Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients
Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients
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DOI：
10.1097/cmr.0000000000000669
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发表时间：
2020-08-01
影响因子：
2.2
通讯作者：
Yan, Yiyi
中科院分区：
文献类型：
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作者：
Vera Aguilera, Jesus;Paludo, Jonas;Yan, Yiyi
转移性黑色素瘤（MM） PD-1阻滞剂耐药性的管理仍然具有挑战性。在这种情况下，单独免疫治疗或化疗的疗效有限。化学免疫疗法（CIT）在肺癌治疗中已显示出良好的疗效和安全性。我们的临床前研究表明，在PD-1阻断失败的MM患者中，化疗的加入增加了CX3CR1+治疗反应性CD8+ t细胞，增强了抗肿瘤活性，从而改善了临床反应。在这里，我们研究了PD-1阻断失败后MM患者CIT的临床结果以及CX3CR1+治疗反应性CD8+ t细胞的治疗相关变化。我们回顾了2012年1月至2018年6月期间观察到的抗pd -1治疗失败并随后接受CIT、免疫检查点抑制剂（ICI）或单独化疗的MM患者。评估总生存期（OS）、客观缓解率（ORR）、无事件生存期（EFS）和毒性。在60名患者中，33名患者在PD-1阻断治疗后疾病进展后接受了CIT治疗。在3.9年的中位随访中，CIT组的中位OS为3.5年[95%可信区间（CI） 1.7-NR]，而随后接受ICI （n = 9）或单独化疗（n = 18）的患者的中位OS为1.8年（95% CI 0.9-2；P= 0.002）， ORR分别为59%对15% （P= 0.0003）。CIT后的中位EFS为7.6个月（95% CI 6-10），而ICI或单独化疗后的中位EFS为3.4个月（95% CI 2.8-4.1；P= 0.0005）。治疗反应性CX3CR1+CD8+ t细胞随着CIT的成功而动态增加，CIT在PD-1阻断抵抗患者中显示出良好的临床结果和可接受的安全性。CX3CR1+CD8+治疗反应性t细胞可以潜在地用于监测疾病对CIT的反应。
Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer. Our pre-clinical study showed that in MM patients who have failed PD-1 blockade, the addition of chemotherapy increases CX3CR1+ therapy-responsive CD8+ T-cells with enhanced anti-tumor activity, resulting in improved clinical response. Here, we examined the clinical outcomes of CIT in MM patients after PD-1 blockade failure and the treatment-related changes in CX3CR1+ therapy-responsive CD8+ T-cells. We reviewed MM patients seen between January 2012 and June 2018 who failed anti-PD-1-based therapy and received subsequent CIT, immune checkpoint inhibitors (ICI) or chemotherapy alone. Overall survival (OS), objective response rate (ORR), event-free survival (EFS), and toxicities were assessed. Among 60 patients, 33 received CIT upon disease progression on PD-1 blockade. At a median follow-up of 3.9 years, the CIT group had a median OS of 3.5 years [95% confidence interval (CI) 1.7-NR] vs. 1.8 years (95% CI 0.9-2;P= 0.002) for those who received subsequent ICI (n = 9) or chemotherapy alone (n = 18), with ORR of 59% vs. 15% (P= 0.0003), respectively. The median EFS was 7.6 months (95% CI 6-10) following CIT vs. 3.4 months (95% CI 2.8-4.1;P= 0.0005) following ICI or chemotherapy alone. Therapy-responsive CX3CR1+CD8+ T-cells showed dynamic increase with successful CIT. CIT showed favorable clinical outcomes and acceptable safety profile in PD-1 blockade-resistant patients. CX3CR1+CD8+ therapy-responsive T-cells can be potentially used for monitoring disease response to CIT.