Immunologic targets in Myeloid Leukemia

描述（由申请人提供）：现在有明确的证据表明，免疫系统能够检测正常细胞发生肿瘤转化和由此产生的癌症所产生的细胞应激信号并作出反应。尽管这种反应的频率和强度在个体之间有很大差异，但临床前模型和临床研究都表明，癌症表型、生物学行为和临床预后受到宿主免疫反应特征的深刻影响。细胞免疫和体液免疫可以识别癌细胞上广泛的抗原靶点，其中许多靶点正被用作免疫治疗的候选靶点。然而，癌症是由异质细胞群组成的，在基因表达模式和靶抗原的最终分布上各不相同。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能力的功能差异上。因此，很少有证据来指导这些抗原中的哪一种在靶向时最有可能带来临床益处。我们试图在两个临床环境中使用无偏抗原鉴定策略来解决这一限制，其中有可测量的证据表明免疫介导的临床效应；1)慢性髓性白血病（CML）和2)急性髓性白血病（AML）的疫苗相关缓解诱导。在这些筛选中发现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（LSCs）的表达，3)抗体和T细胞反应的检测，以及4)该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。这些发现将对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，并指导选择抗原疫苗或白血病过继T细胞治疗的抗原靶点。

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.