Dendritic Cell/Leukemia Fusions and PD-1 Blockade for AML

树突状细胞/白血病融合和 PD-1 阻断治疗 AML

基本信息

批准号：
7892865
负责人：
Jacalyn Rosenblatt
金额：
$ 37.9万
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：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7892865
关键词：
Acute Myelocytic Leukemia Allogenic Animal Model Antibodies Antigens Apoptosis Area Autologous Dendritic Cells Autologous Tumor Cell B-Lymphocytes Binding Cancer Patient Cancer Vaccine Related Development Cancer Vaccines Carcinoma Cell fusion Cells Characteristics Chronic Clinical Clinical Research Clinical Trials Collaborations Cytolysis Dendritic Cells Development Disease Disease Progression Disease Reservoirs Disease regression Disease remission Effector Cell Elements Family Generations Granulocyte-Macrophage Colony-Stimulating Factor Hematologic Neoplasms Hematopoietic Stem Cell Transplantation High Dose Chemotherapy Homologous Transplantation Immune Immune response Immune system Immunity Immunologics Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Investigation Leukemic Cell Life Ligands Ligation Lymphocyte Malignant Neoplasms Measures Mediating Memory Modeling Morbidity - disease rate Multiple Myeloma Mus Myeloid Leukemia Natural Killer Cells Pathway interactions Patients Pharmacologic Substance Phenotype Randomized Reaction Time Recurrence Recurrent disease Regulatory T-Lymphocyte Relapse Resistance Role Signal Transduction Specificity Stem cells T-Cell Proliferation T-Lymphocyte Toxic effect Tumor Antigens Tumor Escape Tumor Expansion Tumor Immunity Vaccination Vaccines Virus Diseases base cancer therapy chemotherapy clinical efficacy cohort cytokine exhaust granzyme B improved in vivo leukemia leukemic stem cell member mortality neoplastic cell preclinical study prevent public health relevance receptor response tumor

项目摘要

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) arises from leukemia stem cells that serve as a reservoir for disease relapse. A promising area of investigation is the development of immunotherapeutic approaches that stimulate the immune system to eliminate leukemia stem cells. We have developed a cancer vaccine in which dendritic cells (DC) are fused to tumor cells. T cells stimulated by DC/AML fusions target leukemia stem cells in vitro. In clinical studies, vaccination with DC/tumor fusions stimulates antitumor immunity in most patients, but only a subset demonstrate disease regression. An important element contributing to tumor mediated immune suppression involves the PD-1/PDL-1 pathway. PD-L1 has been shown to exert a significant role in promoting T cell tolerance by binding PD-1 on activated T cells and suppressing their capacity to secrete stimulatory cytokines. We have demonstrated that blockade of this pathway using antibodies directed against PD-L1 or PD-1 results in enhanced capacity of DC/tumor fusions to stimulate T cell proliferation ex vivo. Similarly, blockade of the PD1 pathway resulted in an increase in T cell expressing granzyme B as a measure of enhanced cytolytic capacity. A clinical grade antibody to PD-1, CPT-11, has been developed by Teva Pharmaceuticals which has been shown to potently induce anti-tumor immunity in murine models. In reversing a key element of tumor mediated immune suppression, we hypothesize that therapy with CT-011 will provide an ideal platform for the expansion of tumor reactive memory effector cells following induction chemotherapy. We hypothesize that the addition of tumor specific immunotherapy using the DC/AML fusion vaccine will further expand tumor specific T cells. In the proposed study, we will examine toxicity, immunologic effect and clinical efficacy of DC/AML fusion vaccination following induction chemotherapy for patients with AML. We will then examine these endpoints in patients undergoing combined therapy with the vaccine and CT-011. PUBLIC HEALTH RELEVANCE: Acute myelogenous leukemia (AML) arises from leukemia stem cells that are difficult to eradicate and serve as a reservoir for disease relapse following chemotherapy. A promising area of investigation is the development of immunotherapeutic approaches that stimulate the immune system to recognize leukemia stem cells as foreign and eliminate them. In this clinical trial, patients are treated with a tumor vaccine alone or in combination with CT-O11, an antibody that may augment response to vaccination; this immunotherapy may help to control leukemic cells that are resistant to chemotherapy and prevent disease recurrence.

描述（由申请人提供）：急性髓性白血病（AML）由白血病干细胞引起，白血病干细胞充当疾病复发的储存库。一个有前景的研究领域是开发刺激免疫系统消除白血病干细胞的免疫治疗方法。我们开发了一种癌症疫苗，其中树突状细胞 (DC) 与肿瘤细胞融合。 DC/AML 融合刺激的 T 细胞在体外靶向白血病干细胞。在临床研究中，DC/肿瘤融合疫苗接种可以刺激大多数患者的抗肿瘤免疫力，但只有一小部分患者表现出疾病消退。 PD-1/PDL-1 通路是导致肿瘤介导的免疫抑制的一个重要因素。 PD-L1 已被证明通过在活化的 T 细胞上结合 PD-1 并抑制其分泌刺激性细胞因子的能力，在促进 T 细胞耐受方面发挥重要作用。我们已经证明，使用针对 PD-L1 或 PD-1 的抗体阻断该通路可增强 DC/肿瘤融合刺激 T 细胞离体增殖的能力。类似地，阻断 PD1 通路会导致 T 细胞表达颗粒酶 B 的增加，作为增强细胞溶解能力的衡量标准。 Teva Pharmaceuticals 开发了一种临床级 PD-1 抗体 CPT-11，已被证明可以在小鼠模型中有效诱导抗肿瘤免疫。在逆转肿瘤介导的免疫抑制的关键因素时，我们假设 CT-011 治疗将为诱导化疗后肿瘤反应性记忆效应细胞的扩增提供理想的平台。我们假设使用 DC/AML 融合疫苗添加肿瘤特异性免疫疗法将进一步扩大肿瘤特异性 T 细胞。在拟议的研究中，我们将检查 AML 患者诱导化疗后 DC/AML 融合疫苗的毒性、免疫学效应和临床疗效。然后，我们将在接受疫苗和 CT-011 联合治疗的患者中检查这些终点。公共卫生相关性：急性髓性白血病 (AML) 源自白血病干细胞，这些细胞难以根除，并且是化疗后疾病复发的储存库。一个有前景的研究领域是开发免疫治疗方法，刺激免疫系统将白血病干细胞识别为外来细胞并消除它们。在这项临床试验中，患者单独接受肿瘤疫苗治疗，或与 CT-O11 联合治疗，CT-O11 是一种可以增强疫苗接种反应的抗体。这种免疫疗法可能有助于控制对化疗有抵抗力的白血病细胞并防止疾病复发。