Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
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DOI：
10.1158/1078-0432.ccr-09-0265
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发表时间：
2009-09-01
期刊：
影响因子：
--
通讯作者：
Demaria S
中科院分区：
文献类型：
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作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
本研究验证了这样一个假设：剂量分割方案的类型决定了放疗与抗CTLA - 4抗体协同作用的能力。
将TSA小鼠乳腺癌细胞在两个不同部位皮下注射到同基因小鼠体内，这两个部位分别定义为接受放疗的“原发”部位和放疗野外的“继发”部位。当两个肿瘤都可触及时，将小鼠随机分为8组，分别接受不进行放疗或3种不同的放疗方案（连续天数内分别为20Gy×1、8Gy×3或6Gy×5分割），同时联合或不联合抗CTLA - 4的9H10单克隆抗体。对小鼠进行肿瘤生长/消退情况的监测。在MCA38小鼠结肠癌模型中进行了类似的实验。
在测试的两种模型中，单独使用9H10治疗均未检测到效果。每种放疗方案都对原发肿瘤造成了相当的生长延迟，但对放疗野外的继发肿瘤没有影响。相反，9H10与任何一种分割放疗方案的组合都使原发部位的肿瘤反应增强（p < 0.0001）。此外，一种远隔效应，即放疗野外肿瘤的显著生长抑制，仅在接受9H10和分割放疗组合治疗的小鼠中出现（p < 0.01）。产生肿瘤特异性干扰素γ的CD8 + T细胞的频率与继发肿瘤的抑制程度成正比。
在两种临床前癌症模型中，分割放疗（而非单次剂量放疗）与抗CTLA - 4抗体联合使用时会诱导远隔效应。
This study tested the hypothesis that the type of dose-fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody. TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated, and a “secondary” site outside the radiotherapy field. When both tumors were palpable mice were randomly assigned to 8 groups receiving no radiotherapy or 3 distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3 or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 mAb against CTLA-4. Mice were followed for tumors growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. In either of the 2 models tested treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors, but had no effect on the secondary tumors, outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (p<0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (p<0.01). Frequency of CD8+ T cells showing tumor-specific IFNγ production was proportional to the inhibition of the secondary tumor. Fractionated, but not single dose radiotherapy, induces an abscopal effect when in combination with anti-CTLA-4 antibody, in two preclinical carcinoma models.