Cell-based tumor vaccines targeting CD4+ T lymphocytes

针对 CD4 T 淋巴细胞的细胞肿瘤疫苗

基本信息

批准号：
7929082
负责人：
SUZANNE OSTRAND-ROSENBERG
金额：
$ 3.29万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929082
关键词：
Alleles Antigen-Presenting Cells Autologous Autologous Tumor Cell CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cancer Vaccines Cell-Mediated Cytolysis Cells Dendritic Cells Disease Disseminated Malignant Neoplasm Engineering Eye Genes Goals Grant HLA-DR Antigens Human Immune Immunity In Vitro Liver MHC Class II Genes MHC class II transactivator protein Mass Spectrum Analysis Melanoma Cell Melanoma Vaccine Memory Mus Neoplasm Metastasis Ocular Melanoma Patients Peptides Peripheral Blood Mononuclear Cell Population Primary Neoplasm Series Site Small Interfering RNA System T-Cell Receptor T-Lymphocyte Testing Therapeutic Trans-Activators Translating Treatment Efficacy Tumor Antigens Vaccine Design Vaccines Work base cross reactivity design immunogenic improved insight invariant chain neoplastic cell novel prevent prophylactic response tumor vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to develop therapeutic and prophylactic vaccines that induce regression and prevent progression of metastatic ocular melanoma, a disease for which there is no current treatment. To achieve this goal we have designed cell-based vaccines that activate tumor-specific CD4+ T cells, a key cell population that facilities CD8+ T cell-mediated cytotoxicity and memory. The ocular melanoma "MHC II vaccines" consist of tumor cells that are genetically modified to express the costimulatory molecule CD80 and MHC class II alleles that are syngeneic to the tumor-bearing host. If the vaccine cells and the host share MHC I alleles, the vaccines also activate CD8+ T cells. Previous studies in mice demonstrated significant therapeutic efficacy against established primary and spontaneously metastatic cancers. Because the vaccines lack the MHC ll-accessory molecule, Invariant chain (li), which is expressed in all professional antigen presenting cells (APC), we have hypothesized that the vaccines present novel MHC ll-restricted peptides which are not produced by professional APC. We have spent years 1-4 of this grant translating the vaccines for human use and have made a series of ocular melanoma vaccines that express CD80 plus a variety of HLA-DR alleles in the absence of li. These vaccines activate human PBMC to endogenously synthesized tumor antigens in vitro. During the next grant period we will determine if the basic concept of MHC II vaccines has therapeutic efficacy in human systems and will exploit the mechanistic insight we have gained during the previous grant period to improve vaccine design. We propose four Specific Aims. Aim 1: Determine if MHC II "cocktail" vaccines activate patients' T cells to autologous tumor and if patients are responsive to the vaccines throughout the course of their disease. Aim 2: Determine if ocular melanoma MHC II vaccines prepared from primary tumors, which reside in the immune privileged site of the eye, are more efficacious than vaccines prepared from metastatic tumor cells that reside in the liver, a non-privileged site. Aim 3: Determine if ocular melanoma cells transduced with CD80, the MHC class II transactivator (CIITA), and down-regulated for li activate tumor-specific T cells. Aim 4: Determine if the MHC ll+li- vaccines produce a novel repertoire of peptides and if ocular melanoma patients' responses are skewed towards the novel peptides.

描述（由申请人提供）：我们的长期目标是开发治疗性和预防性疫苗，以诱导转移性眼部黑色素瘤消退并预防其进展，这种疾病目前尚无治疗方法。为了实现这一目标，我们设计了基于细胞的疫苗，可以激活肿瘤特异性 CD4+ T 细胞，这是一种促进 CD8+ T 细胞介导的细胞毒性和记忆的关键细胞群。眼部黑色素瘤“MHC II 疫苗”由经过基因改造的肿瘤细胞组成，可表达与荷瘤宿主同源的共刺激分子 CD80 和 MHC II 类等位基因。如果疫苗细胞和宿主共享 MHC I 等位基因，疫苗也会激活 CD8+ T 细胞。先前对小鼠的研究证明了对已确定的原发性和自发转移性癌症的显着治疗效果。由于疫苗缺乏在所有专职抗原呈递细胞 (APC) 中表达的 MHC ll 辅助分子、不变链 (li)，因此我们假设疫苗呈现新的 MHC ll 限制性肽，这些肽不是由专职 APC 产生的。我们花了这笔拨款的第 1-4 年来转化人类使用的疫苗，并制造了一系列眼部黑色素瘤疫苗，这些疫苗在缺乏 li 的情况下表达 CD80 和各种 HLA-DR 等位基因。这些疫苗在体外激活人 PBMC 内源合成的肿瘤抗原。在下一个资助期内，我们将确定 MHC II 疫苗的基本概念是否对人体系统具有治疗功效，并将利用我们在上一个资助期内获得的机制见解来改进疫苗设计。我们提出四个具体目标。目标 1：确定 MHC II“鸡尾酒”疫苗是否能激活患者针对自体肿瘤的 T 细胞，以及患者在整个疾病过程中是否对疫苗有反应。目标 2：确定由位于眼睛免疫特权部位的原发性肿瘤制备的眼部黑色素瘤 MHC II 疫苗是否比由位于肝脏（非特权部位）的转移性肿瘤细胞制备的疫苗更有效。目标 3：确定用 CD80、MHC II 类反式激活因子 (CIITA) 转导并下调 li 的眼部黑色素瘤细胞是否会激活肿瘤特异性 T 细胞。目标 4：确定 MHC ll+li- 疫苗是否产生新的肽库，以及眼部黑色素瘤患者的反应是否偏向于新的肽。