Makielski Kelly M, Sarver Aaron L, Henson Michael S, Stuebner Kathleen M, Borgatti Antonella, Suksanpaisan Lukkana, Preusser Caitlin, Tabaran Alexandru-Flaviu, Cornax Ingrid, O'Sullivan M Gerard, Chehadeh Andrea, Groschen Donna, Bergsrud Kelly, Pracht Sara, Winter Amber, Mills Lauren J, Schwabenlander Marc D, Wolfe Melissa, Farrar Michael A, Cutter Gary R, Koopmeiners Joseph S, Russell Stephen J, Modiano Jaime F, Naik Shruthi
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.
Mol Ther Oncolytics. 2023 Oct 14;31:100736. doi: 10.1016/j.omto.2023.100736. eCollection 2023 Dec 19.
Osteosarcoma is a devastating bone cancer that disproportionally afflicts children, adolescents, and young adults. Standard therapy includes surgical tumor resection combined with multiagent chemotherapy, but many patients still suffer from metastatic disease progression. Neoadjuvant systemic oncolytic virus (OV) therapy has the potential to improve clinical outcomes by targeting primary and metastatic tumor sites and inducing durable antitumor immune responses. Here we describe the first evaluation of neoadjuvant systemic therapy with a clinical-stage recombinant oncolytic vesicular stomatitis virus (VSV), VSV-IFNβ-NIS, in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs. Canine osteosarcoma has a similar natural disease history as its human counterpart. VSV-IFNβ-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors. Treatment was well-tolerated and a "tail" of long-term survivors (∼35%) was apparent in the VSV-treated group, a greater proportion than observed in two contemporary control cohorts. An increase in tumor inflammation was observed in VSV-treated tumors and RNA-seq analysis showed that all the long-term responders had increased expression of a T cell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFNβ-NIS is safe and may increase long-term survivorship in dogs with naturally occurring osteosarcoma, particularly those that exhibit pre-existing antitumor immunity.
骨肉瘤是一种极具破坏性的骨癌，在儿童、青少年和年轻成年人中发病率不成比例地高。标准治疗包括手术切除肿瘤并联合多药化疗，但许多患者仍会出现转移性疾病进展。新辅助全身溶瘤病毒（OV）疗法有潜力通过靶向原发性和转移性肿瘤部位并诱导持久的抗肿瘤免疫反应来改善临床结果。在此，我们描述了对一种临床阶段的重组溶瘤水疱性口炎病毒（VSV），即VSV-IFNβ-NIS，在自然发生的癌症，特别是伴侣犬的附肢骨肉瘤中的新辅助全身治疗的首次评估。犬骨肉瘤的自然疾病史与其人类对应物相似。在标准护理手术切除之前给予VSV-IFNβ-NIS，以便对肿瘤进行微观和基因组分析。治疗耐受性良好，在VSV治疗组中出现了一批长期存活者（约35%），这一比例高于两个当代对照队列中观察到的比例。在VSV治疗的肿瘤中观察到肿瘤炎症增加，RNA测序分析表明，所有长期应答者的一个T细胞锚定免疫基因簇的表达均增加。我们得出结论，新辅助VSV-IFNβ-NIS是安全的，可能会提高自然发生骨肉瘤的犬的长期生存率，特别是那些已表现出抗肿瘤免疫力的犬。
