Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy.
Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy.
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DOI：
10.1371/journal.pone.0157164
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Crittenden MR
中科院分区：
文献类型：
--
作者：
Young KH;Baird JR;Savage T;Cottam B;Friedman D;Bambina S;Messenheimer DJ;Fox B;Newell P;Bahjat KS;Gough MJ;Crittenden MR
免疫疗法和放射疗法在晚期恶性肿瘤中所取得的有希望的结果的轶事报道促使了多项将免疫疗法和放射疗法相结合的试验。然而，放射免疫治疗的理想时机尚未明确。用仅递送至肿瘤的20Gy放射结合抗CTLA4抗体或抗OX40激动剂抗体来治疗荷瘤小鼠。免疫治疗是在放射周围的单个时间点进行的。令人惊讶的是，这些疗法的最佳时机各不相同。放射治疗前给予抗 CTLA4 药物最为有效，部分原因在于调节性 T 细胞耗竭。抗OX40激动剂抗体的施用在辐射后一天、在辐射后抗原呈递增加的窗口期间递送是最佳的。在移植的自发性乳腺肿瘤模型中，使用理想的时机进行抗 CTLA4、放射和抗 OX40 的联合治疗证明了肿瘤的治愈。这些数据表明，免疫疗法和放射疗法的组合可提高治疗效果，并且放射疗法的理想给药时机取决于所用免疫疗法的作用机制。
The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized.