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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：该提案的总体目标是表征人类对与MHC相关的磷酸肽的免疫反应，MHC相关的磷酸肽是一种新的癌症抗原（AG）类别，在癌细胞中有选择性地过表达，并与基于恶性肿瘤的过程相关。我们发现，在不同癌细胞上，MHC-I和MHC-II分子提出了超过600个磷酸肽。这些磷酸肽中的大多数来自与细胞生长控制和信号传导过程有关的蛋白质，其中许多在癌细胞中被没关系。在正常细胞上显示的很少。这些磷酸肽代表了一种新颖而独特的癌症收集，可以理解和利用用于癌症免疫疗法。我们最近还发现，健康个体中某些磷酸肽的免疫反应令人惊讶地很强，并且由于CD8 T细胞已经显示出记忆表型。通常，这种预先存在的记忆免疫通常不会对正常人的其他类型的癌症AG观察到，而仅在癌症患者中明显，通常仅在疫苗接种后才能证明。重要的是，慢性淋巴细胞性白血病（CLL）和急性髓性白血病（AML）的患者对许多磷酸肽的强烈免疫力降低或没有。通过同种异体供体的骨髓移植，可以在AML患者中恢复它。总体而言，这些结果表明，在没有可辨别的癌症的情况下，先前暴露于磷酸肽，并且可能是免疫监测的一个方面，会导致磷酸肽特异性T细胞记忆的发展。此外，癌症的进展与未能发展这种免疫力或随着时间的流逝而丧失有关。但是，需要许多其他工作来确定正常个体对与白血病和实体肿瘤恶性肿瘤相关的较大磷酸肽群中既有记忆免疫的存在，并了解其发育的基础。此外，重要的是要了解其他形式的癌症患者是否缺乏磷酸肽特异性免疫。最后，重要的是要确定癌症患者的复苏或这种免疫力的复苏或扩增。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反应； 2）确定这些癌症患者对与MHC相关的磷酸肽的免疫状态选择性表达的； 3）纵向评估对骨髓增生综合征（MDS）患者磷酸肽的免疫力，及其与AML最终发展的关联； 4）评估癌症患者治疗干预措施复苏或增强对磷酸肽的免疫反应的能力。这项工作将为针对癌症相关的磷酸肽的临床试验奠定了阶段，并可能与其他免疫治疗或化学治疗方法结合使用。