New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity.
New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity.
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DOI：
10.18632/oncotarget.17875
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Alpdogan O
中科院分区：
文献类型：
--
作者：
Bailey CP;Budak-Alpdogan T;Sauter CT;Panis MM;Buyukgoz C;Jeng EK;Wong HC;Flomenberg N;Alpdogan O
白细胞介素-15（IL-15）是一种有效的细胞因子，可在实验模型中增加CD 8 + T和NK细胞的数量和功能。然而，在治疗上使用IL-15仍然存在障碍，特别是其低效力和短的体内半衰期。为了帮助克服这一点，开发了一种由IL-15 N72 D突变和IL-15 R αSu/Fc融合物（IL-15 SA，也称为ALT-803）组成的新型IL-15超激动剂复合物。IL-15 SA表现出显著更长的血清半衰期和针对各种肿瘤的增加的体内活性。在此，我们评估了IL-15 SA在异基因造血干细胞移植受者中的作用。每周给予移植受体IL-15 SA显著增加了CD 8 + T细胞（特别是CD 44+记忆/活化表型）和NK细胞的数量。IL-15 SA处理组中CD 8 + T细胞的细胞内IFN-γ和TNF-α分泌增加。IL-15 SA还上调CD 8 + T细胞上的NKG 2D表达。此外，IL-15 SA通过特异性刺激缓慢增殖和非增殖细胞转化为活跃增殖细胞，增强了同基因和同种异体模型中过继转移的CFSE标记的T细胞的增殖和细胞因子分泌。然后，我们评估了IL-15 SA对鼠肥大细胞瘤（P815）和鼠B细胞淋巴瘤（A20）的抗肿瘤活性的影响。IL-15 SA增强T细胞输注后这些肿瘤中的移植物抗肿瘤（GVT）活性。有趣的是，IL-15 SA给药在鼠供体白细胞输注（DLI）模型中提供了针对A20淋巴瘤细胞的GVT活性，而不增加移植物抗宿主病。总之，IL-15 SA可能是一种高效的T细胞淋巴样生长因子和新的免疫调节剂，以补充干细胞移植和过继免疫治疗。
Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8+ T cells (specifically CD44+ memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8+ T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8+ T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells. We then evaluated IL-15SA's effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy.
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影响因子：
5.3
作者：
Duitman, Erwin H.;Orinska, Zane;Bulfone-Paus, Silvia
通讯作者：
Bulfone-Paus, Silvia
影响因子：
11.4
作者：
GIRI, JG;KUMAKI, S;ANDERSON, DM
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ANDERSON, DM
影响因子：
56.9
作者：
GRABSTEIN, KH;EISENMAN, J;GIRI, JG
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GIRI, JG
影响因子：
5.7
作者：
Bessard, Anne;Sole, Veronique;Jacques, Yannick
通讯作者：
Jacques, Yannick
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T