Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

Abstract

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.

Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment

“… 5 , 7 , 8 There is a growing number of clinical trials for oncolytic virus therapy that demonstrate safety in adult and childhood cancer patients, leading to the first Food and Drug Administration-approved oncolytic virus, Talimogene laherparepvec (T-VEC), for the treatment of metastatic melanoma. 9 , 10 , 11 With these recent breakthroughs, oncolytic virotherapy has the potential to become a new therapy option for a wider variety of patients with solid tumors.…”

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

“…Attenuated natural mutants, exemplified by HF10, were also selected [ 6 ]. These viruses have been and still are being tested in clinical trials [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], for a review [ 19 , 20 , 21 ]. Viruses were safely administered intratumorally at doses up to 3 × 10 9 plaque forming units (PFU) [ 12 ].…”

“…Viruses were safely administered intratumorally at doses up to 3 × 10 9 plaque forming units (PFU) [ 12 ]. In general, they exhibit a high safety profile and exert antitumor activity against a variety of tumor types [ 21 ]. However, because of their attenuation, robust growth occurs only in tumors with defects in innate response, autophagy, apoptosis, etc.…”

General and Ophthalmic Manifestations of Herpes Virus Infections

“…ВПГ влияют на онкогенез солидного рака, нейробласто-мы, остеосаркомы, рабдомиосаркомы и других опухолей у детей, а также рака предстательной железы у взрослых, что продемонстрировано крупными многоцентровыми исследованиями в разных странах [40,41]. Опубликова-ны данные о том, что ВПГ-1, ЦМВ, ВЭБ и другие вирусы группы герпеса играют роль в патогенезе болезни Аль-цгеймера [42] и первичного повреждения поджелудоч-ной железы при сахарном диабете I типа [43].…”