Division of Infection and Immunity, Cardiff University, Cardiff, Wales.
Velindre Cancer Centre, National Health Service (NHS) Trust, Cardiff, Wales.
JAMA Oncol. 2017 Oct 12;3(10):e172579. doi: 10.1001/jamaoncol.2017.2579.
The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses.
To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments.
DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat.
Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106.
The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS).
Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed.
This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data.
isrctn.org Identifier: ISRCTN54669986.
重要性：免疫检查点抑制剂在大多数结直肠癌病例中的疗效并不显著，因此急需采用不同的策略。肿瘤胚胎抗原 5T4 在超过 90%的转移性结直肠癌（mCRC）病例中表达。在 mCRC 中使用改良安卡拉痘苗病毒-5T4（MVA-5T4）的初步数据表明，它可以安全地诱导血清学和 T 细胞反应。
目的：确定 mCRC 中是否可以通过使用 MVA-5T4、低剂量环磷酰胺或两者联合治疗来增加抗肿瘤免疫。
设计、地点和参与者：在这项随机临床试验中，在一个单一中心招募了 55 名患有不可切除的 mCRC 且标准化疗后病情稳定的患者，他们被随机分为观察组（n=9）、环磷酰胺治疗组（n=9）、MVA-5T4 治疗组（n=19）和 MVA-5T4 和环磷酰胺联合治疗组（n=18）。患者于 2012 年 7 月 9 日至 2016 年 2 月 8 日入组并接受治疗，随访于 2016 年 12 月 13 日结束。根据意向治疗进行数据分析。
干预措施：环磷酰胺组患者在治疗第 1 天至第 7 天和第 15 天至第 21 天接受每日两次 50mg 的治疗。MVA-5T4 组患者在治疗第 22、36、50、64、78 和 106 天接受 1×10950%组织培养感染剂量的肌肉注射。
主要结果和措施：主要预设终点是在治疗第 7 周时产生的抗 5T4 免疫反应（5T4 特异性 T 细胞和抗体水平）的大小。次要终点包括分析抗 5T4 反应的动力学、无进展生存期（PFS）和总生存期（OS）。
结果：52 名患者（38 名男性和 14 名女性；平均[SD]年龄，64.2[10.1]岁）纳入研究分析。与无治疗组（20.09[7.20]RU）相比，MVA-5T4 组（83.41[36.09]相对单位[RU]；P=0.02）和联合治疗组（65.81[16.68]RU）的 5T4 特异性抗体免疫反应显著增加。环磷酰胺在 27 名接受 MVA-5T4 治疗的患者中消耗了 24 名调节性 T 细胞，独立延长了 PFS（5.0 个月与 2.5 个月；风险比[HR]，0.48；95%CI，0.21-1.11；P=0.09）。MVA-5T4 使 35 名患者中的 16 名患者的基线抗 5T4 反应增加一倍，导致 PFS（5.6 个月与 2.4 个月；HR，0.21；95%CI，0.09-0.47；P<0.001）和 OS（20.0 个月与 10.3 个月；HR，0.32；95%CI，0.14-0.74；P=0.008）显著延长。未观察到 3 级或 4 级不良事件。
结论和相关性：这项初步的随机临床免疫治疗研究表明，mCRC 患者的生存获益显著。环磷酰胺预先耗竭调节性 T 细胞并未增加 MVA-5T4 疫苗接种产生的免疫反应；然而，环磷酰胺和 MVA-5T4 各自独立地诱导了有益的抗肿瘤免疫反应，延长了无毒性作用的生存时间。计划进行更大规模的临床试验以进一步验证这些数据。
试验注册：isrctn.org 标识符：ISRCTN54669986。
