Immunologic targets in Myeloid Leukemia

描述(由申请人提供)：现在有明确的证据表明，免疫系统已经准备好检测和反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大小在个体之间有很大的差异，但临床前模型和临床研究都已经证实，宿主免疫反应的特征深刻地影响着癌症的表型、生物学行为和临床预后。细胞免疫和体液免疫识别癌细胞上广泛的抗原靶点，其中许多是免疫治疗的候选对象。然而，癌症是由不同的细胞群体组成的，在基因表达模式和由此产生的靶抗原分布上各不相同。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的能力的功能差异上。因此，几乎没有证据来指导这些抗原中的哪些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见的抗原识别策略来解决这一局限性，其中有可测量的证据表明免疫介导的临床效果；在疫苗相关缓解诱导中，1)慢性粒细胞白血病(CML)和2)急性髓系白血病(AML)。在这些筛选中确定的抗原将根据以下标准优先考虑：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)基因在白血病发生途径中所起的生物学作用。优先抗原将根据它们的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，并指导定义抗原疫苗或白血病过继T细胞疗法的抗原靶点的选择。 公共卫生相关性：对癌症的免疫反应发生在一些患者身上，并与更有利的结果相关。现在已经有方法来识别由抗体和T细胞识别的癌细胞上的分子，但是还不知道这些众多靶点中的哪一个存在于最负责癌症生长的细胞上。白血病免疫靶点的识别将告诉我们哪些癌症成分是最需要消除的，并为开发和评估更有效的基于免疫的治疗方法提供新的工具。

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.