Abstract 605: Potency of Gp96-Ig/Fc-OX40L cell-based combination vaccine in cancer immunotherapy
Authors: Xin Xu, Louise E. Gonzalez, George J. Fromm, Suresh de Silva, Louise Giffin, Jason Rose, Taylor H. Schreiber
Journal: Cancer Research (2017)

Abstract The breakthrough discoveries of checkpoint inhibitors in the field of tumor immunology have driven the clinical success of immunotherapies for cancer, despite their beneficial efficacy in only a small portion of patients. This is due in part to immuno-evasive mechanisms and the inability of the immune system to recognize tumor antigens as foreign. As a therapeutic approach to effectively present these tumor antigens in order to elicit an anti-tumor immune response, we previously designed and characterized an allogenic, gp96-Ig secreting, cell-based vaccine (ImPACT); currently being assessed in a phase II study in non-muscle invasive bladder cancer and a phase Ib study in non-small cell lung cancer – the latter, in combination with the PD-1 antagonist Nivolumab. We recently characterized a ‘next-generation’ vaccine (ComPACT) that combines the tumor antigen chaperone Gp96-Ig along with the T cell costimulator Fc-OX40L, which are both secreted from the same cell (Fromm et. al. Cancer Immunology Research. 2016). In preclinical assays, ComPACT is effective at stimulating CD4+ and CD8+ antigen-specific T cell expansion, the programing of a durable memory T cell phenotype, and the elimination of melanoma and colon tumors. This anti-tumor efficacy is enhanced when ComPACT is combined with checkpoint inhibition (anti-PD1 or anti-PDL1). To support manufacturing and clinical efforts of both ImPACT and ComPACT, in anticipation of phase III expansion and/or new trial initiation, we have developed novel potency assays to quantify the biologically active form of Gp96-Ig and the in vitro activity of Fc-OX40L on T cell costimulation. It has been shown that gp96 can interact with toll-like receptors (TLR) and that this interaction results in the activation of the NF-κB pathway. Since THP1 cells express abundant TLR2/4, we engineered a THP1 cell line to express luciferase that is regulated by NF-κB response elements. Furthermore, we utilized the human T cell line; Jurkat, as host cells in which we also express NF-κB-luciferase, to quantify Fc-OX40L costimulation. Jurkat/NF-κB-luciferase cells primed with either CD3/CD28 or TNFα, and subsequently cultured with ComPACT-secreted Fc-OX40L, results in a dose dependent increase in NF-κB (luciferase) expression. Our current data in both assays shows a linear correlation with the input of Gp96-Ig and Fc-OX40L, and may serve as an effective potency assay to facilitate the manufacturing of our vaccine product as it transitions into more advanced cancer immunotherapy clinical studies. Citation Format: Xin Xu, Louise E. Gonzalez, George J. Fromm, Suresh de Silva, Louise Giffin, Jason Rose, Taylor H. Schreiber. Potency of Gp96-Ig/Fc-OX40L cell-based combination vaccine in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 605. doi:10.1158/1538-7445.AM2017-605