapy; clinical remission; common treatment; conventional therapy; cytokine; disease characteristic; evidence base; falls; graft vs host disease; healthy volunteer; influenza virus vaccine; interest; lenalidomide; leukemia; leukemic stem cell; meetings; novel; overexpression; peripheral blood; programs; response; seasonal influenza; standard of care; transcriptome sequencing

The fundamental interest of the Myeloid Malignancies Section is the detection, prevention and treatment of AML relapse with the long-term objective of using immunotherapy without the need allo-HSCT. Our research over the past year has involved the following four complementary approaches: Functional characterization of the human immune system in AML patients in remission after treatment: In collaboration with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the trans-NIH Center for Human Immunology, Autoimmunity and Inflammation (CHI) we initiated in fall 2012 a clinical protocol (J1293) to study the functional immune capacity of AML patients after completion of chemotherapy. While a variety of active immunization approaches of cancer-vaccination have been previously tested in clinical trials in this population at risk of relapse, our study represents the first attempt at a systematic deep characterization of the functional capacity of the immune systems of these patients. Using the seasonal influenza vaccine as a robust and well defined immunological challenge, information from 15-color flow cytometry panels will be integrated with gene expression profiles, cytokine luminex, T and B cell elispot and antibody titers and correlated with clinical data including time since chemotherapy, complete blood counts and (if applicable) date of influenza infection or eventual AML relapse. An analogous deep immunome analysis of healthy volunteers undergoing influenza vaccination has recently been performed by CHI and may serve as a baseline for this ongoing analysis. Landmarks: Patient enrollment completed. All samples from clinical protocol collected. Laboratory analysis 75% complete. Identification of unique AML leukemia associated antigens: The ability to target myeloid malignancies using immunotherapy, without allogeneic transplantation, depends on the capability to target leukemic clones while sparing normal tissues. It is now possible to generate clinical grade ex-vivo expanded T cells specific for leukemia associated antigens (LAA) for use in adoptive cell therapy. A variety of putative leukemia associated antigens (LAA) for acute myeloid leukemia (AML) have been identified and consensus panels have attempted to prioritize generic cancer antigens but an evidence-based list of AML antigen targets has not yet been established. We therefore analyzed, using a custom quantitative real-time PCR (qRT-PCR) array, gene expression of 65 potential LAAs in de-identified, highly clinically annotated samples from 48 newly diagnosed untreated adult AML patients collected under IRB-approved protocols from three NCCN cancer centers (Johns Hopkins, Vanderbilt and Massachusetts General) and compared with normal donor peripheral blood, bone marrow and organ specific RNA profiles. This showed that the majority of the proposed AML antigens do not have mRNA overexpression in more than 20% of AML patient samples at diagnosis; a list of the top six AML antigens based on gene expression will be submitted for publication shortly. This finding will be extended by 1) quantification of LAA expression in cell populations enriched for leukemia stem cell function and 2) the characterization of MHC presented LAA epitopes using a novel RNA-Seq, immunoprecipitation and proteomics approach. Landmarks: RT-PCR: Laboratory work completed. Presented at American Society of Clinical Oncology annual meeting. Manuscript in preparation. Proteomics: experimental work ongoing. High sensitivity measurement of AML disease burden for patients in remission to stratify based on risk of relapse and to determine efficacy of additional treatment: The ability to 1) risk stratify patients in clinical remission into high and low risks of relapse based on persistence of molecular minimal residual disease (MRD) and 2) quantify the efficacy of any treatment intervention by determination of changes in this MRD would be of significant utility, especially in trials of novel experimental agents such as immunotherapy. Using information derived from our study of AML antigens (above) we have developed a novel molecular panel that may utility in the quantification and surveillance monitoring of MRD in AML patients. Landmarks: Substantial review of MRD in AML performed (PMID: 23799371). Pilot laboratory work performed. Employee Discovery and Invention Report in preparation. Characterization of the disease biology characteristics and immune parameters associated with successful response to immunotherapy: Cancer immunotherapy is associated, at best, with an overall response rate rarely exceeding 50% with a complete response rate in the range 10-20%. Predictive biomarkers of response would be of great interest to the field, both practically for clinical use but also as a route to understanding the fundamental immunobiological mechanisms associated with response. We have therefore begun to study immune parameters and disease characteristics from a variety of patients treated with immunotherapy for myeloid malignancies (CML, MDS, AML) both retrospectively from completed studies (GVAX, alemtuzumab) but also prospectively in future studies (pomalidomide, lenalidomide, ipilimumab, nivolumab, vaccine immunotherapy) in an attempt to elucidate disease and agent specific characteristics but also those features shared across responders. Such analysis may also serve as a benchmark for future trials. Landmarks: Analysis of clinical trial data from NIH trial of alemtuzumab in myelodysplastic syndromes performed (submitted for presentation). Analysis of laboratory data from Levitsky Laboratory (Johns Hopkins) on induced immune response following GVAX-K562 immunization in chronic myeloid leukemia patients performed and published (PMID 24013666). In summary, the primary interest of the Myeloid Malignancies Section is the detection, prevention and treatment of AML relapse with the aim of understanding and using immunotherapy outside of the setting of stem cell transplantation. This involves a coordinated, overlapping and iterative program of translational research on carefully annotated patient samples from informative clinical time-points in an attempt to understand the fundamental human immunobiology associated with successful responses to cancer immunotherapy in patients with myeloid malignancies.

髓样恶性肿瘤部分的基本利益是对AML复发的检测，预防和治疗，其长期目标是使用免疫疗法而无需Allo-HSCT。 过去一年中，我们的研究涉及以下四种互补方法： 治疗后AML患者中人类免疫系统的功能表征：与Sidney Kimmel综合癌症中心合作，约翰·霍普金斯（Johns Hopkins）和跨NIH人类免疫学中心，自身免疫性和炎症中心（CHI），我们在2012年秋季启动了临床协议（J1293），以研究AMAMENAME AMENAME AMPANE AMENAME AMPANE患者的临床免疫能力（J1293）。 虽然先前已经在该人群的临床试验中测试过各种癌症疫苗接种的主动免疫方法，但我们的研究是对这些患者免疫系统功能能力进行系统性深刻表征的首次尝试。 Using the seasonal influenza vaccine as a robust and well defined immunological challenge, information from 15-color flow cytometry panels will be integrated with gene expression profiles, cytokine luminex, T and B cell elispot and antibody titers and correlated with clinical data including time since chemotherapy, complete blood counts and (if applicable) date of influenza infection or eventual AML relapse. 最近，CHI对接受流感疫苗的健康志愿者进行了类似的深度免疫组分析，可以作为这种正在进行的分析的基线。 地标：患者入学率完成。收集了临床方案的所有样本。 实验室分析75％完成。 鉴定独特的AML白血病相关抗原：使用免疫疗法靶向髓样恶性肿瘤的能力，没有同种异体移植，取决于靶向白血病克隆的能力，同时占据正常组织。 现在可以生成针对白血病相关抗原（LAA）的临床级外扩展的T细胞，用于产卵细胞疗法。已经确定了用于急性髓样白血病（AML）的各种推定的白血病相关抗原（LAA），并且已经确定了共识板试图优先考虑通用癌症抗原，但尚未确定基于证据的AML抗原靶标清单。因此，我们使用定制定量实时PCR（QRT-PCR）阵列分析了65个潜在LAA的基因表达，该基因表达在被诊断出的48名未经IRB批准的NCCN癌症中心的IRB批准方案中收集的48例未经IRB批准方案中收集的未经诊断的未经治疗的成年AML患者的高度临床注释的样品中（Johns Hopkins，vanderbilt controrts prothors prothers prorter Marriarw）和比较和器官特定的RNA曲线。这表明，大多数拟议的AML抗原在诊断时超过20％的AML患者样本中没有mRNA过表达。基于基因表达的前六个AML抗原列表将在短期内提交出版。这一发现将通过1）富含白血病干细胞功能的细胞群中的LAA表达扩展，2）使用新型RNA-Seq，免疫沉淀和蛋白质组学方法的MHC表征呈现LAA表位。 地标：RT-PCR：实验室工作完成。 在美国临床肿瘤学会年会上发表。 手稿准备。 蛋白质组学：正在进行的实验工作。 根据复发的风险和确定其他治疗的疗效，对患者的AML疾病负担的高度敏感性测量值：1）风险分类为1）将临床缓解中的患者分为临床缓解中的患者，基于分子持续性，分子最小疾病的持久性（MRD）和2）在MIR上的效率上进行了更改，以确定MR的效率，以确定此类治疗方法，以确定此次MR的效率。诸如免疫疗法之类的药物。 使用我们对AML抗原的研究得出的信息（上图），我们开发了一个新型的分子面板，可以在AML患者中对MRD进行定量和监视监测实用。地标：对AML进行的MRD进行了大量审查（PMID：23799371）。 飞行员实验室工作进行了。 员工发现和发明报告准备中。 疾病生物学特征和与免疫疗法成功反应相关的免疫参数的表征：癌症免疫疗法充其量是相关的，总体反应率很少超过50％，而完全缓解率在10-20％的范围内。预测性反应的生物标志物实际上是用于临床使用的领域，也将是理解与反应相关的基本免疫生物学机制的途径。 We have therefore begun to study immune parameters and disease characteristics from a variety of patients treated with immunotherapy for myeloid malignancies (CML, MDS, AML) both retrospectively from completed studies (GVAX, alemtuzumab) but also prospectively in future studies (pomalidomide, lenalidomide, ipilimumab, nivolumab, vaccine immunotherapy) in an attempt to elucidate disease和代理特定的特征，以及跨响应者共享的那些功能。 这种分析也可以作为未来试验的基准。地标：对执行骨髓增生性综合征的NIH试验的临床试验数据分析（提交了介绍）。 Levitsky实验室（Johns Hopkins）对GVAX-K562免疫后的免疫反应的实验室数据分析（PMID 24013666）。 总之，髓样恶性肿瘤部分的主要利益是对AML复发的检测，预防和治疗，目的是在干细胞移植的设置之外理解和使用免疫疗法。 这涉及一项对熟悉临床时间点的精心注释的患者样本进行的协调，重叠和迭代的计划，以了解髓样恶性肿瘤患者对癌症免疫疗法的成功反应相关的基本人类免疫生物学。