Abstract 1470: Development & characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1

Abstract

Abstract A number of oncolytic viruses have shown single agent clinical activity and evidence of clinical synergy with immune checkpoint blockade. However, not all patients respond, and as yet most of the promising clinical data have been generated in patients with melanoma. With the objective of maximally activating a patient's immune system against their own cancer which will then provide enhanced synergy with anti-PD1/L1 blockade, we developed a new oncolytic immunotherapy platform based on herpes simplex virus (HSV). This has the dual objectives of killing tumor to provide abundant release of tumor antigens, and potently activating immune responses against these antigens once released. To augment the natural ability of the virus to kill tumors and activate the immune system, these viruses are each armed with multiple therapeutic genes. Initially, we screened 29 new clinical strains of HSV isolated from volunteers who suffer from cold sores across a panel of human tumor cell lines to select a candidate for further development. This strain was then engineered to provide tumor selective replication (deletion of the genes encoding ICP34.5 and ICP47) and to express a potent fusogenic glycoprotein (GALV-GP R-). These modifications greatly enhance both local and systemic antitumor effects, increase immunogenic cell death, potently activate anti-tumor immunity, and are synergistic with PD-1 blockade in pre-clinical models. A virus expressing both GALV-GP R- and human GM-CSF is currently in a Phase 1/2 clinical trial in approximately 150 patients as a single-agent and combined with PD1 blockade in four solid tumor types. Further viruses express additional immune-activating proteins expected to act at the site of immune response initiation in tumors and draining lymph nodes, in particular an anti-CTLA-4 antibody-like molecule and immune co-stimulatory pathway-activating ligands. Each of these demonstrated increased activity in pre-clinical models, particularly an enhanced anenestic effect. The anti-CTLA-4 expressing virus (RP2) is targeted to enter clinical trials in the first half of 2019. Thus, a modular approach to oncolytic immunotherapy development can rapidly generate multiple clinical candidates with multiple mechanisms of action intended to act synergistically with other approaches to cancer therapy. The latest pre-clinical data utilizing this platform will be presented. Citation Format: Suzanne Thomas, Linta Juncheria, Victoria Roulstone, Joan N. Kyula, Howard L. Kaufman, Kevin J. Harrington, Robert S. Coffin. Development & characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1470.