Jiang Di Maria, Fyles Anthony, Nguyen Linh T, Neel Benjamin G, Sacher Adrian, Rottapel Robert, Wang Ben X, Ohashi Pamela S, Sridhar Srikala S
Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.
Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.
Oncotarget. 2019 Apr 26;10(31):2947-2958. doi: 10.18632/oncotarget.26893.
Immunotherapy has shown modest activity in metastatic breast cancer (MBC). In this phase I dose escalation study, we assessed safety of tremelimumab, a humanized anti-CTLA4 monoclonal antibody, at starting dose 3 mg/kg, on the third day of palliative radiotherapy (2000cGy in 5 daily fractions) in patients with MBC. Primary objective was to determine the maximum tolerated dose (MTD) of tremelimumab combined with RT. Secondary objective was to assess response. Among 6 patients enrolled between July 2010 and October 2011, 5 had hormone receptor-positive MBC, 1 had triple negative MBC. Median age was 45 years. Common toxicities included lymphopenia (83%), fatigue (50%) and rash (33%). One dose-limiting toxicity occurred at 6 mg/kg, however the trial closed before MTD could be determined. One patient discontinued treatment due to a pathological fracture. Best response was stable disease (SD), 1 patient had SD for >6 months. Median follow up was 27.0 months. Median OS was 50.8 months, with 1 patient surviving >8 years. Peripheral blood mononuclear cell (PBMC) profiles showed increasing proliferating (Ki67+) Treg cells 1 week post treatment in 5 patients. Overall, tremelimumab at 3 mg/kg combined with RT appears to be a tolerable treatment strategy. Further studies are needed to optimize this combination approach.
免疫疗法在转移性乳腺癌（MBC）中已显示出一定活性。在这项I期剂量递增研究中，我们评估了曲美木单抗（一种人源化抗CTLA4单克隆抗体）在MBC患者姑息性放疗（5天内分5次给予2000cGy）第3天起始剂量为3mg/kg时的安全性。主要目的是确定曲美木单抗联合放疗的最大耐受剂量（MTD）。次要目的是评估疗效。在2010年7月至2011年10月入组的6例患者中，5例为激素受体阳性MBC，1例为三阴性MBC。中位年龄为45岁。常见毒性包括淋巴细胞减少（83%）、疲劳（50%）和皮疹（33%）。在6mg/kg时发生了1例剂量限制性毒性，但在确定MTD之前试验就结束了。1例患者因病理性骨折停止治疗。最佳疗效为疾病稳定（SD），1例患者疾病稳定超过6个月。中位随访时间为27.0个月。中位总生存期为50.8个月，1例患者存活超过8年。外周血单个核细胞（PBMC）分析显示，5例患者在治疗后1周增殖性（Ki67+）调节性T细胞增多。总体而言，3mg/kg的曲美木单抗联合放疗似乎是一种可耐受的治疗策略。需要进一步研究以优化这种联合治疗方法。
