Description

Attenuated Oncolytic Virus HSV1716 Enhances in vivo Expansion of GD2 CAR T cells in Murine Solid Tumor Models

Samuel T. Haile¹, Joe Conner², and Crystal L. Mackall¹

¹Stanford Cancer Institute, Stanford University, Stanford CA; ²Department of Neurology, Virttu Biologics, Scotland, UK

Neuroblastoma, osteosarcoma, and rhabdomyosarcoma are among the most prevalent childhood solid tumors. Each of these tumor types as well as melanomas exhibit increased levels of the tumor associated carbohydrate, GD2 on their cell surface making them ideal targets for chimeric antigen receptor (CAR) T cell-directed therapies. Despite the ability of GD2 CAR (GD2-28z) T cells to target tumor cells in vitro, there is great interest in improving tumor clearance in vivo, especially for solid tumors where current outcomes remain poor. We hypothesize that the immunosuppressive milieu present within the solid tumor microenvironment serves as a major factor limiting the effectiveness of GD2-28z T cells. Additionally, we propose that administration of oncolytic viruses could induce inflammation within the tumor microenvironment that may enhance, rather than inhibit, the effectiveness of immune based therapies. GD2-28z was expressed in murine lymphocytes and evaluated for the ability to target and lyse GD2-expressing cells. GD2-28z T cells were also evaluated for their ability to secrete proinflammatory cytokines. In order to determine the oncolytic ability of attenuated HSV1716, tumor cells were cultured in the presence or absence of HSV1716 and cell survival was measured. We observed specific lysis of GD2-expressing target cells by GD2-28z, but not mock T cells. Interestingly, melanoma cell lines were not susceptible to oncolytic lysis while rhabdomycosarcoma (RMS) cell lines were susceptible. The combination of GD2-28z and HSV1716 enhanced CAR expansion in both melanoma and RMS models. Given that the melanoma cells in our model are not susceptible to oncolytic lysis yet we observe an increase in T cell expansion when used in combination with HSV1716, this supports our hypothesis that HSV1716 is inducing inflammation, which may then trigger T cell expansion.