Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.
Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-19-0972
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发表时间：
2020-02-01
影响因子：
11.5
通讯作者：
Nghiem, Paul
中科院分区：
文献类型：
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作者：
Bhatia, Shailender;Longino, Natalie V.;Miller, Natalie J.;Kulikauskas, Rima;Iyer, Jayasri G.;Ibrani, Dafina;Blom, Astrid;Byrd, David R.;Parvathaneni, Upendra;Twitty, Christopher G.;Campbell, Jean S.;Le, Mai H.;Gargosky, Sharron;Pierce, Robert H.;Heller, Richard;Daud, Adil I.;Nghiem, Paul
IL12促进获得性I型免疫，并已显示出抗肿瘤效果，但全身用药会导致严重的不良事件(AE)，包括死亡。这项试点试验研究了通过体内电穿孔(I.T.-Tavo-EP)将IL12质粒DNA(Tavo)转移到肿瘤内的安全性、有效性和免疫学活性。15例伴有浅表可注射肿瘤的MCC患者(S)分别于第1、5、8天接受Tavo-EP治疗。局部MCC患者(队列A，N=3)在第4周接受最终手术前一个周期。转移性MCC患者(队列B，N=12)总共接受最多4个周期，间隔至少6周。连续采集肿瘤和血液样本。所有患者成功地完成了至少一个周期，出现一过性、轻度(1级和2级)不良反应，且没有明显的全身毒性。观察到IL12蛋白在肿瘤内持续(第22天)表达，同时伴有局部炎症和肿瘤特异性CD8+T细胞的增加，这导致了全身免疫学和临床反应。队列B的总有效率为25%(3/12)，有2名患者获得了持久的临床益处(分别为16个月和55个月以上)。2例A组患者(1例病理完全缓解)分别在44个月以上和75个月以上无复发。静脉注射Tavo-EP安全可行，无全身毒性。持续的局部IL12蛋白表达和局部炎症导致了全身免疫反应，对一些患者有临床意义。基因电转移，特别是I.T.-Tavo-EP，为肿瘤的免疫治疗提供了进一步的研究基础。
IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.