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

• 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
• 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

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tunnor特异性T细胞的过继转移， 从中央记忆细胞改造而来治疗乳腺癌。免疫系统是用来区分 疾病从正常细胞与精致的特异性和敏感性，有越来越多的证据表明， 肿瘤的发展和进展受到适应性宿主T细胞对肿瘤相关免疫应答的抑制。 抗原然而，利用这种活性来提供乳腺癌的治疗益处需要确定 肿瘤细胞表达并可安全靶向的抗原，并开发实现 有效和持久的T细胞免疫力。许多候选的肿瘤相关抗原已经被研究。 在乳腺癌中发现，我们专注于HER-2癌蛋白和NY-BR-1。我们 我一直在寻求过继转移对这些抗原特异性的T细胞，因为这种方法应该允许 用于控制抗肿瘤反应的特异性、功能和大小， 限制内源性宿主应答或由疫苗接种引起的T细胞应答的障碍。疗效 在其他人类恶性肿瘤的临床试验中，过继性T细胞疗法的应用受到限制， 肿瘤特异性效应细胞已经在体外扩增，在过继后在体内持续高水平， 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细胞所来源的前体T细胞的分化状态有关。分离的效应细胞 来自中央记忆而不是效应记忆T细胞提供持久的植入，迁移到记忆T细胞， 细胞小生境，过继转移后在体内起作用，并且可以通过短时间内维持在非常高的水平。 IL-15。该项目将建立在这些发现和评估过继转移的T细胞来源 或者从中央记忆细胞中改造出来治疗乳腺癌。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乳腺癌患者中用HER-2肽疫苗体内引发后 2.为了通过T细胞受体（TCR）基因转移工程化CD 45 RO * CD 62 L * TCM衍生的效应T细胞， 表达靶向NY-BR-1的TCR。 3.在患者中进行使用TCR修饰的TCM 10靶标NY-BR-1的过继性T细胞疗法的I期研究 晚期NY-BR-I乳腺癌