Dai Fang, Zhang Peng-Bo, Feng Qiang, Pan Xin-Yan, Song Shu-Ling, Cui Jing, Yang Ju-Lun
Graduate School, Kunming Medical University, Kunming, Yunnan, China.
920 th Hospital of the Joint Logistics Support Force of PLA, Kunming, Yunnan, China.
J Cancer. 2021 Mar 10;12(9):2768-2776. doi: 10.7150/jca.51434. eCollection 2021.
Oncolytic adenovirus-mediated gene therapy is an emerging strategy for cancer treatment. However, oncolytic adenoviruses are mainly administered locally at tumor site. Intravenous administration of oncolytic adenovirus for cancer gene therapy is a problem that needs to be solved urgently. We constructed recombinant oncolytic adenovirus KGHV500 carrying anti-p21Ras scFv and employed CIK cells to deliver KGHV500. TUNEL, wound healing, MTT, and Transwell invasion assays were used to determine the anti-tumor efficacy of KGHV500 on liver cancer cells . Nude mouse xenograft model was used to examine the anti-tumor efficacy of CIK cells combined with KGHV500 . Furthermore, KGHV500 accumulation in different organs was detected to assess the safety. KGHV500 inhibited the migration, proliferation, invasion, and induced the apoptosis of liver cancer cells. CIK cells carrying KGHV500 reached tumor site and exerted much better anti-tumor efficacy than CIK cells or KGHV500 alone in nude mouse xenograft model. Moreover, we detected KGHV500 and anti-p21Ras scFv in different organs of nude mice, with little effects on the organs. We develop a novel strategy for the treatment of Ras-driven liver cancer by combining CIK cells with oncolytic adenovirus expressing anti-p21Ras scFv. Intravenous injection of CIK cells carrying KGHV500 significantly inhibits tumor growth, has little effect on normal organs, and is relatively safe.
溶瘤腺病毒介导的基因治疗是一种新兴的癌症治疗策略。然而，溶瘤腺病毒主要在肿瘤部位进行局部给药。通过静脉注射溶瘤腺病毒进行癌症基因治疗是一个亟待解决的问题。我们构建了携带抗p21Ras单链抗体片段（scFv）的重组溶瘤腺病毒KGHV500，并利用细胞因子诱导的杀伤细胞（CIK细胞）来递送KGHV500。采用末端脱氧核苷酸转移酶介导的缺口末端标记法（TUNEL）、伤口愈合实验、MTT法和Transwell侵袭实验来确定KGHV500对肝癌细胞的抗肿瘤疗效。利用裸鼠异种移植模型来检测CIK细胞与KGHV500联合使用时的抗肿瘤疗效。此外，检测KGHV500在不同器官中的蓄积情况以评估其安全性。KGHV500抑制了肝癌细胞的迁移、增殖和侵袭，并诱导其凋亡。在裸鼠异种移植模型中，携带KGHV500的CIK细胞到达肿瘤部位，其抗肿瘤疗效比单独使用CIK细胞或KGHV500要好得多。此外，我们在裸鼠的不同器官中检测到了KGHV500和抗p21Ras scFv，对各器官影响较小。我们通过将CIK细胞与表达抗p21Ras scFv的溶瘤腺病毒相结合，开发出一种治疗Ras驱动型肝癌的新策略。静脉注射携带KGHV500的CIK细胞可显著抑制肿瘤生长，对正常器官影响较小，且相对安全。
