Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice.
Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice.
复制标题
DOI：
10.1097/cji.0b013e3181ee7095
复制
发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Weinberg AD
中科院分区：
文献类型：
--
作者：
Gough MJ;Crittenden MR;Sarff M;Pang P;Seung SK;Vetto JT;Hu HM;Redmond WL;Holland J;Weinberg AD
肿瘤局部残留或微转移的复发仍然是肿瘤治疗中的一个问题。在软组织肉瘤患者和不能手术的非小细胞肺癌患者中，局部复发是常见的，随后出现的转移性疾病导致了显著的死亡率。因此，虽然主要治疗的目的是治愈性的，但可以通过额外靶向残留的显微镜病变来改善结局。我们在小鼠模型中证明，手术切除大的原发性肉瘤会导致大约50%的动物局部复发。CD8 T细胞的消耗导致100%的动物局部复发，表明这些细胞参与控制残留疾病。我们进一步证明，手术时全身辅助给予αOX40可消除局部复发。在该模型中，αOX40可直接增强手术部位引流淋巴结中的肿瘤抗原特异性CD8 T细胞增殖，并导致体内肿瘤抗原特异性细胞毒性增加。这些结果也证实了在小鼠模型的大分割放射治疗肺癌。与单独使用任何一种药物相比，αOX40联合放射治疗显着延长了生存期，并产生了很大比例的长期无肿瘤生存者。我们得出结论，αOX40增加肿瘤抗原特异性CD8 T细胞的细胞毒活性，从而改善对残留显微镜下病变的内源性免疫控制，我们提出，辅助αOX40给药可能是对癌症手术和放射治疗的有价值的补充。
Tumor recurrence from residual local or micro-metastatic disease remains a problem in cancer therapy. In patients with soft-tissue sarcoma and patients with inoperable non-small cell lung cancer, local recurrence is common and significant mortality is caused by the subsequent emergence of metastatic disease. Thus, while the aim of the primary therapy is curative, the outcome may be improved by additional targeting of residual microscopic disease. We demonstrate in a murine model that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals. Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in control of residual disease. We further demonstrate that systemic adjuvant administration of αOX40 at surgery eliminates local recurrences. In this model, αOX40 acts to directly enhance tumor antigen-specific CD8 T cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo. These results are also corroborated in a murine model of hypofractionated radiation therapy of lung cancer. Administration of αOX40 in combination with radiation significantly extended survival compared to either agent alone, and resulted in a significant proportion of long-term tumor free survivors. We conclude that αOX40 increases tumor antigen-specific CD8 T cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant αOX40 administration may be a valuable addition to surgical and radiation therapy for cancer.