Tarhini Ahmad A, Eroglu Zeynep, Eljilany Islam, Zager Jonathan S, Gonzalez Ricardo J, Sarnaik Amod A, Cruse Carl Wayne, Khushalani Nikhil I, De Aquino Deanryan B, Abraham Edith, Acevedo Diana M, Richards Allison, Schell Michael J, Kalos Denise, Chen Pei-Ling, Messina Jane L, Canton David A, Sondak Vernon K
Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Clin Cancer Res. 2024 Dec 2;30(23):5333-5341. doi: 10.1158/1078-0432.CCR-24-2768.
Intratumoral tavokinogene telseplasmid delivered by electroporation (TAVO-EP) results in localized expression of IL-12 within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous nivolumab followed by surgery and adjuvant nivolumab in patients with operable, locoregionally advanced melanoma.
The neoadjuvant phase comprised up to 3 × 4-week cycles during which TAVO-EP was given intratumorally on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab intravenously 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 pathologic response (MPR; pCR or near pCR).
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, the pCR rate was 60% and the 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+ tumor-infiltrating lymphocytes, 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+ tumor-infiltrating lymphocytes, and proliferating immune cell subsets.
The clinical efficacy of neoadjuvant intratumoral 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-PD-1 based regimens.
通过电穿孔递送的肿瘤内注射替沃基因替西质粒（TAVO-EP）可导致白细胞介素-12（IL-12）在肿瘤微环境（TME）中局部表达。本研究评估了新辅助TAVO-EP联合静脉注射纳武利尤单抗，随后进行手术及辅助纳武利尤单抗治疗可手术的局部晚期黑色素瘤患者的疗效。
新辅助阶段包括最多3个4周周期，在此期间，在第1、8和15天（可选）进行肿瘤内注射TAVO-EP，同时在每个4周周期的第8天静脉注射480mg纳武利尤单抗。随后进行手术，并在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缓解（MPR；pCR或接近pCR）。
共纳入16例患者，术前放射学缓解率为63%。1例患者在出现显著临床缓解后拒绝手术。在其余15例患者中，pCR率为60%，MPR为80%。在中位随访时间为自手术日期起15.4个月时，无MPR患者出现疾病复发。基线时，大多数患者表现出低水平的CD8+肿瘤浸润淋巴细胞、程序性死亡受体1（PD-L1）和干扰素-γ（IFN-γ）基因表达特征。治疗后，TME和血液中的免疫激活增强，包括免疫相关基因表达增加、CD8+肿瘤浸润淋巴细胞增多以及增殖性免疫细胞亚群增多。
新辅助肿瘤内注射TAVO-EP联合纳武利尤单抗的临床疗效前景良好，80%的患者实现了MPR。全身和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和抗程序性死亡蛋白1（PD-1）方案的活性。
