Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNFα
Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNFα
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DOI：
10.1002/ijc.25018
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发表时间：
2010-07-01
影响因子：
6.4
通讯作者：
Borsi, Laura
中科院分区：
文献类型：
--
作者：
Balza, Enrica;Carnemolla, Barbara;Borsi, Laura
L19-IL 2和L19 TNF α是由L19（scFv）和IL-2或TNF α组成的融合蛋白，所述L19（scFv）对含有纤连蛋白同种型的血管生成相关ED-B具有特异性。由于L19的肿瘤靶向性质，IL-2和TNF α在肿瘤血管水平以治疗剂量浓缩。为了评价L19-IL 2和L19 mTNF α在携带神经母细胞瘤（NB）的小鼠中的治疗效果，用L19-IL 2和L19 mTNF α单独或以组合方案全身性治疗携带Neuro 2A或NIE 115 NB的A/J小鼠。70%的Neuro 2A荷瘤小鼠和30%的NIE 115荷瘤小鼠通过L19-IL 2和L19 mTNF α的联合治疗治愈，并进一步拒绝同源肿瘤攻击，表明特异性抗肿瘤免疫记忆。探讨了肿瘤治疗和排斥反应的免疫学基础。在肿瘤细胞植入后第16天，CD 4（+）和CD 8（+）T细胞在肿瘤组织中大量浸润，产生了CD 4（+）T辅助细胞和CD 8（+）CTL效应物的高效引发，此时，治疗后，肿瘤体积急剧减小，肿瘤坏死达到约80%。治愈性治疗导致持久的抗肿瘤免疫记忆，伴随着混合的Th 1/Th 2型反应。结论，L19-IL 2和L19 mTNF α有效地合作确定高百分比的NB治愈，在我们的实验模型中，与涉及CD 4（+）和CD 8（+）T细胞的适应性免疫的产生密切相关。
L19-IL2 and L19TNF alpha are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNF alpha. Because of the tumor targeting properties of L19, IL-2 and TNF alpha concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNF alpha in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNF alpha, alone or in combination protocols. Seventy percent of Neuro2A- and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNF alpha, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4(+) T helper cells and CD8(+) CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4(+) and CD8(+) T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNF alpha efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4(+) and CD8(+) T cells.