Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy.

Laetitia Fend,Murielle Gantzer,Takahiro Yamazaki,Julien Adam,Eric Quéméneur,Virginie Nourtier,Laurence Zitvogel,Catherine Fahrner,Guido Kroemer,Xavier Préville,Oliver Kepp,Christelle Remy,Jonathan M Pitt,Aurélien Marabelle

doi:10.1158/0008-5472.can-16-2165

Abstract

Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.

Highlights

Oncolytic virotherapy is an attractive and emerging modality for treating cancer, boosted by the recent approval of IMLYGIC (TVEC/talimogene laherparepvec), a modified herpes simplex virus 1 encoding human GM-CSF, for use in stage III melanoma patients with injectable but nonresectable lesions in the skin and lymph nodes [1]
We here report that WR, a surrogate model for the preclinical study of TG6002, a first-in class oncolytic poxvirus, is able to induce immunogenic cell death and to beneficially reprogram cell populations within the tumor microenvironment
We demonstrate that WR, alone or in combination with oxaliplatin or immune checkpoint blockers, produces abscopal effects on distant untreated tumors, when the treated tumor displays attenuated type I IFN signaling

Summary

Introduction

Oncolytic virotherapy is an attractive and emerging modality for treating cancer, boosted by the recent approval of IMLYGIC (TVEC/talimogene laherparepvec), a modified herpes simplex virus 1 encoding human GM-CSF, for use in stage III melanoma patients with injectable but nonresectable lesions in the skin and lymph nodes [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Malignant cells upon replication, while sparing normal cells. This selective effect essentially results from the fact that tumor cells have a limited ability to respond to infection due to defects in their antiviral signaling pathways, such as the type I IFN signaling pathway [2, 3]. It is believed that this level of oncolytic activity can only occur in situations where both natural innate and adaptive antiviral responses are outpaced [2]

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Conclusion