STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

增强 T 细胞克隆过继转移的策略

• 批准号: 7958859
• 负责人: STANLEY R. RIDDELL
• 金额: $ 31.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958859
• 关键词: Adoptive Transfer; Aftercare; Antigens; CD19 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cell Survival; Cells; Computer Retrieval of Information on Scientific Projects Database; Dose; Funding; Grant; Human; IL2 gene; Immunity; Immunotherapy; Infection; Institution; Interleukin-15; Interleukin-2; Macaca; Maintenance; Malignant Neoplasms; Memory; Natural Killer Cells; Phenotype; Primates; Reporting; Research; Research Personnel; Resources; Role; Source; T memory cell; T-Lymphocyte; Toxic effect; United States National Institutes of Health; cytokine; in vivo; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The adoptive transfer of antigen-specific CD8+ T cells is a promising treatment for human malignancies and infections. However, this approach is often limited by the poor persistence of transferred effector T cells (TE). Interleukin (IL)2 is frequently administered to support the survival of transferred T cells. High-dose IL2 can cause systemic toxicity, promotes the expansion of CD4+FoxP3+ regulatory T cells (Treg), which can inhibit antitumor immunity, and may promote activationinduced cell death of the transferred TE, if exposure is prolonged. IL15 is a novel cytokine that has a critical role in the maintenance of T-cell memory and may be an alternative to IL2 for supporting transferred T-cell survival. We first treated 5 macaques with IL15 (2.515 ¿g/kg s.c.) alone, either daily or every 3 days, and assessed toxicity and immunological effects. Daily IL15 increased the circulating NK and CD8+ T cells and expanded CD8+CD95+CCR7- effector memory (TEM) and CD95+CCR7+ central memory T cells (TCM). However, daily IL15 (515 ¿g/kg) accumulated in vivo, causing reversible toxicities. Intermittent IL15 treatment was safe, increased NK cells and CD8+ TEM or TCM, without boosting the CD4+ Treg. We then evaluated the ability of IL15 to support transferred CD8+ TE marked with CD19 in 2 macaques. As previously reported,1 TCM-derived CD8+ TE transferred without cytokines persisted in vivo at low levels of 0.20.8% of CD8+ cells. By contrast, T cells given with IL15 persisted at high levels (up to 10 % of CD8+ T cells) during and after treatment. The cells retained the ability to re-acquire a TCM phenotype and migrated to memory niches. Thus, IL15 can be safely administered and exerts a biologic effect on endogenous and transferred T cells. IL15 may be an alternative to IL2 or lymphodepletion to support the persistence of transferred T cells in human immunotherapy.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 过继转移抗原特异性CD8+T细胞是治疗人类恶性肿瘤和感染的一种有前途的治疗方法。然而，这种方法往往受到转移效应T细胞(TE)持久性差的限制。白介素2经常被用来支持被转移的T细胞的存活。大剂量的IL2可引起全身毒性，促进CD4+FoxP3+调节性T细胞(Treg)的增殖，从而抑制抗肿瘤免疫，如果暴露时间延长，可能会促进被转移TE的激活诱导的细胞死亡。IL15是一种新的细胞因子，在维持T细胞记忆中起关键作用，可能成为IL2的替代品，以支持转移的T细胞存活。我们首先用IL15(2.515克/公斤皮下注射)处理5只猕猴。每天或每3天单独使用一次，并评估毒性和免疫效果。IL15可增加外周血中NK细胞和CD8+T细胞的数量，增加CD8+CD95+CCR7-效应记忆T细胞和CD95+CCR7+中枢记忆T细胞。然而，每天IL15(515g/kg)在体内累积，导致可逆毒性。间歇性IL15治疗是安全的，可提高NK细胞和CD8+T细胞亚群，但不能提高CD 4+T细胞亚群。然后，我们在2只猕猴身上评估了IL15支持CD19标记的转移的CD8+TE的能力。正如先前报道的那样，1在没有细胞因子的情况下，1中药来源的CD8+TE在体内以0.20.8%的CD8+细胞水平持续存在。相比之下，给予IL15的T细胞在治疗期间和治疗后保持在高水平(高达CD8+T细胞的10%)。这些细胞保留了重新获得中医表型的能力，并迁移到记忆利基。因此，IL15可以安全地给药，并对内源性和转移性T细胞产生生物学效应。在人类免疫治疗中，IL15可能是IL2或淋巴滤除的替代品，以支持转移的T细胞的持久性。