Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer

Abstract

Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30). Radiologists infused low-or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…Recently, sipuleucel-T (Provenge, Dendreon, Seattle, WA, USA), indicated for patients with metastatic castration-resistant prostate cancer, received FDA's approval as the first therapeutic cancer vaccine. 5 In addition, extensive Phase II clinical trials have demonstrated that the oncolytic herpes simplex virus talimogene laherparepvec (T-Vec, Amgen Inc., Thousand Oaks, CA, USA) 6 and vaccinia virus JX-547 (Pexa-Vec, Jennerex Biotherapeutics, Inc., San Francisco, CA, USA), 7 both of which carry the gene encoding the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), hold great promise for the treatment of advanced cancer patients. Furthermore, cytotoxic T-cell responses directed against oncolytic virus-infected cancer cells have been identified as an essential factor in the process of destruction of cancer.…”

“…Indeed, the results of clinical trials of the GM-CSF gene-harboring oncolytic vaccinia virus JX-594 and the GM-CSF gene-harboring oncolytic herpes virus talimogene laherparepvec demonstrated that a clinical benefit can be accomplished by combined respective oncolytic activity with the recruitment of immune cells. 6,7,131 The combination of adoptive T-cell therapy with oncolytic viruses is shown to elicit an increased antitumor effect. 131,132 Collectively, the design of combinatorial therapies of oncolytic viruses with immunotherapeutic modalities may 136,137 and (6) directly targets not only the primary tumor but also metastases.…”

Current management of hepatocellular carcinoma: An Eastern perspective

“…Emerging therapies: Recently, the oncolytic and immunotherapeutic vaccinia virus has been reported to induce antibody-mediated, complement-dependent cancer cell lysis in humans [116] . Immunotherapy may benefit patients with advanced stage HCC who do not have further treatment options.…”

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

“…2). While promising early-and late-phase clinical trials employing OVs to treat cancers continue to generate great enthusiasm, heterogeneity in clinical response remains a challenge [2][3][4] . To this end, it has been long recognized that improvements to therapeutic efficacy either through viral engineering or through combination therapies will be critical to the success of these platforms 2,5 .…”