Viral ILP augments the efficacy of PD-1 blockade in an animal model of extremity soft tissue sarcoma.


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Henry Smith1,Kevin Harrington2,Andrew Hayes3
1The Royal Marsden Hospital/The Institute of Cancer Research,2The Institute of Cancer Research,3The Royal Marsden Hospital

Abstract

Background

Systemic relapse is the major cause of mortality in extremity soft-tissue sarcoma (ESTS). Traditional systemic therapies for metastatic sarcoma are of limited efficacy, as are novel agents such as immune checkpoint inhibitors (ICI). Oncolytic virotherapy (OV) has been shown to improve the efficacy of ICI in other pathologies, although the ideal route of OV delivery in sarcoma is unknown. We have previously demonstrated that isolated limb perfusion (ILP) is ideally suited to delivering OV in an animal model of ESTS. Using this model, we sought to investigate whether combining ICI with OV delivered by ILP improved the efficacy of these agents.

Method

In vivo experiments were performed using the BN175 sarcoma cell line in Brown Norway rats under a Home Office approved project license. ILPs were performed with melphalan and TNF╬▒ with or without the addition of the vaccinia virus, GLV-1h68.

Results

BN175 sarcomas were found to contain tumour infiltrating lymphocytes (TILs) and express PD-L1, characteristics predictive of response to ICI in melanoma. Anti-PD-1 antibodies were of limited efficacy in this model, delaying tumour growth and improving survival from 10 to 13 days. However, when preceded by an induction viral ILP, treatment with anti-PD-1 antibodies resulted in a reduction in tumour volume in all subjects and complete regression in 33.3%. The responsible mechanism for these effects appears to be the induction of immunogenic cell death with melphalan and GLV-1h68 inducing recognised markers of this process, such as secreted ATP, cell surface calreticulin and secreted HMGB1, in sarcoma cell lines in vitro. Ex vivo, viral ILP increased PD-1 expression on TILs compared with standard ILP, suggestive of immune cell activation.

Conclusion

The combination of GLV-1h68 delivered by ILP promotes a more favourable tumour microenvironment and augments the efficacy of PD-1 blockade. Viral ILP may be an effective mechanism of addressing resistance to ICI.