Clinic of Radiotherapy and Radiation Oncology, University Hospital Basel, Basel, Switzerland.
CureVac AG, Tübingen, Germany.
J Immunother Cancer. 2019 Feb 8;7(1):38. doi: 10.1186/s40425-019-0520-5.
Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
ClinicalTrials.gov identifier: NCT01915524 .
临床前研究表明，癌症免疫疗法与局部放射治疗具有协同作用，可增强抗肿瘤作用并促进免疫反应。BI1361849（CV9202）是一种活性癌症免疫疗法，由富含鱼精蛋白的、经序列优化的 mRNA 组成，编码六种非小细胞肺癌（NSCLC）相关抗原（NY-ESO-1、MAGE-C1、MAGE-C2、survivin、5T4 和 MUC-1），旨在诱导靶向免疫反应。
我们描述了一项 Ib 期临床试验，该试验评估了 26 例接受标准一线治疗后部分缓解（PR）/疾病稳定（SD）的 IV 期 NSCLC 患者联合 BI1361849 与局部放射治疗。患者分为 3 个亚组（1：非鳞状 NSCLC，无表皮生长因子受体（EGFR）突变，PR/SD 后接受≥4 个周期的铂类和培美曲塞为基础的治疗[16 例]；2：鳞状 NSCLC，PR/SD 后接受≥4 个周期的铂类和非铂类化合物治疗[8 例]；3：非鳞状 NSCLC，EGFR 突变，PR/SD 后接受≥3 且≤6 个月的 EGFR 酪氨酸激酶抑制剂（TKI）治疗[2 例]）。患者接受皮内 BI1361849、局部放射治疗（4×5 Gy），然后接受 BI1361849 直至疾病进展。亚组 1 和 3 还分别接受培美曲塞维持治疗或继续 EGFR-TKI 治疗。主要终点是评估安全性；次要目标包括评估临床疗效（治疗期间每 6 周评估一次）和免疫反应（在第 1 天[基线]、第 19 天和第 61 天）。
研究治疗耐受性良好；注射部位反应和流感样症状是最常见的 BI1361849 相关不良事件。3 例患者发生 3 级 BI1361849 相关不良事件（疲劳、发热）；有 1 例 3 级放射相关事件（吞咽困难）。与基线相比，免疫监测显示大多数患者（84%）的 BI1361849 抗原特异性免疫反应增强，其中 80%的患者抗原特异性抗体水平升高，40%的患者功能性 T 细胞升高，52%的患者涉及多种抗原特异性。1 例患者与培美曲塞维持治疗联合时出现部分缓解，46.2%的患者总体最佳缓解为疾病稳定。最佳总体反应在靶病变中为 SD 占 57.7%。
结果支持进一步研究 NSCLC 中的基于 mRNA 的免疫疗法，包括与免疫检查点抑制剂联合应用。
ClinicalTrials.gov 标识符：NCT01915524。
