Immunologic targets in Myeloid Leukemia

髓系白血病的免疫靶点

• 批准号: 8204738
• 负责人: RICHARD J JONES
• 金额: $ 33.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204738
• 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; Screening procedure; 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

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. PUBLIC HEALTH RELEVANCE: Immune responses to cancer occur in some patients and are associated with a more favorable outcome. Methods now exist to identify the molecules on cancer cells recognized by antibodies and T cells, however it is not known which of these many targets are present on the cells most responsible for cancer growth. The identification of immune targets in leukemia will teach us what components of the cancer are most essential to eliminate, and provide new tools to develop and evaluate more effective immune-based therapies.

描述（由申请人提供）：现在有明确的证据表明，免疫系统能够检测并响应由经历肿瘤转化的正常细胞和由此产生的癌症产生的细胞应激信号。尽管这种反应的频率和程度在个体之间存在很大差异，但临床前模型和临床研究都已证实，癌症表型、其生物学行为和临床预后深受宿主免疫反应特征的影响。细胞和体液免疫可识别癌细胞上的多种抗原靶点，其中许多靶点正在被作为免疫治疗的候选者。然而，癌症由异质细胞群组成，其基因表达模式和靶抗原的分布各不相同。这些表型差异叠加在癌细胞亚群自我更新和传播恶性肿瘤的能力的功能差异上。因此，几乎没有证据可以指导哪些抗原在靶向时最有可能带来临床益处。我们寻求在两种临床环境中使用无偏见的抗原识别策略来解决这一限制，在这两种环境中，有可测量的证据表明免疫介导的临床效果；在 1) 慢性粒细胞白血病 (CML) 和 2) 急性粒细胞白血病 (AML) 的疫苗相关缓解诱导中。这些筛选中确定的抗原将根据以下标准进行优先排序：1）免疫识别与临床反应的相关性，2）白血病干细胞（LSC）的表达，3）抗体和T细胞反应的检测，以及4）基因在白血病发生途径中发挥的生物学作用。优先抗原将根据其靶向对白血病体内植入与正常造血的影响进行验证。这些发现将为癌症干细胞的基本成分提供重要的见解，有助于建立预测临床反应的免疫实验室相关性，并指导针对白血病的确定抗原疫苗或过继性 T 细胞疗法的抗原靶标的选择。 公共卫生相关性：一些患者会出现对癌症的免疫反应，并且与更有利的结果相关。现在有方法可以识别癌细胞上被抗体和 T 细胞识别的分子，但尚不清楚这些目标中的哪一个存在于对癌症生长最负责的细胞上。白血病免疫靶标的识别将告诉我们哪些癌症成分最需要消除，并提供新工具来开发和评估更有效的免疫疗法。