Immunologic targets in Myeloid Leukemia

粒细胞白血病的免疫靶点

基本信息

批准号：
8599752
负责人：
RICHARD J JONES
金额：
$ 32.02万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2010-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599752
关键词：
Acute Myelocytic Leukemia Address Antibodies Antigen Targeting Antigens Behavior Biological Cells Cellular Immunity Cellular Stress Chronic Myeloid Leukemia Clinical Clinical Research Commit Detection Disease Educational process of instructing Engraftment Frequencies Gene Expression Profile Genes Granulocyte-Macrophage Colony-Stimulating Factor Growth Hematopoiesis Hematopoietic Hematopoietic stem cells Humoral Immunities Immune Immune Targeting Immune response Immune system Immunologics Immunotherapy Individual Laboratories Malignant Neoplasms Measurable Mediating Methods Myeloid Leukemia Neoplastic Cell Transformation Normal Cell Outcome Pathway interactions Patients Phenotype Play Population Pre-Clinical Model Relative (related person)Remission Induction Role Sampling Signal Transduction Stress T cell response T cell therapy T-Lymphocyte Vaccine Antigen Vaccines Xenograft Model base cancer cell cancer stem cell clinical effect in vivo insight leukemia leukemic stem cell leukemogenesis neoplastic cell outcome forecast progenitor public health relevance response self-renewal tool

项目摘要

DESCRIPTION (provided by applicant): There is now unequivocal evidence that the immune system is equipped to detect and react to cellular stress signals generated by normal cells undergoing neoplastic transformation and the cancers that arise from them. Although the frequency and magnitude of such responses vary considerably between individuals, both pre-clinical models and clinical studies have established that the cancer phenotype, its biological behavior, and clinical prognosis are profoundly influenced by the character of the host immune response. Cellular and humoral immunity recognize a wide range of antigenic targets on cancer cells, many of which are being pursued as candidates for immunotherapy. Yet cancers are comprised of heterogeneous cell populations, varying in patterns of gene expression and in the resulting distribution of target antigens. These phenotypic differences are superimposed upon functional differences in the capacity of subsets of cancer cells to self-renew and propagate the malignancy. Consequently, there is little evidence to guide which of these antigens when targeted are most likely to confer clinical benefit. We seek to address this limitation using an unbiased antigen identification strategy in two clinical settings where there is measurable evidence of an immune mediated clinical effect; in vaccine associated remission induction in 1) chronic myelogenous leukemia (CML) and 2) acute myelogenous leukemia (AML). Antigens identified in these screenings will be prioritized based on the following criteria: 1) correlation of immune recognition with clinical response, 2) expression by leukemic stem cells (LSCs), 3) detection of both antibody and T cell responses, and 4) the biological role played by the gene in pathways of leukemogenesis. Prioritized antigens will be validated based on the impact of their targeting on in vivo engraftment of leukemia versus normal hematopoiesis. These findings will provide significant insight into the essential components of cancer stem cells, help to establish immune laboratory correlates predictive of clinical responses, and guide the selection of antigenic targets for defined-antigen vaccine or adoptive T cell therapies for leukemia.

描述（由申请人提供）：现在有明确的证据表明，免疫系统有能力检测并反应由正常细胞所产生的细胞应激信号，而正常细胞正在经历了肿瘤性转化和由它们产生的癌症。尽管个人之间这种反应的频率和幅度差异很大，但临床前模型和临床研究都表明，癌症表型，其生物学行为和临床预后都受到宿主免疫反应特征的深刻影响。细胞和体液免疫识别癌细胞上广泛的抗原靶标，其中许多靶标被作为免疫疗法的候选者。然而，癌症由异质细胞种群组成，基因表达模式和靶抗原的分布不同。这些表型差异被叠加在癌细胞子集自我更新和传播恶性肿瘤子集的功能差异上。因此，几乎没有证据可以指导靶向时哪种抗原最有可能赋予临床益处。我们试图在两个临床环境中使用公正的抗原鉴定策略来解决这种局限性，在两个临床环境中，有可测量的证据表明免疫介导的临床效果。在疫苗相关的缓解诱导中，1）慢性粒细胞性白血病（CML）和2）急性骨髓性白血病（AML）。在这些筛查中鉴定的抗原将根据以下标准确定：1）免疫识别与临床反应的相关性，2）通过白血病干细胞（LSC）表达（LSC），3）检测抗体和T细胞反应，以及4）4）4）生物学作用在Leukemegenosease的途径中所起的生物学作用。优先考虑的抗原将根据其靶向对白血病与正常造血的体内植入的影响进行验证。这些发现将为癌症干细胞的基本组成部分提供重要的见解，有助于建立免疫实验室的临床反应，并指导选择定义的抗原疫苗或白血病的抗原靶标的抗原靶标。