Purpose: Intratumoral (IT) TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of interleukin-12 (IL-12) within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous (IV) nivolumab followed by surgery and adjuvant nivolumab in patients with operable locoregionally advanced melanoma. Patients and Methods: The neoadjuvant phase comprised up to 3 Χ 4-week cycles where TAVO-EP was given IT on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab IV on day 8 of each 4-week cycle. Surgery followed, and adjuvant nivolumab was initiated after surgery. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathological response (MPR; pCR or near pCR). Results: Sixteen patients were enrolled and the preoperative radiological response rate was 63%. One patient declined surgery after experiencing a significant clinical response. Among the remaining 15 patients, pCR rate was 60% and MPR was 80%. No patient with MPR has had disease recurrence with a median follow-up from the date of surgery of 15.4 months. At baseline, most patients exhibited low CD8+ TIL, PD-L1 and IFN-γ gene expression signature. There was enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL and proliferating immune cell subsets. Conclusions: The clinical efficacy of neoadjuvant IT TAVO-EP + nivolumab is promising with 80% of patients achieving an MPR. Evidence of potent immune activation both systemically and within the TME along with a favorable safety profile supports the activity of local IL-12 and anti-PD1 based regimens.

中文翻译：

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新辅助瘤内质粒白细胞介素 12 电基因转移和纳武利尤单抗治疗可手术局部晚期黑色素瘤患者


目的：瘤内 （IT） TAVO-EP （通过电穿孔递送的 tavokinogene telseplasmid） 导致白细胞介素 12 （IL-12） 在肿瘤微环境 （TME） 内局部表达。本研究评估了新辅助 TAVO-EP 联合静脉内 （IV） 纳武利尤单抗，然后手术和辅助纳武利尤单抗治疗可手术局部晚期黑色素瘤患者。患者和方法：新辅助阶段包括多达 3 个 Χ 4 周周期，其中 TAVO-EP 在第 1 、 8 和 15 天（可选）同时给药，在每个 4 周周期的第 8 天同时给予 480 mg 纳武利尤单抗静脉注射。随后进行手术，术后开始辅助纳武利尤单抗治疗。主要终点是病理完全缓解 （pCR）。次要终点包括主要病理反应 （MPR;pCR 或接近 pCR）。结果： 入组 16 例患者，术前放射学缓解率为 63%。1 例患者在出现显著的临床反应后拒绝手术。其余 15 例患者中，pCR 率为 60%，MPR 为 80%。没有 MPR 患者出现疾病复发，从手术之日起的中位随访时间为 15.4 个月。基线时，大多数患者表现出低 CD8 + TIL 、 PD-L1 和 IFN-γ 基因表达特征。TME 和血液治疗后免疫激活增强，包括免疫相关基因表达、CD8+ TIL 和免疫细胞亚群增殖增加。结论：新辅助 IT TAVO-EP + nivolumab 的临床疗效很有希望，80% 的患者达到 MPR。系统性和 TME 内有效免疫激活的证据以及良好的安全性支持基于局部 IL-12 和抗 PD1 方案的活性。