STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们已经在研究使用IL-15来增强过继转移的中枢记忆（TCM）衍生的效应T细胞（TE）的体内持久性的研究上取得了进展。我们先前在NHP中的工作表明，来源于CD 62 L + TCM而不是来源于CD 62 L-TEM的CD 8 + TE能够在体内长期存活，迁移到记忆小生境，并恢复到记忆（TM）库。TCM-derived TE的一个显著特征是在不存在TCR刺激的情况下在低剂量IL-15中存活的能力，这表明体内补充IL-15可能进一步改善转移细胞的持久性。我们建立了一种安全的IL-15间歇方案，增加了内源性CD 8 + TM的增殖，并产生了IL-15的峰值血清水平，超过了体外促进中药衍生TE存活所需的水平。我们用基因标记的T细胞治疗了2组动物。第1组由6只动物组成，其接受单独的（3只动物）或与IL-15一起（3只动物）的CD 19标记的TCM衍生的CMV特异性TE克隆。第2组由3只动物组成，其接受不含或含IL-15的多克隆TCM TE细胞的顺序输注。这些细胞用CD 19或CD 20进行基因标记，以使我们能够区分分别在没有或有IL-15的情况下输注的T细胞。我们发现IL-15增强了每组3只动物中2只动物的转移T细胞持久性。在所有动物中，持续存在的T细胞在体内获得记忆表型并迁移到淋巴结和骨髓。这些数据表明，IL-15支持过继转移的T细胞的存活，并且可能在癌症的临床免疫治疗中有用。

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.