Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma

Abstract

The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP‐delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV‐1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology.

Viruses as nanomedicine for cancer

“…Isolated limb perfusion administration of GLV-1h68 in combinations with biochemotherapy and radiotherapy showed increased treatment efficacy in an animal model of extremity soft tissue sarcoma. 86 Intravesical therapy of bladder cancer with oncolytic HSV also showed enhanced treatment efficacy. 87 Good treatment efficacy of aforementioned methods might be linked with avoidance of immune system.…”

Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms

“…As this oncolytic virus is not targeted to a speci c type of tumor, oncolytic activity has already been detected in a broad spectrum of tumor entities in preclinical models as well as in several clinical trials [13][14][15][16]. Moreover, combinatorial approaches with chemotherapy, radiation or targeted therapies have displayed synergistic antitumor activities [17][18][19][20][21].…”

GLV-1h68 vaccinia virus therapy of neuroendocrine tumors

“…As this oncolytic virus is not targeted to a specific type of tumor, oncolytic activity has already been detected in a broad spectrum of tumor entities in preclinical models as well as in several clinical trials [13][14][15][16]. Moreover, combinatorial approaches with chemotherapy, radiation or targeted therapies have displayed synergistic antitumor activities [17][18][19][20][21].…”