Immunity to MHC-restricted phosphopeptides in healthy donors and cancer patients

健康捐献者和癌症患者对 MHC 限制性磷酸肽的免疫力

• 批准号: 8800677
• 负责人: VICTOR H ENGELHARD
• 金额: $ 43.01万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800677
• 关键词: Acute Myelocytic Leukemia; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Allogeneic Bone Marrow Transplantation; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Breast Cancer Cell; CD8B1 gene; Cancer Patient; Cancer cell line; Categories; Cell Proliferation; Cell physiology; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Collection; Colorectal; Colorectal Cancer; Development; Disease; Distant Metastasis; Dysmyelopoietic Syndromes; Environment; Exposure to; Failure; Goals; HLA-A1 Antigen; Human; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Lead; Life; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of ovary; Mass Spectrum Analysis; Memory; Modality; Morbidity - disease rate; Normal Cell; Normal tissue morphology; Patients; Peptides; Pharmacologic Substance; Phenotype; Phosphopeptides; Phosphoproteins; Phosphorylated Peptide; Phosphorylation; Principal Investigator; Process; Proteins; Radiation therapy; Recombinants; Resuscitation; Sampling; Solid Neoplasm; Source; Specificity; Staging; T memory cell; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic Intervention; Time; Toxic effect; Tumor Immunity; Vaccination; Vaccines; Work; base; cancer cell; cancer immunotherapy; cancer therapy; cell growth; chemotherapy; cohort; inhibitor/antagonist; leukemia; link protein; malignant phenotype; melanoma; mortality; neoplastic cell; novel; overexpression; public health relevance; response; selective expression; signal processing; success; tumor; tumor progression

DESCRIPTION (provided by applicant): The Overall Goal of this proposal is to characterize human immune responses to MHC-associated phosphopeptides, a new category of cancer antigens (Ag) that are selectively overexpressed in cancer cells and linked to processes that underlie malignancy. We have discovered over 600 phosphopeptides are presented by MHC-I and MHC-II molecules on different cancer cells. Most of these phosphopeptides come from proteins that have been linked to cellular growth control and signaling processes, many of which are disregulated in cancer cells. Very few are displayed on normal cells. These phosphopeptides represent a novel and unique collection of cancer Ags to be understood and exploited for cancer immunotherapy. We have also recently discovered that immune responses to some phosphopeptides in healthy individuals are surprisingly strong and are due to CD8 T cells that already show a memory phenotype. This pre-existing memory immunity is not generally observed to other kinds of cancer Ags in normal individuals, but is only evident in cancer patients, and often only after vaccination. Importantly, strong immunity to many phosphopeptides was diminished or absent in patients with chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). It could be restored in AML patients by bone marrow transplantation from an allogeneic donor. Overall, these results suggest the hypothesis that prior exposure to phosphopeptides, in the absence of discernible cancer and potentially as an aspect of immune surveillance, leads to the development of phosphopeptide-specific T cell memory. Furthermore, cancer progression is associated with failure to develop this type of immunity, or its loss over time. However, much additional work is needed to establish the existence of pre-existing memory immunity in normal individuals to a larger cohort of phosphopeptides associated with leukemias and solid tumor malignancies, and to understand the basis for its development. In addition, it is important to understand whether lack of phosphopeptide-specific immunity is evident in patients with other forms of cancer. Finally, it is important to determine whether resuscitation or amplification of this immunity is possible in cancer patients. Accordingly, the Specific Aims are: 1) To determine whether the development of pre-existing memory in normal individuals is based on responses to phosphopeptides associated with EBV transformation; 2) To determine the status of immunity to MHC-associated phosphopeptides selectively expressed on leukemias and solid tumor malignancies in patients with these cancers; 3) To longitudinally evaluate immunity to phosphopeptides in myelodysplastic syndrome (MDS) patients, and its association with the eventual development of AML; 4) To evaluate the ability of therapeutic interventions in cancer patients to resuscitate or augment immune responses to phosphopeptides. This work will set the stage for clinical trials targeting cancer-associated phosphopeptides through vaccination or adoptive transfer approaches, potentially combined with other immunotherapeutic or chemotherapeutic modalities.

描述（由申请方提供）：本提案的总体目标是表征对MHC相关磷酸肽的人体免疫应答，MHC相关磷酸肽是一类新的癌抗原（Ag），在癌细胞中选择性过表达，并与恶性肿瘤的基础过程相关。我们已经发现超过600种磷酸肽由不同癌细胞上的MHC-I和MHC-II分子呈递。这些磷酸肽大多来自与细胞生长控制和信号传导过程相关的蛋白质，其中许多在癌细胞中失调。在正常细胞中很少显示。这些磷酸肽代表了一个新的和独特的收集癌症抗原的理解和利用癌症免疫治疗。我们最近还发现，健康个体对某些磷酸肽的免疫应答非常强，这是由于CD 8 T细胞已经显示出记忆表型。这种预先存在的记忆免疫通常不会在正常个体中观察到其他类型的癌症抗原，但仅在癌症患者中明显，并且通常仅在接种疫苗后。重要的是，慢性淋巴细胞白血病（CLL）和急性髓细胞白血病（AML）患者对许多磷酸肽的免疫力减弱或缺失。AML患者通过异基因供者的骨髓移植可以恢复。总的来说，这些结果表明，假设之前暴露于磷酸肽，在没有可辨别的癌症和潜在的免疫监视的一个方面，导致磷酸肽特异性T细胞记忆的发展。此外，癌症进展与未能发展这种类型的免疫力或随着时间的推移而丧失有关。然而，还需要更多的工作来建立正常个体中存在的预先存在的记忆免疫，以更大的队列与白血病和实体瘤恶性肿瘤相关的磷酸肽，并了解其发展的基础。此外，重要的是要了解缺乏磷酸肽特异性免疫是否在其他形式的癌症患者中明显。最后，重要的是要确定是否复苏或扩增这种免疫是可能的癌症患者。因此，具体目的是：1）确定正常个体中预先存在的记忆的发展是否基于对与EBV转化相关的磷酸肽的应答; 2）确定患有这些癌症的患者对选择性表达在白血病和实体瘤恶性肿瘤上的MHC相关磷酸肽的免疫状态; 3）纵向研究骨髓增生异常综合征（MDS）患者对磷酸肽的免疫反应及其与AML发展的关系; 4）评估癌症患者中治疗性干预恢复或增强对磷酸肽的免疫应答的能力。这项工作将为通过疫苗接种或过继转移方法靶向癌症相关磷酸肽的临床试验奠定基础，可能与其他免疫疗法或化疗方式相结合。