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: 8357607
• 负责人: STANLEY R. RIDDELL
• 金额: $ 15.66万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357607
• 关键词: Adoptive Transfer; Animals; Bone Marrow; CD19 gene; CD8B1 gene; Cells; Clinical; Cytomegalovirus; Data; Dose; Funding; Genes; Grant; In Vitro; Infusion procedures; Interleukin-15; MS4A1 gene; Memory; National Center for Research Resources; Phenotype; Primates; Principal Investigator; Regimen; Research; Research Infrastructure; Resources; SELL gene; Serum; Source; T-Lymphocyte; United States National Institutes of Health; Work; cancer immunotherapy; cost; improved; in vivo; lymph nodes

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have made progress on our studies investigating the use of IL-15 to enhance the in vivo persistence of adoptively transferred central memory (TCM) derived effector T cells (TE). Our prior work in NHP showed that CD8+ TE derived from CD62L+ TCM but not from CD62L- TEM were capable of surviving long-term in vivo, migrating to memory niches, and reverting to the memory (TM) pool. A distinguishing feature of TCM-derived TE was the ability to survive in low-dose IL-15 in the absence of TCR stimulation, suggesting that supplementing IL-15 in vivo might further improve persistence of transferred cells. We established an intermittent regimen of IL-15 that was safe, increased the proliferation of endogenous CD8+ TM, and yielded peak serum levels of IL-15 that exceed the level needed to promote the survival of TCM-derived TE in vitro. We treated 2 groups of animals with gene marked T cells. Group 1 consisted of 6 animals that received CD19-marked TCM-derived CMV-specific TE clones either alone (3 animals) or with IL-15 (3 animals). Group 2 consisted of 3 animals that received sequential infusions of polyclonal TCM TE cells without or with IL-15. The cells were gene-marked with either CD19 or CD20 to enable us to distinguish T cells infused without or with IL-15, respectively. We found that IL-15 enhanced transferred T cell persistence in 2 of 3 animals in each group. The persisting T cells acquired a memory phenotype in vivo and migrated to lymph nodes and bone marrow in all of the animals. This data suggests that IL-15 supports the survival of the adoptively transferred T cells, and may be useful in clinical immunotherapy for cancer.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们在研究IL-15的使用方面取得了进展，以增强过继转移的中央记忆（TCM）衍生的效应T细胞（TE）的体内持久性。我们先前在NHP中的工作表明，CD8+ TE源自CD62L+ TCM，但不能从CD62L-TEM衍生出的CD8+ TE能够在体内长期生存，迁移到记忆壁ches，并恢复到记忆（TM）池。 TCM衍生的TE的一个显着特征是在没有TCR刺激的情况下在低剂量IL-15中生存的能力，这表明在体内补充IL-15可能会进一步改善转移的细胞的持久性。我们建立了一个安全的IL-15的间歇性方案，该方案是安全的，增加了内源性CD8+ TM的增殖，并产生了IL-15的峰值血清水平，超过了促进TCM衍生TE在体外生存所需的水平。我们用标记T细胞的基因处理了2组动物。第1组由6只动物组成，这些动物单独接受CD19标记的TCM衍生的CMV特异性TE克隆（3只动物）或IL-15（3只动物）。第2组由3只动物组成，这些动物接收了无IL-15或没有IL-15的多克隆TCM TE细胞的顺序输注。用CD19或CD20标记基因，使我们能够分别区分未经IL-15或IL-15的T细胞。我们发现，IL-15在每组3只动物中有2只动物中增强了T细胞的持久性。持续的T细胞在体内获得了一种记忆表型，并迁移到所有动物中的淋巴结和骨髓。该数据表明，IL-15支持了采用转移的T细胞的存活，并且可能对癌症的临床免疫疗法有用。