Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression

“…We previously showed that a human glioblastoma xenograft with <20% nectin-1 expression was less sensitive to infection and killing by HSV-1 than tumors with higher expression, and other groups determined that nectin-1 predicted oncolysis by HSV-1 in squamous cell carcinoma, thyroid cancer, and EBV-associated lymphoproliferative disease 25 – 28 . Of note, in preclinical animal models and in human clinical trials, subsequent doses of virus were effective at controlling tumor indicating that uninfected tumor cells maintain sensitivity to oHSV 14 , 29 . While nectin-1 predicts sensitivity in some tumor types, expression levels do not correlate with oHSV sensitivity in all tumor types; sensitivity of neuroblastoma cell lines to γ 1 34.5-deleted HSV1716 was independent of nectin-1 or other known entry molecules such as nectin-2, herpes virus entry mediator (HVEM), or 3-OS heparin sulfate 30 .…”

The Effects of Green Tea and Propolis Extracts on pro-inflammatory cytokines TNF-?, IFN-?, IL2, and Immunoglobulin Production in Experimentally Infected Rabbits with Bovine Herpesvirus-1.

“…Second, the kaempferol for inhibition of influenza B virus indicated that the more planar flavonol structure with only one C-4′ phenolic hydroxyl group in the B ring is necessary for the anti-influenza B virus activity. The green tea polyphenols also blocked viral penetration and binding to cells triggering the self-defense of the host cell influencing the activity of a variety of signal transduction pathways (Narotzki et al, 2012;Waters et al, 2016;Dhakal et al, 2018).…”

Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients

“…Thus, the effective use of virus may require combination therapy with targeted therapies, chemotherapy, or low-dose radiotherapy to slow tumor growth while allowing time for virolytic or viroimmunotherapeutic effects to develop. Preclinical studies support these approaches (23)(24)(25), although concurrent therapies should be chosen and perhaps timed carefully to not interfere with virus replication (26) or the development of virus-induced antitumor immunity. In addition, giving oncolytic virotherapy earlier in the disease course may also allow time to develop an antitumor immune response.…”