Targeted immunotherapy of breast cancer with central memory T cells

中央记忆T细胞对乳腺癌的靶向免疫治疗

基本信息

批准号：
8181485
负责人：
STANLEY R. RIDDELL
金额：
$ 22.68万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8181485
关键词：
Adjuvant Therapy Adoptive Transfer Antibodies Antigens Antitumor Response Avidity Back Breast Cell Therapy Cell surface Cells Clinical Trials Development ERBB2 gene Effector Cell Engineering Engraftment Exhibits Gene Transfer Goals Human Immune response Immune system Immunity Immunotherapy In Vitro Instruction Interleukin-15 Link Lymphoma Malignant Neoplasms Mammary Neoplasms Memory Methods Modality Modeling NY-BR-1 Gene Neuroblastoma Normal Cell Oncogene Proteins Outcome Patients Peptide Vaccines Phase I Clinical Trials Progressive Disease Radiosurgery Reproduction spores SELL gene Sensitivity and Specificity Specificity T cell response T memory cell T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Therapeutic Tumor Antigens Vaccination Vaccines advanced disease chemotherapy design hormone therapy improved in vivo insight killings leukemia/lymphoma malignant breast neoplasm melanoma neoplastic cell nonhuman primate novel novel strategies overexpression phase 1 study programs response success terminally differentiated effector memory (TEM) T cells tumor

项目摘要

The translational goal of this project is to evaluate the adoptive transfer of tunnor-specific T cells derived or engineered from central memory cells to treat breast cancer. The immune system is designed to distinguish diseased from normal cells with exquisite specificity and sensitivity, and there is increasing evidence that tumor development and progression is restrained by adaptive host T cell responses to tumor-associated antigens. However, harnessing this activity to provide therapeutic benefit in breast cancer requires identifying antigens that are expressed by tumor cells and can be safely targeted, and developing methods to achieve potent and durable T cell immunity in patients. Many candidate tumor associated antigens have been discovered in breast cancer and we have focused on targeting the HER-2 oncoprotein and NY-BR-1. We have pursued the adoptive transfer of T cells specific for these antigens because this approach should allow for control ofthe specificity, function, and magnitude ofthe antitumor response, and could overcome obstacles that limit the endogenous host response, or T cell responses elicited by vaccination. The efficacy of adoptive T cell therapy in clinical trials for other human malignancies has been limited by the inability of tumor-specific effector cells that have been expanded in vitro to persist at high levels in vivo after adoptive transfer. Studies in our lab have demonstrated that the survival of adoptively transferred T cells is correlated with the differentiation state of the precursor T cell from which the T cells are derived. Effector cells isolated from central memory but not effector memory T cells provide persistent engraftment, migrate to memory T cell niches, function in vivo after adoptive transfer, and can be sustained at remarkably high levels by a short course of IL-15. This project will build on these findings and evaluate the adoptive transfer of T cells derived or engineered from central memory cells to treat breast cancer. The specific aims are: 1. To perform a phase I trial of adoptive T cell therapy with TcM-derived HER-2/neu (HER-2)-specific T cells following in vivo priming with a HER-2 peptide vaccine in patients with advanced HER-2 breast cancer 2. To engineer CD45RO* CD62L* TCM derived effector T cells through T cell receptor (TCR) gene transfer to express a TCR that targets NY-BR-1. 3. To perform a phase I study of adoptive T cell therapy with TCR modified TCMIO target NY-BR-1 in patients with advanced NY-BR-I breast cancer

该项目的翻译目标是评估隧道特异性T细胞的收养转移或从中央记忆细胞设计以治疗乳腺癌。免疫系统旨在区分从正常细胞中以精致的特异性和敏感性从正常细胞中患病，并且有越来越多的证据表明肿瘤发育和进展受到自适应宿主T细胞对肿瘤相关的反应的限制抗原。但是，利用这项活动在乳腺癌中提供治疗益处需要确定由肿瘤细胞表达并可以安全靶向的抗原，并开发实现的方法患者的有效耐用T细胞免疫。许多候选肿瘤相关抗原已经在乳腺癌中发现，我们专注于靶向HER-2癌蛋白和NY-BR-1。我们已经追求了针对这些抗原特有的T细胞的收养转移，因为这种方法应允许控制抗肿瘤反应的特异性，功能和大小，并且可以克服限制内源性宿主反应或疫苗接种引起的T细胞反应的障碍。功效其他人类恶性肿瘤的临床试验中的养育T细胞疗法受到了无法受到的限制肿瘤特异性效应细胞已在体外扩展，以在收养后持续在体内持久持续转移。我们实验室的研究表明，采用转移的T细胞的存活率是相关的与衍生T细胞的前体T细胞的分化状态。效应细胞分离从中央记忆中，而不是效应器记忆T细胞提供持续的植入，迁移到内存t 细胞壁ni，在继产后的体内功能，可以在很高的水平上持续一小段 IL-15课程。该项目将基于这些发现并评估T细胞得出的收养转移或从中央记忆细胞设计以治疗乳腺癌。具体目的是： 1。用TCM衍生的HER-2/NEU（HER-2）特异性T细胞进行I阶段试验在患有晚期HER-2乳腺癌患者的HER-2肽疫苗的体内启动后进行启动 2。通过T细胞受体（TCR）基因转移到CD45RO* CD62L* TCM衍生的效应T细胞表达针对NY-BR-1的TCR。 3。用TCR修饰的TCMIO靶标NY-BR-1进行I期T细胞疗法进行I期研究与晚期NY-BR-I乳腺癌