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.

骨髓恶性肿瘤科的根本兴趣是检测、预防和治疗 AML 复发，长期目标是使用免疫疗法而不需要异基因造血干细胞移植。 我们过去一年的研究涉及以下四种互补方法： 治疗后缓解期 AML 患者的人体免疫系统功能特征：与约翰·霍普金斯大学 Sidney Kimmel 综合癌症中心和跨 NIH 人类免疫学、自身免疫和炎症中心 (CHI) 合作，我们于 2012 年秋季启动了一项临床研究方案（J1293）研究 AML 患者化疗完成后的功能免疫能力。 虽然之前已经在具有复发风险的人群中进行了临床试验，测试了各种癌症疫苗的主动免疫方法，但我们的研究代表了对这些患者免疫系统功能进行系统深入表征的首次尝试。 使用季节性流感疫苗作为强大且明确的免疫学挑战，来自 15 色流式细胞术面板的信息将与基因表达谱、细胞因子 luminex、T 和 B 细胞酶联斑点和抗体滴度相整合，并与临床数据（包括化疗后的时间）相关联、全血细胞计数以及（如果适用）流感感染或最终 AML 复发的日期。 CHI 最近对接受流感疫苗接种的健康志愿者进行了类似的深度免疫组分析，可作为正在进行的分析的基线。 里程碑：患者登记已完成。收集临床方案中的所有样本。 实验室分析已完成 75%。 识别独特的 AML 白血病相关抗原：使用免疫疗法（无需同种异体移植）靶向骨髓恶性肿瘤的能力取决于靶向白血病克隆同时不伤害正常组织的能力。 现在可以产生针对白血病相关抗原 (LAA) 的临床级体外扩增 T 细胞，用于过继细胞治疗。急性髓性白血病 (AML) 的多种假定的白血病相关抗原 (LAA) 已被鉴定，共识小组已尝试优先考虑通用癌症抗原，但尚未建立基于证据的 AML 抗原靶标列表。因此，我们使用定制的定量实时 PCR (qRT-PCR) 阵列分析了 48 名新诊断的未经治疗的成人 AML 患者的去识别化、高度临床注释的样本中 65 种潜在 LAA 的基因表达，这些患者是根据 IRB 批准的方案从三个国家收集的。 NCCN 癌症中心（约翰霍普金斯大学、范德比尔特大学和马萨诸塞州总医院）并与正常供体外周血、骨髓和器官特异性 RNA 谱进行比较。这表明，大多数提出的 AML 抗原在诊断时超过 20% 的 AML 患者样本中没有 mRNA 过度表达；基于基因表达的六大 AML 抗原列表将很快提交出版。这一发现将通过以下方式得到扩展：1) 对富含白血病干细胞功能的细胞群中 LAA 表达进行定量，以及 2) 使用新型 RNA-Seq、免疫沉淀和蛋白质组学方法表征 MHC 呈现的 LAA 表位。 里程碑： RT-PCR：实验室工作已完成。 在美国临床肿瘤学会年会上发表。 手稿正在准备中。 蛋白质组学：实验工作正在进行中。 对缓解期患者的 AML 疾病负担进行高灵敏度测量，根据复发风险进行分层并确定额外治疗的疗效：能够 1) 根据分子最小复发风险的持续性，将临床缓解期患者风险分层为高复发风险和低复发风险残留病灶（MRD）和2）通过确定该MRD的变化来量化任何治疗干预的功效将具有重要的用途，特别是在免疫疗法等新型实验药物的试验中。 利用我们对 AML 抗原的研究（上文）中获得的信息，我们开发了一种新型分子组合，可用于 AML 患者 MRD 的量化和监测。里程碑：对 AML 中的 MRD 进行了实质性审查（PMID：23799371）。 进行了试点实验室工作。 员工发现和发明报告正在准备中。 与免疫治疗成功反应相关的疾病生物学特征和免疫参数的表征：癌症免疫治疗充其量与总体反应率很少超过 50% 相关，完全反应率在 10-20% 范围内。反应的预测生物标志物将引起该领域的极大兴趣，不仅可实际用于临床用途，而且还可作为理解与反应相关的基本免疫生物学机制的途径。因此，我们开始研究接受免疫疗法治疗髓系恶性肿瘤（CML、MDS、AML）的各种患者的免疫参数和疾病特征，既回顾性地研究已完成的研究（GVAX、阿仑单抗），又前瞻性地研究未来的研究（泊马度胺、来那度胺、 ipilimumab、nivolumab、疫苗免疫疗法）试图阐明疾病和药物的具体特征，以及应答者之间共有的特征。 这样的分析也可以作为未来试验的基准。里程碑：对 NIH 进行的阿仑单抗治疗骨髓增生异常综合征试验的临床试验数据进行分析（已提交供演示）。对 Levitsky 实验室（约翰霍普金斯大学）对慢性粒细胞白血病患者 GVAX-K562 免疫后诱导免疫反应的实验室数据进行分析并发表 (PMID 24013666)。 总之，骨髓恶性肿瘤科的主要兴趣是 AML 复发的检测、预防和治疗，目的是了解和使用干细胞移植之外的免疫疗法。 这涉及对来自信息丰富的临床时间点的仔细注释的患者样本进行协调、重叠和迭代的转化研究计划，以试图了解与骨髓恶性肿瘤患者对癌症免疫治疗成功反应相关的基本人类免疫生物学。