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Lee, J-H,Roh, M-S,Lee, Y-K,Kim, M-K,Han, J-Y,Park, B-H,Trown, P,Kirn, D H,Hwang, T-H Nature Publishing Group 2010 Cancer gene therapy Vol.17 No.2
<P>Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species.</P>
Kim, M. K.,Breitbach, C. J.,Moon, A.,Heo, J.,Lee, Y. K.,Cho, M.,Lee, J. W.,Kim, S.-G.,Kang, D. H.,Bell, J. C.,Park, B. H.,Kirn, D. H.,Hwang, T.-H. American Association for the Advancement of Scienc 2013 Science translational medicine Vol.5 No.185
<P>Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec-treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody-mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.</P>
( C Breitbach ),( M Cho ),( T H Hwang ),( C W Kim ),( U B Jeon,),( H Y Woo ),( K T Yoon ),( J W Lee ),( J Burke ),( T Hickman ),( K Duboi ),( L Longpre ),( R Patt ),( D H Kirn ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1
Background: JX-594 is a targeted oncolytic vaccinia virus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ ras pathway activation. Direct oncolysis plus granulocyte macrophage?colony stimulating factor (GM-CSF) expression is accompanied by tumor vascular disruption and anti-tumoral immunity (Reviewed in Nat Rev Cancer 2009). JX-594 was well-tolerated intravenously (IV) (Nature 2011) and intratumorally (IT) (Lancet Oncol 2008). Complementary anti-tumor effects are predicted with JX-594 followed by sorafenib due to acute vascular disruption effects with JX-594 and anti-angiogenic effects with sorafenib. Objectives: The primary objective of the study was to determine the safety of JX-594 followed by sorafenib in patients with advanced HCC. Secondary objectives include disease control rate (DCR) based on mRECIST and/or Choi response criteria at Day 6 (optional), Day 25 (after JX-594 only), 6 and 12 weeks. Methods: Treatment-refractory HCC patients received JX-594 for three weeks (Day 1 IV, Day 8 IT and Day 22 IT) followed by sorafenib. An IT boost dose of JX-594 at Week 12 was optional. Results: Twenty-five (25) patients were treated in this study; twenty (20) were refractory to sorafenib. Enrollment has been completed. The sequential treatment regimen was well-tolerated. Transient flu-like symptoms (Grade 1-2) and transient leukopenia (lymphopenia, neutropenia) were the most common adverse events following JX-594 therapy. Sorafenib toxicities were consistent with the expected toxicity profile. After JX-594 alone at Day 25, 56% of patients exhibited Choi tumor responses (range 19-48% reduced enhancement). Following subsequent sorafenib therapy, 76% had Choi responses at Week 6-12, including 83% sorafenib-failure patients. The disease control rate was 80% with JX-594 alone and 38% following initiation of sorafenib. Conclusions: JX-594 was well-tolerated and associated with Choi tumor responses following IV and IT injections in patients with advanced HCC. Subsequent sorafenib was associated with the expected toxicity profile. Further trials of JX-594 in HCC patients are warranted.