Errington Fiona, Bateman Andrew, Kottke Tim, Thompson Jill, Harrington Kevin, Merrick Alison, Hatfield Paul, Selby Peter, Vile Richard, Melcher Alan
Cancer Research UK Clinical Center, St. James's University Hospital, Leeds, UK.
Clin Cancer Res. 2006 Feb 15;12(4):1333-41. doi: 10.1158/1078-0432.CCR-05-1113.
Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination.
Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects.
Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion.
FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.
融合性膜糖蛋白（FMG），如水泡性口炎病毒G糖蛋白（VSV-G），代表了一类新型的癌症基因治疗方法，其在肿瘤细胞中表达时会引发细胞毒性融合。此外，FMG介导的肿瘤细胞死亡会刺激抗肿瘤免疫，这表明表达FMG的细胞疫苗具有潜在应用价值。本研究探讨了表达FMG的同种异体肿瘤细胞作为一种用于离体和原位疫苗接种的新型平台的前景，这种细胞在临床应用中最为实用。
使用表达自体或同种异体MHC I类分子、表达融合性或非融合性VSV-G的小鼠B16黑色素瘤衍生细胞系，在体内对小鼠进行接种，以应对活肿瘤挑战。还测试了通过融合同种异体细胞（多核体）释放的外泌体样囊泡以及瘤内注射融合疫苗作为其抗肿瘤作用的新型治疗策略。
融合性VSV-G的表达增强了同种异体细胞疫苗的免疫原性，其比融合性自体疫苗更有效。同种异体多核体仅在与佐剂一起给药时才与细胞疫苗一样有效，这表明多核体不能完全解释免疫启动机制。使用融合性或非融合性VSV-G进行瘤内注射表达FMG的同种异体细胞均导致显著的肿瘤消退。然而，只有当初始疫苗具备细胞融合能力时，才会发生针对肿瘤相关抗原表位的特异性启动以及对二次再攻击的保护作用。
表达FMG的同种异体肿瘤细胞是抗肿瘤疫苗的有力来源。与佐剂一起给予的多核体以及瘤内注射融合细胞代表了非常适合临床转化的新型策略。
