Personalized vaccine for patients with AML

为 AML 患者提供个性化疫苗

基本信息

批准号：
10312712
负责人：
DAVID E AVIGAN
金额：
$ 65.33万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312712
关键词：
Acute Myelocytic Leukemia Age Antibodies Antigen Presentation Antigens Area Autologous Automobile Driving Bone Marrow Cancer Vaccines Cell Compartmentation Cell fusion 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 Investigation Leukemic Cell Lymphocyte Mediating Mutation Outcome PD-1/PD-L1 PD-L1 blockade PDL1 pathway 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 acute myeloid leukemia cell anergy anti-PD-L1 antibodies base biomarker discovery cancer genomics chemotherapy cohort disorder risk driver mutation exome sequencing follow-up genetic signature high risk immune checkpoint blockade immunoregulation innovation leukemia leukemic stem cell neoantigens neoplastic cell older patient peripheral blood phase 2 study predicting response predictive marker prevent programmed cell death protein 1 randomized trial rational design response response biomarker standard of care stem cell biology synergism therapeutic target transcriptome sequencing treatment arm trial design tumor tumor microenvironment vaccination outcome vaccine immunotherapy vaccine response

项目摘要

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.

抽象的：急性髓系白血病 (AML) 是一种致命的血液恶性肿瘤，其标准治疗很少有疗效。我们开发了一种个性化 AML 疫苗，其中患者来源的白血病细胞与自体 DC 融合，从而产生广泛的抗原是在 DC 介导的共刺激的背景下呈递的。疫苗有效地靶向包括 LSC 区室在内的克隆多样性，并诱导针对患者特异性突变产生的新抗原靶标的反应事件。我们正在完成一项 II 期研究，其中 AML 患者达到标准治疗后的缓解期接受 DC/AML 融合的连续疫苗接种。疫苗接种导致 AML 特异性淋巴细胞急剧扩增外周血和骨髓。值得注意的是，尽管中位年龄为 60 岁主要的中危和高危疾病，75%的患者在中位随访时间为 4 年。本研究的目标是更全面地检查 DCAML 融合疫苗并证实这些引人注目的临床发现随机试验设计的背景。发展可持续发展的根本挑战抗白血病免疫力和持久的疾病反应正在克服肿瘤细胞逃避宿主免疫并重新引入免疫抑制环境宽容。在本研究中，我们还将研究疫苗的潜在协同作用通过阻断 PDL1 介导 T 细胞扩增，以防止 T 细胞重建宽容。每个治疗组都将根据扩展的情况进行评估 T 细胞靶向整个 AML 细胞、LSC 和白血病相关抗原。基于分析 AML 突变事件后，将为每个突变事件生成新抗原谱将通过评估本地患者及其功能相关性来询问接触全细胞疫苗后的免疫反应。定义生物标志物预测反应、骨髓微环境的免疫景观、存在 AML 驱动突变、LSC 的基因特征和免疫调节途径，以及调节抗原呈递和共刺激的非编码RNA将询问它们与免疫反应和临床的相关性结果。