Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy.
Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy.
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DOI：
10.1371/journal.pone.0060031
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Radvanyi L
中科院分区：
文献类型：
--
作者：
Chacon JA;Wu RC;Sukhumalchandra P;Molldrem JJ;Sarnaik A;Pilon-Thomas S;Weber J;Hwu P;Radvanyi L
使用肿瘤浸润淋巴细胞（TIL）的连续性T细胞疗法（ACT）可诱导高达50%或更多的不可切除转移性黑色素瘤患者的肿瘤消退。然而，目前用于扩增黑素瘤TIL的方法，特别是“快速扩增方案”（REP）并没有被设计为增强用于输注的最佳效应记忆CD 8 + T细胞的产生。解决这个问题的一种方法是操纵特定的共刺激信号通路以增强CD 8+效应记忆T细胞扩增。在这项研究中，我们确定了在活化的CD 8 + T细胞中特异性诱导的活化TNF-R家族成员4-1BB/CD 137对REP期间扩增的CD 8 + T细胞的产量、表型和功能活性的影响。我们发现，在初始TCR刺激后的REP期间早期，CD 8 + TIL上调4-1BB表达，但REP中的PBMC饲养细胞和活化的TIL均不表达4-1BB配体。然而，向REP中添加外源性激动性抗4-1BB IgG 4（BMS 663513）显著增强了CD 8 + T细胞的频率和总产量以及它们对CD 28的维持，并增加了它们的抗肿瘤CTL活性。基因表达分析发现，4-1BB诱导的bcl-2和生存素表达的增加与CD 8+后REP TIL在细胞因子存在或不存在下再培养时的增强的存活能力相关。我们的研究结果表明，在TIL REP启动期间添加激动性抗4-1BB抗体产生能够改善效应子功能和存活的CD 8 + T细胞群。这可以在过继转移到患者体内后大大改善TIL的持久性和体内抗肿瘤活性。
Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the “rapid expansion protocol” (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.
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影响因子：
11.2
作者：
Singh H;Figliola MJ;Dawson MJ;Huls H;Olivares S;Switzer K;Mi T;Maiti S;Kebriaei P;Lee DA;Champlin RE;Cooper LJ
通讯作者：
Cooper LJ
DOI：
10.1038/nri3191
发表时间：
2012-03-22
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Restifo NP;Dudley ME;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
15.3
作者：
Hendricks, J;Xiao, YL;Borst, J
通讯作者：
Borst, J
影响因子：
4.4
作者：
Li, Yufeng;Liu, Shujuan;Radvanyi, Laszlo
通讯作者：
Radvanyi, Laszlo
DOI：
10.1097/cji.0b013e318209e7ec
发表时间：
2011-04
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Hernandez-Chacon JA;Li Y;Wu RC;Bernatchez C;Wang Y;Weber JS;Hwu P;Radvanyi LG
通讯作者：
Radvanyi LG