4506 - Single intravenous preoperative administration of the oncolytic virus Pexa-Vec to prime anti-tumor immunity

Background

Oncolytic viruses constitute a promising modality of cancer therapy. Pexa-Vec, a Thymidine Kinase-Deactivated Vaccinia Virus expressing GM-CSF, has been shown to target tumor tissue after intravenous (i.v.) administration (Breitbach C.J. et al., 2011). Herein, we report on the immunostimulatory effects of Pexa-Vec prior to surgical resection in patients with advanced solid tumors.

Methods

Patients with operable tumors (3 with metastatic melanoma and 6 with colorectal cancer metastases to the liver (CRLM)) received a single i.v. dose of 1x10⁹ plaque forming units of Pexa-Vec, approximately 14 days prior to surgical resection. Translational and histologic assessment was performed on blood samples collected pre- and post-injection and tumor collected at surgery.

Results

Pexa-Vec injection was well tolerated in all cases. Pexa-Vec was detected in serum immediately after iv administration but not in PBMC. Histologic examination of tumor tissue indicates the presence of virus in tumor at the time of surgery 14 days after administration. Of the 4 evaluable CRLM, one showed complete necrosis, and another partial necrosis, within a normal background liver. Analysis of peripheral blood mononuclear cells and tumor infiltrating lymphocytes showed robust activation of Natural Killer (NK) cells and CD8⁺ cells, with high CD69 and PD-L1 expression. Functional assays revealed increased NK cell degranulation and elevated tumor-associated antigen recognition by T cells. Furthermore, Pexa-Vec induced a significant elevation of serum cytokines associated with immune response including IFNα, IFNβ, TRAIL and CXCL10.

Conclusions

When administered intravenously, Pexa-Vec exhibited a selective persistence in tumor suggesting a tumor-targeted oncolytic action. Concurrently, Pexa-Vec triggered a robust immune activation of both innate and adaptive immune cells and infiltration of lymphocytes into tumor, associated with extensive necrosis in some patient tumours. These data strongly support the rationale for sequential i.v. use of oncolytic vaccinia virus in combination with immune checkpoint modulation therapy.

Clinical trial identification

ISRCTN13913966.

Editorial acknowledgement

Legal entity responsible for the study

University of Leeds.

Funding

Transgene.

Disclosure

A. Samson: Research grant / Funding (institution): Transgene. K. Bendjama: Full / Part-time employment: Transgene. N. Stojkowitz: Full / Part-time employment: Transgene. M. Lusky: Full / Part-time employment: Transgene. A. Melcher: Research grant / Funding (institution): Transgene. F. Collinson: Research grant / Funding (institution): Transgene. All other authors have declared no conflicts of interest.