http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans
Breitbach, Caroline J.,Burke, James,Jonker, Derek,Stephenson, Joe,Haas, Andrew R.,Chow, Laura Q. M.,Nieva, Jorge,Hwang, Tae-Ho,Moon, Anne,Patt, Richard,Pelusio, Adina,Le Boeuf, Fabrice,Burns, Joe,Evgi Nature Publishing Group, a division of Macmillan P 2011 Nature Vol.477 No.7362
The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.
( 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.
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>
Heo, Jeong,Reid, Tony,Ruo, Leyo,Breitbach, Caroline J,Rose, Steven,Bloomston, Mark,Cho, Mong,Lim, Ho Yeong,Chung, Hyun Cheol,Kim, Chang Won,Burke, James,Lencioni, Riccardo,Hickman, Theresa,Moon, Anne Nature Publishing Group, a division of Macmillan P 2013 Nature medicine Vol.19 No.3
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.