STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 抗原特异性CD8 + T细胞的过继转移是一种有前途的治疗人类恶性肿瘤和感染的方法。然而，这种方法通常受到转移的效应T细胞（TE）的持久性差的限制。白细胞介素（IL）2经常被施用以支持转移的T细胞的存活。大剂量IL 2可引起全身毒性，促进CD4 + FoxP3+调节性T细胞（Treg）的扩增，抑制抗肿瘤免疫，并可能促进活化如果暴露时间延长，则诱导转移的TE的细胞死亡。IL 15是一种新的细胞因子，在维持T细胞记忆中具有关键作用，并且可能是IL 2的替代物，用于支持转移的T细胞存活。我们首先用IL 15（2.5%）治疗5只猕猴，15微克/千克皮下注射）每天或每3天单独给药，并评估毒性和免疫学效应。每日IL 15增加循环NK和CD8 + T细胞并扩增CD8 + CD95 + CCR7效应记忆（TEM）和CD95 + CCR7+中枢记忆T细胞（TCM）。但每日IL 15（515 μ g/kg）在体内蓄积，引起可逆毒性。间歇性IL 15治疗是安全的，增加了NK细胞和CD8 + TEM或TCM，而没有加强CD4 + Treg。然后，我们在2只猕猴中评估了IL 15支持用CD 19标记的转移的CD 8 + TE的能力。如前所述，在无细胞因子的情况下转移的1个TCM衍生的CD8 + TE在体内持续低水平0.20.8%的CD8+细胞。相比之下，给予IL 15的T细胞在治疗期间和治疗后保持在高水平（高达10%的CD8 + T细胞）。这些细胞保留了重新获得TCM表型的能力，并迁移到记忆龛。因此，IL 15可以安全地施用并对内源性和转移的T细胞发挥生物学作用。IL 15可能是IL 2或淋巴细胞清除的替代方案，以支持转移的T细胞在人类免疫治疗中的持久性。

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.