个性化肿瘤负载单核细胞衍生树突状细胞疫苗联合阿替利珠单抗作为广泛期小细胞肺癌(ES-SCLC)维持治疗:VENEZOLUNG Ib-II 期试验
Personalized tumor-loaded monocyte-derived dendritic cell vaccination in combination with atezolizumab as maintenance treatment in extensive-stage small cell lung cancer (ES-SCLC): phase Ib-II VENEZOLUNG trial.
作者
作者单位
- Instituto Oncologico Dr Rosell, Dexeus University Hospital, Barcelona, Spain mgonzalezcao@oncorosell.com.
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
- Medical Oncology Department, Catalan Institute of Oncology, Badalona, Spain.
- Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain.
- Immunology Department, Hospital Clinic de Barcelona, FRCB-IDIBAPS, UB, Barcelona, Spain.
- Instituto Oncologico Dr Rosell, Dexeus University Hospital, Barcelona, Spain.
- Instituto Oncologico Dr Rosell and PangaeaOncology Lab, Dexeus University Hospital, Barcelona, Spain.
- Apheresis Unit, IDIBAPS, Hospital Clinic de Barcelona, Barcelona, Spain.
- Instituto Oncologico Dr Rosell, Hospital Universitari Sagrat Cor, Barcelona, Spain.
摘要
中文
尽管将抗程序性死亡配体 1(PD-L1)抗体 atezolizumab 纳入一线化疗方案,广泛期小细胞肺癌(ES-SCLC)患者的生存期仍不理想。鉴于树突状细胞(DCs)在调节抗程序性细胞死亡蛋白 1(PD-1)抗体应答中的作用,一个有前景的方向是基于 DCs 开发疫苗,并评估 DC 表型修饰如何影响治疗疗效。本研究是一项单臂、Ib/II 期、开放标签临床试验,旨在评估皮下注射自体肿瘤裂解物负载的成熟 DCs 联合静脉 atezolizumab 作为 ES-SCLC 患者维持治疗的安全性和活性。单采后,单核细胞在体外分化为成熟 DCs,并负载经照射处理的自体肿瘤裂解物。在标准诱导治疗(四个周期卡铂、依托泊苷联合 atezolizumab)后,患者接受最多六剂皮下注射成熟 DCs,同时每 3 周静脉给予 atezolizumab 1200 mg,直至疾病进展。共入组 20 例患者,其中 6 例伴脑转移。18 例患者接受 DC 疫苗接种,中位接种 3 剂(范围 1-6 剂)。大多数 3-4 级治疗相关不良事件为血液学事件,且与化疗相关。DC 疫苗接种耐受性良好,仅注射部位出现 1-2 级短暂皮肤刺激。在 18 例可评估患者中,17 例(94.4%)获得客观缓解。中位随访 31.4 个月后,2 年无进展生存率(PFS2y)为 20%(95% CI 6.4%-39.1%),中位总生存期(OS)为 11.2 个月(95% CI 6.3-26.0),3 年总生存率(OS3y)为 22.5%(95% CI 6.8%-43.6%)。6 例患者获得长期生存(中位 30.5 个月,范围 23.4-36.2)。化疗联合 atezolizumab 后常规 1 型 DC(cDC1s)XCR1+ 和干细胞样祖细胞-耗竭型(CXCR5+PD-1+)CD8+ T 细胞的扩增与 PFS 改善相关(HR 0.94, 95% CI 0.90-0.99;HR 0.59, 95% CI 0.39-0.89)。标准化疗联合 atezolizumab 治疗后,DC 免疫联合 atezolizumab 维持治疗耐受性良好。由于该方案作为维持治疗给药,其临床活性在本研究中无法确定;然而,长期生存者的比例提示其潜在获益。我们的研究结果提示 cDC1s 在介导长期生存者抗肿瘤活性中发挥关键作用。NCT04487756。
English
Despite the incorporation of atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, into first-line chemotherapy regimen, survival in patients with extensive-stage small cell lung cancer (ES-SCLC) remains poor. Given the role of dendritic cells (DCs) in modulating responses to anti-programmed cell death protein 1 (PD-1) antibodies, a promising avenue is the development of vaccines based on DCs, together with the evaluation of how DC phenotypic modifications shape treatment efficacy. This is a single-arm, phase Ib/II, open-label clinical trial investigating the safety and activity of combining autologous tumor lysate pulsed DCs administered intradermally with intravenous atezolizumab as maintenance therapy for patients with ES-SCLC. Following leukapheresis, monocytes were differentiated ex vivo into mature DCs and loaded with irradiated autologous tumor lysate. After standard induction therapy (four cycles of carboplatin, etoposide, and atezolizumab), patients received up to six doses of mature DCs intradermally, along with intravenous atezolizumab 1,200 mg every 3 weeks, until disease progression. 20 patients were enrolled, including six patients with brain metastases. 18 patients received DC vaccination, with a median of three doses (range 1-6). Most grade 3-4 treatment-related adverse events were hematological and related to chemotherapy. DC vaccination was well tolerated, with only grade 1-2 transient skin irritation at the injection site. Among 18 evaluable patients, 17 (94.4%) achieved an objective response. After a median follow-up of 31.4 months, progression-free survival at 2 years (PFS2y) was 20% (95% CI 6.4% to 39.1%), median overall survival (OS) 11.2 months (95% CI 6.3 to 26.0) and OS3y 22.5% (95% CI 6.8% to 43.6%). Six patients achieved long survival (median 30.5 months, range 23.4-36.2). Expansion of conventional type DC1 (cDC1s) XCR1+ and stem-like progenitor-exhausted (CXCR5+PD-1+) CD8+ T cells following chemotherapy plus atezolizumab was associated with improved PFS (HR 0.94, 95% CI 0.90 to 0.99 and HR 0.59, 95% CI 0.39 to 0.89). DC immunization combined with atezolizumab maintenance following standard chemotherapy plus atezolizumab treatment is well tolerated. Its clinical activity cannot be definitively determined in this study, as it was administered as maintenance therapy; however, the observed rate of long-term survivors suggests a potential benefit. Our findings suggest a pivotal role for cDC1s in mediating the antitumor activity in long-term survivors. NCT04487756.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 11.7
- 新锐分区
- 1区