TCR Engineered CD4 Cells as Helpers in Tumor Immunity

TCR 工程 CD4 细胞作为肿瘤免疫的助手

基本信息

批准号：
7647734
负责人：
BIJAY MUKHERJI
金额：
$ 24.69万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647734
关键词：
Address Adoptive Immunotherapy Adoptive Transfer Affect Alleles Antigens Biological Assay Biology CCL2 gene CD4 Positive T Lymphocytes Cancer Center Cancer Vaccines Cause of Death Cell Communication Cell Therapy Cells Clinical Trials Cytoplasmic Granules Cytotoxic T-Lymphocytes Data Dendritic Cells Development Effector Cell Employee Strikes Employment Engineering Epitopes Exhibits Exocytosis Generations Helper-Inducer T-Lymphocyte Human Immune Immune response Immune system Immunoglobulin Constant Region Immunoglobulin Variable Region Immunotherapeutic agent Immunotherapy In Vitro Interleukin-2 Lead Life Literature Lymphocyte Activation Lytic MHC Class I Genes MHC Class II Genes Malignant Neoplasms Mediating Melanoma Cell Modality Modeling Monophenol Monooxygenase Mus Patients Peptides Progress Reports Provider Regulation Research Role Source T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Transgenic Mice Transgenic Organisms Treatment Protocols Tumor Antigens Tumor Immunity Work base cancer immunotherapy cancer therapy cellular engineering cytokine design in vitro Assay in vivo insight interest killer T cell melanoma novel novel strategies public health relevance receptor response selective expression tumor

项目摘要

DESCRIPTION (provided by applicant): Active specific and adoptive immunotherapy for cancer centering on cytolytic T lymphocyte (CTL) response have shown encouraging results. These treatment modalities, however, would benefit from the involvement of cognate CD4+ T helper (Th) cells. We have found that CD4+ T cells -- engineered to express a MHC class I- restricted melanoma epitope specific T cell receptor (TCR) that is also used by CTL to recognize the epitope -- synthesize Th1 type cytokines and exhibit cytolytic potential against melanoma cells and surrogate target cells in an epitope specific manner. We propose a comprehensive study of the biology of such MHC class I-restricted TCR engineered CD4 T cells in an anti-melanoma immune response focusing on their role as effector cells and as helper T cells. The central hypothesis is that "considering that help and suppression are two mutually opposed conditions, if one could engage CTL and helper cells recognizing a tumor associated epitope of interest simultaneously through an identical TCR and on the same MHC restricting molecules, the CD4+ T cells would facilitate the generation of a robust and long-lasting CTL response and mitigate Treg activation. Additionally, by exhibiting anti-tumor effector function of their own, they would expand the anti-tumor repertoire". We propose to test this hypothesis through several specific aims designed with CD4+ T cells engineered to express melanoma epitope (MART-127-35 and Tyrosinase368-376)-specific TCR in in vitro assays, and in HLA- A2.1/Kb transgenic mice employing a chimeric human-mouse TCR consisting of mouse constant regions and human variable regions, in vivo. The biology of the CD4+ Th cells will be assessed through a comprehensive phenotypic and functional characterization in in vitro CTL generation assay, in vitro Treg activation assay, and in adoptive transfers of chimeric TCR engineered T cells into HLA-A2.1/Kb mice bearing A2.1/Kb transgenic B-16 melanoma cells. The proposed research will lead to the development of a new and complementary strategy to active specific and adoptive immunotherapy for cancer. Lay Summary: The proposed research is designed to develop a novel way to engage killer T cells and helper T cells (two important players in the immune system) to work in a collaborative and synergistic manner so as to orchestrate a robust and long-lived cellular immune attack against human cancers - a major cause of death. PUBLIC HEALTH RELEVANCE: "Cancer vaccines" and adoptive cell therapy for cancer have shown promising results but the two basic approaches need new strategies addressing two major impediments -- the lack of an effective way that would engage cognate CD4 T helper (Th) cells in the treatment and T regulatory (Treg) cell activities. We propose a novel strategy that could address both constraints through the employment of CD4 T cells engineered to express an MHC class I-restricted and tumor epitope specific T cell receptor (TCR) that are also used by cytolytic T cells (CTL) to recognize the tumor antigen. The TCR-engineered CD4 Th cells, therefore, could provide "help" towards the generation of a robust and long-lived CTL response as well as expand the therapeutic repertoire by mitigating Treg activities (as help and suppression are mutually opposed conditions) and through their own cytolytic potential.

描述（由申请人提供）：以细胞溶解T淋巴细胞（CTL）反应为中心的癌症的主动特异性和收养免疫疗法表现出令人鼓舞的结果。然而，这些治疗方式将受益于同源CD4+ T辅助辅助器（Th）细胞的参与。我们已经发现，CD4+ T细胞（设计用于表达MHC I类限制的黑色素瘤表位特异性T细胞受体（TCR），CTL也用于识别表位 - 合成TH1型细胞因子并在主观构件特异性方式中表现出针对黑色素瘤细胞和替代靶细胞的细胞溶解剂。我们提出了一项全面的研究，对抗黑素瘤的免疫反应中这种MHC I限制性TCR工程CD4 T细胞的生物学重点是其作为效应细胞和助手T细胞的作用。中心假设是：“考虑到帮助和抑制是两个相互对立的条件，如果一个人可以通过相同的TCR和同一MHC限制分子来识别与肿瘤相关的肿瘤相关的肿瘤的细胞，那么CD4+ T细胞会促进稳健的和长期的CTITLENG COTTITION CATTICTIAN和MITEG treg treg treg treg treg treg treg treg treg treg and，他们自己将扩大反肿瘤曲目。”我们建议通过几个特定目的通过设计用于表达黑色素瘤表位的CD4+ T细胞（MART-127-35和酪氨酸酶368-376）设计的特定目标来检验这一假设。 CD4+ TH细胞的生物学将通过体外CTL生成测定，体外Treg激活测定法以及嵌合TCR工程T细胞的收养转移中的全面表型和功能表征进行评估，并在HLA-A2.1/KB小鼠中携带A2.1/KB转基因B-16糖细胞。拟议的研究将导致制定一种新的和互补的策略，以进行癌症的主动特异性免疫疗法。 LIE摘要：拟议的研究旨在开发一种新颖的方式来吸引杀手T细胞和助手T细胞（免疫系统中的两个重要参与者）以协作和协同的方式工作，以便策划对人类癌症的强大而长期寿命的细胞免疫攻击 - 死亡的主要原因。公共卫生相关性：癌症的“癌症疫苗”和收养细胞疗法已显示出令人鼓舞的结果，但是两种基本方法需要解决两个主要障碍的新策略 - 缺乏一种有效的方法，可以使同源CD4 T助手（TH）细胞参与治疗和调节性（TREG）蜂窝活动。我们提出了一种新的策略，该策略可以通过使用旨在表达MHC I类限制性和肿瘤表位特异性T细胞受体（TCR）的CD4 T细胞来解决这两种约束，这些细胞也被细胞溶解T细胞（CTL）使用，以识别肿瘤抗原。因此，TCR工程的CD4 TH细胞可以为产生健壮且长寿的CTL反应提供“帮助”，并通过减轻Treg活性（作为帮助和抑制是相互对立的条件）以及通过其自身的细胞溶性来扩展治疗库。