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用于晚期转移性实体瘤的个体化异源黑猩猩腺病毒和自我扩增mRNA新抗原疫苗
作者:小柯机器人 发布时间:2022/8/17 16:23:32

美国Gritstone bio生物技术公司Karin Jooss研究团队近期取得重要工作进展,他们报告了用于晚期转移性实体瘤的个体化异源黑猩猩腺病毒和自我扩增mRNA新抗原疫苗的1期试验中期结果。相关工作成果2022年8月15日在线发表于《自然—医学》杂志上。

检查点抑制剂(CPI)疗法对免疫反应性低的肿瘤患者的益处有限。T 细胞诱导疫苗有望与CPI治疗相结合,实现长期的疾病控制。在一项正在进行的1/2期临床研究(NCT03639714)中,个体化、异源黑猩猩腺病毒(ChAd68)和自扩增mRNA(samRNA)为基础的新抗原疫苗,联合nivolumab和ipilimumab治疗晚期转移性实体肿瘤(NCT03639714)的安全性、耐受性和推荐的2期剂量(RP2D)是主要的研究终点。个体化疫苗方案安全且耐受性良好,没有剂量限制性毒性。>10%的治疗相关不良事件(TRAE)包括发热、疲劳、肌肉骨骼和注射部位疼痛以及腹泻。严重的TRAE包括发热、十二指肠炎、转氨酶升高和甲状腺功能亢进各一项。RP2D是 1012个病毒颗粒(VP)ChAd68和30 µg samRNA。次要终点包括免疫原性、制造可行性和总生存期(OS)。

疫苗生产是可行的,疫苗接种可诱导持久的新抗原特异性CD8 T细胞反应。几名微卫星稳定型结直肠癌(MSS-CRC)患者的OS有所改善。探索性生物标志物分析显示,OS延长患者的循环肿瘤DNA(ctDNA)减少。尽管小型研究限制了统计和转化分析,但在MSS-CRC中观察到的OS增加值得在更大的随机研究中进一步探索。

附:英文原文

Title: Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results

Author: Palmer, Christine D., Rappaport, Amy R., Davis, Matthew J., Hart, Meghan G., Scallan, Ciaran D., Hong, Sue-Jean, Gitlin, Leonid, Kraemer, Lauren D., Kounlavouth, Sonia, Yang, Aaron, Smith, Lindsey, Schenk, Desiree, Skoberne, Mojca, Taquechel, Kiara, Marrali, Martina, Jaroslavsky, Jason R., Nganje, Charmaine N., Maloney, Elizabeth, Zhou, Rita, Navarro-Gomez, Daniel, Greene, Adrienne C., Grotenbreg, Gijsbert, Greer, Renee, Blair, Wade, Cao, Minh Duc, Chan, Shawn, Bae, Kyounghwa, Spira, Alexander I., Roychowdhury, Sameek, Carbone, David P., Henick, Brian S., Drake, Charles G., Solomon, Benjamin J., Ahn, Daniel H., Mahipal, Amit, Maron, Steve B., Johnson, Benny, Rousseau, Raphael, Yelensky, Roman, Liao, Chih-Yi, Catenacci, Daniel V. T., Allen, Andrew, Ferguson, Andrew R., Jooss, Karin

Issue&Volume: 2022-08-15

Abstract: Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 1012 viral particles (VP) ChAd68 and 30μg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.

DOI: 10.1038/s41591-022-01937-6

Source: https://www.nature.com/articles/s41591-022-01937-6

 

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex