Earle A. Chiles Research Institute, Portland, OR 97213, USA.
Sci Transl Med. 2012 Jun 6;4(137):137ra74. doi: 10.1126/scitranslmed.3003649.
Preclinical models suggest that focal high-dose radiation can make tumors more immunogenic. We performed a pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) to assess safety and tumor response rate and perform exploratory immune monitoring studies. Patients with metastatic melanoma or renal cell carcinoma (RCC) who had received no previous medical therapy for metastatic disease were eligible. Patients received one, two, or three doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting IL-2. IL-2 (600,000 IU per kilogram by means of intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Patients with regressing disease received up to six IL-2 cycles. Twelve patients were included in the intent-to-treat analysis, and 11 completed treatment per the study design. Response Evaluation Criteria in Solid Tumors criteria were used to assess overall response in nonirradiated target lesions. Eight of 12 patients (66.6%) achieved a complete (CR) or partial response (PR) (1 CR and 7 PR). Six of the patients with PR on computed tomography had a CR by positron emission tomography imaging. Five of seven (71.4%) patients with melanoma had a PR or CR, and three of five (60%) with RCC had a PR. Immune monitoring showed a statistically significantly greater frequency of proliferating CD4(+) T cells with an early activated effector memory phenotype (CD3(+)CD4(+)Ki67(+)CD25(+)FoxP3(-)CCR7(-)CD45RA(-)CD27(+)CD28(+/-)) in the peripheral blood of responding patients. SBRT and IL-2 can be administered safely. Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data, we believe that the combination and investigation of CD4(+) effector memory T cells as a predictor of response warrant further study.
临床前模型表明，局部高剂量辐射可以使肿瘤更具免疫原性。我们进行了一项立体定向体部放射治疗（SBRT）后高剂量白细胞介素-2（IL-2）的试验研究，以评估安全性和肿瘤反应率，并进行探索性免疫监测研究。符合条件的患者为患有转移性黑色素瘤或肾细胞癌（RCC），且此前未接受转移性疾病的任何药物治疗。患者接受一次、两次或三次 SBRT（每次 20 Gy），最后一次剂量在开始 IL-2 前 3 天进行。IL-2（通过静脉推注给予 600,000 IU/kg）每 8 小时给予一次，最多 14 次剂量，在休息 2 周后进行第二个周期。疾病消退的患者接受多达六个 IL-2 周期。12 名患者纳入意向治疗分析，11 名患者按照研究设计完成治疗。实体瘤反应评估标准用于评估非照射靶病变的总体反应。12 名患者中有 8 名（66.6%）达到完全缓解（CR）或部分缓解（PR）（1 例 CR 和 7 例 PR）。CT 上有 7 例 PR 的患者中有 6 例 PET 成像显示 CR。5 例黑色素瘤患者中有 71.4%（5 例）有 PR 或 CR，5 例 RCC 患者中有 60%（3 例）有 PR。免疫监测显示，与未反应患者相比，反应患者外周血中增殖的 CD4(+)T 细胞具有早期激活的效应记忆表型（CD3(+)CD4(+)Ki67(+)CD25(+)FoxP3(-)CCR7(-)CD45RA(-)CD27(+)CD28(+/-)）的频率更高。SBRT 和 IL-2 可安全使用。由于黑色素瘤患者的反应率明显高于基于历史数据的预期，我们认为 CD4(+)效应记忆 T 细胞作为反应预测因子的组合和研究值得进一步研究。
