Neoadjuvant intratumoral plasmid interleukin-12 electro-gene-transfer and nivolumab in patients with operable locoregionally advanced melanoma.

IF 10 1区 医学 Q1 ONCOLOGY
Ahmad A Tarhini,Zeynep Eroglu,Islam Eljilany,Jonathan S Zager,Ricardo J Gonzalez,Amod A Sarnaik,C Wayne Cruse,Nikhil I Khushalani,Deanryan B De Aquino,Edith Abraham,Diana M Acevedo,Allison Richards,Michael J Schell,Denise Kalos,Pei-Ling Chen,Jane L Messina,David A Canton,Vernon K Sondak
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引用次数: 0

Abstract

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.
对可手术的局部晚期黑色素瘤患者进行新辅助瘤内质粒白细胞介素-12电基因转移和尼夫单抗治疗。
目的瘤体内(IT)TAVO-EP(通过电穿孔递送的tavokinogene telseplasmid)可导致白细胞介素-12(IL-12)在肿瘤微环境(TME)中的局部表达。本研究评估了可手术局部晚期黑色素瘤患者的新辅助TAVO-EP联合静脉注射(IV)尼维单抗,然后进行手术和辅助尼维单抗的情况。患者和方法新辅助阶段包括最多3个Χ4周的周期,在每个4周周期的第1、8和15天(可选)给予TAVO-EP,同时在第8天静脉注射480毫克尼维单抗。随后进行手术,术后开始辅助使用 nivolumab。主要终点是病理完全反应(pCR)。次要终点包括主要病理反应(MPR;pCR 或接近 pCR)。结果16 名患者入组,术前放射学反应率为 63%。一名患者在经历了显著的临床反应后拒绝了手术。其余 15 名患者中,pCR 率为 60%,MPR 率为 80%。自手术之日起,中位随访时间为 15.4 个月,没有 MPR 患者复发。基线时,大多数患者的 CD8+ TIL、PD-L1 和 IFN-γ 基因表达特征较低。结论新辅助 IT TAVO-EP + nivolumab 的临床疗效很好,80% 的患者达到了 MPR。全身和TME内的强效免疫激活证据以及良好的安全性支持了基于IL-12和抗PD1的局部治疗方案的活性。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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