Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies
Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies
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DOI：
10.1002/eji.200838208
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Glennie, Martin J.
中科院分区：
文献类型：
--
作者：
Gray, Juliet C.;French, Ruth R.;Glennie, Martin J.
免疫刺激单抗作为治疗癌症的疫苗佐剂，当用于免疫原性肿瘤时，或与各种其他疫苗联合使用时，具有增强弱反应的巨大潜力。我们现在表明，当与OVA一起使用时，抗4- 1bb单抗与抗cd40、抗ox40或抗cd25联合使用，与单独使用抗4- 1bb单抗相比，抗原特异性t细胞反应增强了四倍，在再次使用OVA后，记忆反应也有类似的增强。尽管使用每种组合治疗后产生的抗原特异性t细胞数量相似，但检测到显着的功能差异。特别是，抗4- 1bb /抗cd25导致特异性CD8+ T细胞的极好扩增，但产生的ifn - γ分泌效应细胞比其他组合少。抗4- 1bb /抗ox40被证明是最有效的，在RIPmOVA糖尿病模型中通过过过转移ova特异性T细胞诱导最有效的T细胞反应，并且当与肽疫苗一起给予时，保护小鼠免受免疫原性差的B16-F10肿瘤的侵害。总的来说，结果表明，尽管这些单抗组合在治疗潜力方面看起来很有希望，但需要进一步的功能分析来比较它们的效果。
Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. in particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD8+ T cells but produced fewer IFN-gamma-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.