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

该项目的转化目标是评估肿瘤特异性 T 细胞的过继转移，这些 T 细胞来源于或由中央记忆细胞改造而成，用于治疗乳腺癌。免疫系统旨在区分正常细胞的病变具有精致的特异性和敏感性，并且越来越多的证据表明肿瘤的发生和进展受到宿主 T 细胞对肿瘤相关细胞的适应性反应的抑制。抗原。然而，利用这一活动为乳腺癌提供治疗益处需要确定肿瘤细胞表达的并且可以安全靶向的抗原，并开发方法来实现患者体内有效且持久的 T 细胞免疫。许多候选肿瘤相关抗原已被我们在乳腺癌中发现了 HER-2 癌蛋白和 NY-BR-1。我们已经追求对这些抗原具有特异性的 T 细胞的过继转移，因为这种方法应该允许用于控制抗肿瘤反应的特异性、功能和强度，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。功效过继性 T 细胞疗法在其他人类恶性肿瘤临床试验中的应用受到了以下因素的限制：肿瘤特异性效应细胞已在体外扩增，在过继后在体内持续保持高水平转移。我们实验室的研究表明，过继转移的 T 细胞的存活率与与 T 细胞来源的前体 T 细胞的分化状态有关。分离的效应细胞来自中枢记忆而非效应记忆 T 细胞提供持久植入，迁移至记忆 T 细胞生态位，在过继转移后在体内发挥作用，并且可以在短时间内维持在非常高的水平 IL-15的过程。该项目将建立在这些发现的基础上，评估 T 细胞的过继转移或由中央记忆细胞改造来治疗乳腺癌。具体目标是： 1. 使用 TcM 衍生的 HER-2/neu (HER-2) 特异性 T 细胞进行过继性 T 细胞治疗的 I 期试验在晚期 HER-2 乳腺癌患者体内接种 HER-2 肽疫苗后 2. 通过 T 细胞受体 (TCR) 基因转移来改造 CD45RO* CD62L* 中药来源的效应 T 细胞表达针对 NY-BR-1 的 TCR。 3. 对患者进行TCR修饰的TCMIO靶点NY-BR-1过继性T细胞治疗的I期研究患有晚期 NY-BR-I 乳腺癌