STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们在使用IL-15增强过继转移的中枢记忆来源的效应T细胞(TE)体内持久性的研究方面取得了进展。我们在NHP的前期工作表明，来自CD62L Tcm而不是CD62L-Tm的CD8 TE能够在体内长期存活，迁移到记忆小生境，并恢复到记忆池(TM)。中药来源的TE的一个显著特征是，在没有TCR刺激的情况下，能够在低剂量的IL-15中存活，这表明在体内补充IL-15可能会进一步提高转移细胞的持久性。我们建立了一种安全的间歇性IL-15方案，促进了内源性CD8 TM的增殖，并产生了超过促进中药来源TE体外存活所需的血清IL-15峰值水平。我们用基因标记的T细胞处理两组动物。第1组6只动物接受CD19标记的中药来源的CMV特异性TE克隆(3只)或联合IL-15(3只)。第2组为连续输注含或不含IL-15的多克隆中药TE细胞3只。用CD19或CD20对这些细胞进行基因标记，以使我们能够区分注入了不含IL-15或含有IL-15的T细胞。我们发现，IL-15增强了每组3只动物中的2只转移的T细胞的持久性。存留的T细胞在体内获得了记忆表型，并迁移到所有动物的淋巴和骨髓。这一数据表明，IL-15支持过继转移的T细胞的存活，并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.