Abstract 1452: Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response

Abstract

Abstract Oncolytic viruses, through cancer cell-selective lysis and accompanying release of danger signals that promote immune activation, have demonstrated antitumor efficacy in monotherapy of metastatic melanoma and have shown promising activity in combination with checkpoint inhibitors. We present here the activity of ONCR-148, a recombinant oncolytic Herpes Simplex Virus (oHSV) designed to be a safe and efficacious therapy for the treatment of solid tumors. Neuron-specific miR attenuation of ICP4 gene inhibits viral replication in neurons while preserving its potent oncolytic activity in tumor cells. The antitumor potency of the virus is enhanced by incorporating in its genome a transgene expressing fibroblast activation protein (FAP)- and CD3- bispecific antibody that recruits and re-directs the cytolytic activity of T cells toward FAP-expressing stromal cells. FAP is a cell-surface serine protease that is almost exclusively found in fibroblasts within tumor stroma. However, systemic administration of a FAP-CD3 bispecific antibody was not tolerated due to the toxicity toward FAP-expressing bone marrow mesenchymal cells (Tran et al., 2013. J.Exp.Med, 210(6), 1125-1135). Thus, the local intra-tumoral delivery of FAP-CD3 is an attractive approach to promote tumor lysis and T cell activation against cancerous lesions. To test the in vivo activity of ONCR-148, as FAP is poorly expressed in syngeneic mouse tumor models, we developed a bilateral mouse FAP-expressing MC38 syngeneic colon carcinoma model (MC38-FAP), allowing to test local antitumor activity in oHSV-injected tumors and abscopal efficacy mediated by immune cells in the non-injected tumors. Intra-tumoral administration of ONCR-148 in the MC38-FAP model resulted in tumor growth inhibition of 60% (p<0.03) and 46% (p<0.01) on the injected (ipsilateral) and non-injected (contralateral) tumor, respectively. We then investigated additional transgenes that could potentiate the antitumor activity of ONCR-148. We combined in vivo ONCR-148 with ONCR-153, an oHSV armed with the NK and T cell activating cytokine IL-12 and the chemokines CXCL10 and CCL4, allowing for expansion and recruitment of T cells and antigen presenting cells in the tumor milieu. Combined intra-tumoral administration of ONCR-148 and ONCR-153 increased the antitumor response to 90% on the injected tumor (p<0.0001), leading to complete tumor remission in 5 out of 9 treated mice and to 80% on distant tumors (p<0.0001, with no complete responses observed).These data indicate that oHSV expressing bispecific antibodies, while being well tolerated, is efficacious in injected tumors and mediate systemic antitumor immune response. The efficacy can be potentiated by a local co-expression of immunostimulatory cytokines. Such data support the further development of oHSV-1 armed with CD3 bispecific antibodies for the therapy of patients with metastatic cancer. Citation Format: Agnieszka Denslow, Brian B. Haines, Michael S. Ball, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Allison Colthart, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Caitlin Goshert, Edward M. Kennedy, Lorena Lerner, Christophe Quéva. Development of ONCR-148, a miR-attenuated oncolytic HSV-1 designed to potently activate antitumor T cell response [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 1452.