Personalized vaccine for patients with AML

为 AML 患者提供个性化疫苗

• 批准号: 9218966
• 负责人: DAVID E AVIGAN
• 金额: $ 73.94万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-09 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218966
• 关键词: Acute Myelocytic Leukemia; Age; Antibodies; Antigen Presentation; Antigens; Area; Autologous; Automobile Driving; Bone Marrow; Cancer Vaccines; Cell Compartmentation; Cell fusion; Cells; Cellular biology; Characteristics; Clinical; Clinical Trials; Collaborations; Cytolysis; Cytotoxic Chemotherapy; Development; Disease; Disease remission; Elements; Event; Exposure to; Goals; Hematologic Neoplasms; Heterogeneity; Immune; Immune System Diseases; Immune response; Immunity; Immunologics; Immunosuppressive Agents; Immunotherapy; Investigation; Lymphocyte; Mediating; Mutation; Outcome; PDCD1LG1 gene; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Randomized; Relapse; Resistance; Role; Solid Neoplasm; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic Trials; Toxic effect; Tumor Burden; Tumor Immunity; Untranslated RNA; Up-Regulation; Vaccination; Vaccines; Whole Cell Vaccine; actionable mutation; anergy; arm; base; biomarker discovery; cancer genomics; chemotherapy; cohort; design; disorder risk; exome sequencing; follow-up; genetic signature; high risk; immune checkpoint blockade; immunoregulation; innovation; leukemia; leukemic stem cell; neoplastic cell; older patient; peripheral blood; phase 2 study; predicting response; predictive marker; prevent; randomized trial; response; response biomarker; standard of care; synergism; therapeutic target; transcriptome sequencing; trial design; tumor; tumor microenvironment; vaccine response

Abstract: Acute Myeloid Leukemia (AML) is a lethal hematological malignancy for which standard therapy is rarely curative. We have developed a personalized AML vaccine in which patient derived leukemia cells are fused with autologous DCs such that a broad array of antigens are presented in the context of DC mediated costimulation. The vaccine effectively targets clonal diversity including the LSC compartment and induces responses against neoantigen targets generated from the patient specific mutational events. We are completing a phase II study in which patients with AML who achieve remission following standard therapy undergo serial vaccination with DC/AML fusions. Vaccination resulted in the dramatic expansion of AML specific lymphocytes in the peripheral blood and bone marrow. Remarkably, despite a median age of 60 with predominant intermediate and high risk disease, 75% of patients remain in remission at a median of 4 years of follow up. The goals of the present study are to more fully examine the DCAML fusion vaccine and confirm these dramatic clinical findings in the context of a randomized trial design. A fundamental challenge to developing sustained anti-leukemia immunity and durable disease response is overcoming the immunosuppressive milieu by which tumor cells evade host immunity and re-introduce tolerance. In the present study, we will also examine the potential synergy of vaccine mediated T cell expansion with PDL1 blockade to prevent the reestablishment of tolerance. Each of the treatment arms will be assessed with respect to the expansion of T cells targeting whole AML cells, LSCs, and leukemia associated antigens. Based on analysis of the AML mutational events, a neo-antigen profile will be generated for each patient and their functional relevance will be interrogated by assessing the native immune response following exposure to the whole cell vaccine. To define biomarkers predictive of response, the immune landscape of the bone marrow microenvironment, presence of AML driver mutations, gene signature for LSCs and immunoregulatory pathways, and noncoding RNAs regulating antigen presentation and costimulation will be interrogated with respect to their correlation with immune response and clinical outcome.

摘要： 急性髓系白血病（AML）是一种致命的血液恶性肿瘤，其标准治疗方法是： 治疗很少能治愈。我们已经开发了一种个性化的AML疫苗， 患者来源的白血病细胞与自体DC融合， 抗原在DC介导的共刺激的情况下呈递。疫苗 有效地靶向克隆多样性，包括LSC区室，并诱导 针对由患者特异性突变产生的新抗原靶标的应答 事件我们正在完成一项II期研究， 在标准治疗后缓解的患者接受DC/AML融合体的系列疫苗接种。 疫苗接种导致AML特异性淋巴细胞在受试者中急剧扩增。 外周血和骨髓。值得注意的是，尽管平均年龄为60岁， 主要的中、高危疾病，75%的患者在治疗后仍处于缓解状态。 中位随访时间为4年。本研究的目的是更充分地 检查DCAML融合疫苗，并证实这些戏剧性的临床发现， 随机试验设计的背景。发展可持续发展的一个根本挑战 抗白血病免疫和持久的疾病反应是克服 肿瘤细胞通过其逃避宿主免疫并重新引入 宽容在本研究中，我们还将研究疫苗的潜在协同作用， PDL 1阻断介导的T细胞扩增，以防止 宽容将评估每个治疗组的扩展情况， 靶向全AML细胞、LSC和白血病相关抗原的T细胞。基于 分析AML突变事件后，将生成每个突变事件的新抗原谱。 患者及其功能相关性将通过评估本地 免疫反应后暴露于全细胞疫苗。定义生物标志物 预测反应，骨髓微环境的免疫景观， AML驱动突变的存在、LSC的基因特征和免疫调节 途径，非编码RNA调节抗原呈递和共刺激， 就其与免疫应答和临床的相关性进行询问 结果。