Department of Radiation Oncology, Weill Cornell Medical College, New York, NY.
Department of Radiation Oncology, University of California, Los Angeles, California.
Clin Cancer Res. 2018 Jun 1;24(11):2493-2504. doi: 10.1158/1078-0432.CCR-17-3322. Epub 2018 Feb 23.
This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum. Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. .
这项研究旨在探讨在转移性乳腺癌患者放疗期间阻断 TGFβ 的可行性、疗效（远隔效应）和免疫效应。前瞻性随机试验比较了两种剂量的 TGFβ 阻断抗体 fresolimumab。入组标准为至少有三个不同转移部位且在至少一线治疗后进展的转移性乳腺癌患者，随机接受 1 或 10 mg/kg 的 fresolimumab，每 3 周一次，共 5 个周期，在第 1 周（3 次 7.5 Gy）给予转移部位的局部放疗，第 7 周时可对第二个病变重复放疗。研究血液标本在基线、第 2、5 和 15 周采集，用于分离 PBMCs、血浆和血清。23 例患者随机分组，中位年龄 57 岁（范围 35-77 岁）。1 mg/kg 组的 11 例患者中有 5 例发生 7 级/4 级不良事件，10 mg/kg 组的 12 例患者中有 2 例发生不良事件。缓解仅限于 3 例疾病稳定。中位随访 12 个月时，23 例患者中有 20 例死亡。接受 10 mg/kg fresolimumab 治疗的患者中位总生存期显著长于接受 1 mg/kg fresolimumab 治疗的患者[风险比：2.73，95%置信区间（CI）：1.02-7.30；P = 0.039]。较高剂量与外周血单核细胞计数升高和 CD8 中央记忆池显著增加相关。放疗期间阻断 TGFβ 是可行的且耐受良好。接受较高 fresolimumab 剂量的患者具有有利的全身免疫反应，总生存期长于接受较低剂量组。
