Abstract 4698: ONCR-1, a novel herpes simplex virus expressing MMP9 and ULBP3 transgenes, evokes potent oncolysis and development of antitumor immune responses

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor prognosis and resistance to current therapies. ONCR-1 is a novel oncolytic herpes simplex virus type-1 vector in development for the treatment of GBM. ONCR-1 utilizes a unique conditional-lethal strategy in which miR124 binding sites are inserted into the ICP4 locus to prevent viral replication in neuronal cells while preserving one copy of the γ34.5 gene and enabling potent cytotoxicity in tumor cells. ONCR-1 is armed with a matrix metalloproteinase 9 (MMP9) transgene to facilitate viral spread in the tumor extracellular matrix. Further, ONCR-1 expresses a UL16 binding protein 3 (ULBP3) transgene to activate NK and CD8+ T cells via the NKG2D receptor and promote antitumor immune responses. In human and murine tumor cells in vitro, ONCR-1 evoked potent cytotoxicity. ONCR-1 increased proteolytic MMP in cell supernatants and ULBP3 cell surface expression with no effect on related NKG2D ligands. In mice bearing subcutaneous or orthotopic human U251 GBM tumors, ONCR-1 administered intratumorally (3x105-3x106 PFU QDx1) inhibited tumor growth and prolonged survival. Ex vivo analysis of immune cells in subcutaneous tumors showed significant increases in virally evoked NKG2D+ NK cells with ONCR-1 treatment. In mice bearing dual flank subcutaneous syngeneic A20 tumors, ONCR-1 significantly inhibited tumor growth in injected tumors (1x105-3x105 PFU, Q2Dx3) and evoked potent systemic antitumor immune responses as evidenced by significant inhibition of distal noninjected left flank tumors. IFNγ production from isolated splenocytes cultured in the absence and presence of A20 tumor cells was significantly augmented in ONCR-1-treated animals, providing further evidence of an enhanced antitumor immune response. Moreover, in mice bearing subcutaneous A20 tumors in which ONCR-1 evoked complete tumor regression, complete protection from rechallenge with A20 tumor cells was observed. Depletion of NK cells or CD8+ T cells in mice resulted in inhibition of ONCR-1-mediated antitumor effects in both injected and noninjected murine A20 tumors, supporting an immune mechanism of action. Our preclinical studies demonstrate that ONCR-1 evokes tumor cell killing by direct oncolysis and by enhancing antitumor immune responses. ONCR-1 represents a novel clinical candidate for the treatment of GBM. Citation Format: Alexandra Hicks, Paola Grandi, Michael Paglia, Jingzang Miu, Cecilia Kwong, Jacqueline Gursha, Michael Ball, Weiguo Yao, Daniel Wambua, Terry Farkaly, Kyle Grant, Laura Viggiano Salta, Lorenz Ponce, Joseph Glorioso, Christophe Queva, Mitchell Finer. ONCR-1, a novel herpes simplex virus expressing MMP9 and ULBP3 transgenes, evokes potent oncolysis and development of antitumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4698.

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

“… 96 ONCR-1 F ∆ICP4, -γ34.5, +miR-124, +ULBP3, +MMP9 U251 3x10 5 -3x10 6 (1 dose) ONCR-1 inhibited tumor growth and prolonged survival compared to mock group. 98 Pro-drug activating genes MGH2 F ∆ICP6, -/-γ34.5, -UL39, +CYP2B1, +shiCE Gli36ΔEGF 1.4×10 6 MGH2 did not prolong median survival compared to mock group. 99 Abbreviations: PFU, plaque forming unit; (-), single deletion; (-/-), diploid deletion; ∆, mutation/inactivation; (+), insertion.…”

“… 96 Another oHSV (designated ONCR-1) was engineered by deleting one copy of γ34.5, inserting miR-124 binding sites into the ICP4 locus and arming with both ULBP3 and MMP-9. 98 Although ONCR-1 controlled tumor growth and extended survival in mice bearing subcutaneous or orthotopic human U251 GBM tumors, it was not determined whether the absence of MMP-9 expression would have facilitated a better spread/efficacy of a single transgene (ULBP3)-armed virus. 98 …”

“… 98 Although ONCR-1 controlled tumor growth and extended survival in mice bearing subcutaneous or orthotopic human U251 GBM tumors, it was not determined whether the absence of MMP-9 expression would have facilitated a better spread/efficacy of a single transgene (ULBP3)-armed virus. 98 …”