Fighting Fire With Fire: Effects of Oncolytic Virotherapy on Underlying Viral Hepatitis in Hepatocellular Carcinoma
Authors: Tony Reid
Journal: Molecular Therapy (2008)

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death.1El-Serag HB Rudolph KL Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4372) Google Scholar It arises in the context of cirrhosis, due most commonly to chronic alcohol exposure or chronic infection with either hepatitis B or hepatitis C virus.2Llovet JM Burroughs A Bruix J Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3755) Google Scholar With the exception of a minority of patients who can undergo liver transplant, HCC is generally fatal within a short period of time.3Marrero CR Marrero JA Viral hepatitis and hepatocellular carcinoma.Arch Med Res. 2007; 38: 612-620Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,4Walzer N Kulik LM Hepatocellular carcinoma: latest developments.Curr Opin Gastroenterol. 2008; 24: 312-319Crossref PubMed Scopus (13) Google Scholar A critical factor for the high mortality is the underlying liver cirrhosis. This comorbidity not only limits treatment options owing to poor residual hepatic function but is often the cause of death among these patients. Thus, without an effective treatment for viral hepatitis, the long-term value of effective therapy for HCC will be limited.In this issue of Molecular Therapy, Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar present provocative clinical findings arising out of the use of a molecularly targeted oncolytic vaccinia virus (JX-594) for the treatment of patients with advanced-stage HCC. The article describes the evaluation of JX-594 in three patients with hepatitis B–related HCC. These three patients are a subset of 14 patients with advanced cancer treated in a phase I study with JX-594. The analysis of the three patients highlights several critical issues confronting the development of novel therapeutic agents as well as the complexity associated with treatment of HCC. Most importantly, the article describes the suppression of hepatitis B viral genomes associated with concurrent treatment with vaccinia virus. It further shows replication of JX-594 in the presence of high-titer neutralizing antibody to vaccinia and extensive tumor necrosis following treatment with an oncolytic virus.The incidence of HCC is highest in Asia and sub-Saharan Africa but has been rising rapidly in the United States and Europe.1El-Serag HB Rudolph KL Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4372) Google Scholar,3Marrero CR Marrero JA Viral hepatitis and hepatocellular carcinoma.Arch Med Res. 2007; 38: 612-620Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Hepatitis B infection, as discussed by Liu et al.,5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar is the main risk factor in Asia and Africa, whereas hepatitis C infection is the main risk factor in Japan and Europe and is the primary main cause for the increased incidence of HCC in the United States. Median survival of patients with HCC is 2 to 9 months, depending on the stage of the cancer and underlying comorbidities. Partial hepatectomy and liver transplantation are the mainstays of curative treatment but are restricted to a minority of patients with small tumor burdens without evidence of metastatic spread.6Llovet JM Updated treatment approach to hepatocellular carcinoma.J Gastroenterol. 2005; 40: 225-235Crossref PubMed Scopus (447) Google Scholar Local ablative therapy, including radiofrequency ablation, transarterial chemoembolization, and radiotherapy, are used for patients who have inoperable HCC and good hepatic function. Chemotherapy is reserved for patients with advanced disease who are not candidates for local or regional therapy.Despite extensive testing, no chemotherapeutic agent or combination of agents has been shown to reliably control HCC. Recently, sorafenib (Nexavar)—an oral multikinase inhibitor that targets the Raf/MEK/ERK signaling pathways and also inhibits angiogenesis through the vascular endothelial growth factor (VEGF) pathway—has demonstrated benefit for HCC patients with well-preserved liver function.7Mendez-Sanchez N Vasquez-Fernandez F Zamora-Valdes D Uribe M Sorafenib, a systemic therapy for hepatocellular carcinoma.Ann Hepatol. 2008; 7: 46-51PubMed Google Scholar,8Llovet JM Bruix J Novel advancements in the management of hepatocellular carcinoma in 2008.J Hepatol. 2008; 48 (suppl. 1): S20-37Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar,9Liu L et al.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.Cancer Res. 2006; 66: 11851-11858Crossref PubMed Scopus (1214) Google Scholar,10Abou-Alfa GK Schwartz L Ricci S Amadori D Santoro A Figer A et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2006; 24: 4293-4300Crossref PubMed Scopus (1090) Google Scholar In November 2007 the US Food and Drug Administration approved sorafenib on the basis of data from a multinational, randomized, placebo-controlled trial of sorafenib vs. best supportive care. In this study, which is the first randomized trial to demonstrate the benefit of a molecularly targeted agent for the treatment of HCC, the median survival of the patients receiving the placebo was 34 weeks, as compared with 46 weeks for patients receiving sorafenib. The median time to progression was 12 weeks for the placebo group but 24 weeks among the patients randomized to sorafenib. Based on these results, sorafenib can be considered the standard of care for patients with advanced and metastatic HCC with good liver function who are not candidates for curative or locoregional therapies. Despite these results, the prognosis for patients with HCC remains poor. Notably, only 2 % of patients receiving sorafenib had objective responses to the therapy, and the primary benefit was due to disease stabilization.Thus, the new study5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar in this issue showing suppression of hepatitis B genomes by concurrent infection with an attenuated strain of vaccinia deserves more detailed analysis. The authors documented that hepatitis B genomes were effectively suppressed during the period of treatment with JX-594, and that they increased when this therapy was held. Upon resumption of therapy with JX-594, further suppression of hepatitis B genomes was observed. Effective long-term control of hepatitis B due to concurrent treatment with an oncolytic virus was not specifically addressed in this study, but it remains an important issue because of the high incidence of liver failure among these patients. In addition, patients with HCC effectively controlled by locoregional therapy remain at high risk for a second HCC.11Varela M Sala M Llovet JM Bruix J Treatment of hepatocellular carcinoma: is there an optimal strategy?.Cancer Treat Rev. 2003; 29: 99-104Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,12Llovet JM Treatment of hepatocellular carcinoma.Curr Treat Options Gastroenterol. 2004; 7: 431-441Crossref PubMed Scopus (44) Google Scholar Among patients with early-stage HCC who are amenable to resection, 50 % to 80 % will have a recurrence within 5 years after the resection. The recurrences may be due to independent clones of tumor cells arising from premalignant cells exposed to continued active hepatitis or due to occult metastases from the primary tumor. Thus, the report by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar may suggest a dual function for JX-594 in treating both the pre-existing macroscopic and microscopic disease, as well as potentially inhibiting or delaying the transformation of premalignant clones of HCC. Although the data discussed are limited to three patients, the effect observed is of critical importance and requires more detailed analysis in subsequent controlled trials.Oncolytic viruses have been developed with the objective of exploiting tumor-selective replication of the virus followed by lysis of the tumor cell by mature virons and subsequent infection of additional tumor cells.13Kelley E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar Ongoing viral replication has been limited by the rapid development of neutralizing antibody against the virus. ONYX-015, an E1b-55K-deleted adenovirus, is the prototype of an oncolytic virus. It has been extensively studied in phase I/II/III clinical trials and has recently been approved in China for treatment of head and neck cancer by local injection.14Kirn DH The end of the beginning: oncolytic virotherapy achieves clinical proof-of-concept.Mol Ther. 2006; 13: 237-238Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,15Garber K China approves world's first oncolytic virus therapy for cancer treatment.J Natl Cancer Inst. 2006; 98: 298-300Crossref PubMed Scopus (335) Google Scholar Clinical studies demonstrated rapid induction of high titers of neutralizing antibody, and limited activity was observed in patients treated by intravenous administration of ONYX-015. The data presented by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar demonstrate secondary and tertiary peaks of viral genomes in the circulation of patients with repeated treatment despite the presence of high titers of neutralizing antibody. The capacity of JX-594 to replicate and infect cells even in the presence of high titers of neutralizing antibody, as indicated by the secondary and tertiary peaks of viral DNA in the circulation, suggests that JX-594 may eventually be suitable for systemic treatment of HCC and other malignancies.The increasing use of molecularly targeted agents has ushered in a new era for analysis of clinic response to therapy. Unlike that of traditional cytotoxic agents, the activity of many targeted agents is not reliably captured by traditional anatomic measurement of tumor size. An example is Gleevec (imatinib mesylate), a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors.16Druker BJ Current treatment approaches for chronic myelogenous leukemia.Cancer J. Sudbury, MA2001: S14-18Google Scholar,17Maki RG Recent advances in therapy for gastrointestinal stromal tumors.Curr Oncol Rep. 2007; 9: 165-169Crossref PubMed Scopus (14) Google Scholar Recent studies have demonstrated that measurement of tumor cell viability by uptake of radioactively labeled glucose—positron emission tomography (PET)—is highly predictive of response to therapy with Gleevec, whereas anatomic measurements of tumor size are less predictive and can even lead to an erroneous assessment of tumor progression among patients responding to the treatment.18Antoch G Kanja J Bauer S Kuehl H Renzing-Koehler K Schuette J et al.Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors.J Nucl Med. 2004; 45: 357-365PubMed Google Scholar,19Choi H Response evaluation of gastrointestinal stromal tumors.Oncologist. 2008; 13 (suppl. 2): 4-7Crossref PubMed Scopus (191) Google Scholar Similar results have been observed with ONYX-015, with which transient increases in tumor size were paradoxically associated with clinical responses and prolonged survival.20Sze DY Freeman SM Slonim SM Samuels SL Andrews JC Hicks M et al.Dr. Gary J. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival.J Vasc Interv Radiol. 2003; 14: 279-290Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,21Reid TR Freeman S Post L McCormick F Sze DY Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin.Cancer Gene Ther. 2005; 12: 673-681Crossref PubMed Scopus (83) Google Scholar The transient increases in tumor size following treatment with ONYX-015 were attributed to tumor-selective viral infection and subsequent inflammation localized to the tumor. The report by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar demonstrates extensive necrosis of the tumor masses following treatment with JX-594. The necrosis was confirmed by quantification of loss of metabolic activity within the tumor by PET scan as well as significant decreases in circulating markers of tumor activity, including α-fetoprotein (AFP) and VEGF. Extensive necrosis of the tumor masses can lead to delayed resorption of the measurable tumor mass and a prolonged time interval before the size of the tumor has decreased sufficiently to achieve a partial or complete response by size based criteria. Consequently, response to treatment, as determined by traditional size based criteria, may significantly lag metabolic response criteria as determined by PET scan and biochemical markers such as AFP and VEGF.In summary, HCC is a common cancer worldwide, with a rising incidence in the United States. Despite extensive study, the treatment options for patients with inoperable cancer are very limited and the overall prognosis for these patients is poor because of both the cancer and the underlying cirrhosis and related comorbidities. Although the study described by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar is small, the reported clinical results coupled with the suppression of hepatitis B DNA pave the way for more detailed studies of this oncolytic vaccinia virus for the treatment of HCC. Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death.1El-Serag HB Rudolph KL Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4372) Google Scholar It arises in the context of cirrhosis, due most commonly to chronic alcohol exposure or chronic infection with either hepatitis B or hepatitis C virus.2Llovet JM Burroughs A Bruix J Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3755) Google Scholar With the exception of a minority of patients who can undergo liver transplant, HCC is generally fatal within a short period of time.3Marrero CR Marrero JA Viral hepatitis and hepatocellular carcinoma.Arch Med Res. 2007; 38: 612-620Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,4Walzer N Kulik LM Hepatocellular carcinoma: latest developments.Curr Opin Gastroenterol. 2008; 24: 312-319Crossref PubMed Scopus (13) Google Scholar A critical factor for the high mortality is the underlying liver cirrhosis. This comorbidity not only limits treatment options owing to poor residual hepatic function but is often the cause of death among these patients. Thus, without an effective treatment for viral hepatitis, the long-term value of effective therapy for HCC will be limited. In this issue of Molecular Therapy, Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar present provocative clinical findings arising out of the use of a molecularly targeted oncolytic vaccinia virus (JX-594) for the treatment of patients with advanced-stage HCC. The article describes the evaluation of JX-594 in three patients with hepatitis B–related HCC. These three patients are a subset of 14 patients with advanced cancer treated in a phase I study with JX-594. The analysis of the three patients highlights several critical issues confronting the development of novel therapeutic agents as well as the complexity associated with treatment of HCC. Most importantly, the article describes the suppression of hepatitis B viral genomes associated with concurrent treatment with vaccinia virus. It further shows replication of JX-594 in the presence of high-titer neutralizing antibody to vaccinia and extensive tumor necrosis following treatment with an oncolytic virus. The incidence of HCC is highest in Asia and sub-Saharan Africa but has been rising rapidly in the United States and Europe.1El-Serag HB Rudolph KL Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007; 132: 2557-2576Abstract Full Text Full Text PDF PubMed Scopus (4372) Google Scholar,3Marrero CR Marrero JA Viral hepatitis and hepatocellular carcinoma.Arch Med Res. 2007; 38: 612-620Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Hepatitis B infection, as discussed by Liu et al.,5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar is the main risk factor in Asia and Africa, whereas hepatitis C infection is the main risk factor in Japan and Europe and is the primary main cause for the increased incidence of HCC in the United States. Median survival of patients with HCC is 2 to 9 months, depending on the stage of the cancer and underlying comorbidities. Partial hepatectomy and liver transplantation are the mainstays of curative treatment but are restricted to a minority of patients with small tumor burdens without evidence of metastatic spread.6Llovet JM Updated treatment approach to hepatocellular carcinoma.J Gastroenterol. 2005; 40: 225-235Crossref PubMed Scopus (447) Google Scholar Local ablative therapy, including radiofrequency ablation, transarterial chemoembolization, and radiotherapy, are used for patients who have inoperable HCC and good hepatic function. Chemotherapy is reserved for patients with advanced disease who are not candidates for local or regional therapy. Despite extensive testing, no chemotherapeutic agent or combination of agents has been shown to reliably control HCC. Recently, sorafenib (Nexavar)—an oral multikinase inhibitor that targets the Raf/MEK/ERK signaling pathways and also inhibits angiogenesis through the vascular endothelial growth factor (VEGF) pathway—has demonstrated benefit for HCC patients with well-preserved liver function.7Mendez-Sanchez N Vasquez-Fernandez F Zamora-Valdes D Uribe M Sorafenib, a systemic therapy for hepatocellular carcinoma.Ann Hepatol. 2008; 7: 46-51PubMed Google Scholar,8Llovet JM Bruix J Novel advancements in the management of hepatocellular carcinoma in 2008.J Hepatol. 2008; 48 (suppl. 1): S20-37Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar,9Liu L et al.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.Cancer Res. 2006; 66: 11851-11858Crossref PubMed Scopus (1214) Google Scholar,10Abou-Alfa GK Schwartz L Ricci S Amadori D Santoro A Figer A et al.Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2006; 24: 4293-4300Crossref PubMed Scopus (1090) Google Scholar In November 2007 the US Food and Drug Administration approved sorafenib on the basis of data from a multinational, randomized, placebo-controlled trial of sorafenib vs. best supportive care. In this study, which is the first randomized trial to demonstrate the benefit of a molecularly targeted agent for the treatment of HCC, the median survival of the patients receiving the placebo was 34 weeks, as compared with 46 weeks for patients receiving sorafenib. The median time to progression was 12 weeks for the placebo group but 24 weeks among the patients randomized to sorafenib. Based on these results, sorafenib can be considered the standard of care for patients with advanced and metastatic HCC with good liver function who are not candidates for curative or locoregional therapies. Despite these results, the prognosis for patients with HCC remains poor. Notably, only 2 % of patients receiving sorafenib had objective responses to the therapy, and the primary benefit was due to disease stabilization. Thus, the new study5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar in this issue showing suppression of hepatitis B genomes by concurrent infection with an attenuated strain of vaccinia deserves more detailed analysis. The authors documented that hepatitis B genomes were effectively suppressed during the period of treatment with JX-594, and that they increased when this therapy was held. Upon resumption of therapy with JX-594, further suppression of hepatitis B genomes was observed. Effective long-term control of hepatitis B due to concurrent treatment with an oncolytic virus was not specifically addressed in this study, but it remains an important issue because of the high incidence of liver failure among these patients. In addition, patients with HCC effectively controlled by locoregional therapy remain at high risk for a second HCC.11Varela M Sala M Llovet JM Bruix J Treatment of hepatocellular carcinoma: is there an optimal strategy?.Cancer Treat Rev. 2003; 29: 99-104Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,12Llovet JM Treatment of hepatocellular carcinoma.Curr Treat Options Gastroenterol. 2004; 7: 431-441Crossref PubMed Scopus (44) Google Scholar Among patients with early-stage HCC who are amenable to resection, 50 % to 80 % will have a recurrence within 5 years after the resection. The recurrences may be due to independent clones of tumor cells arising from premalignant cells exposed to continued active hepatitis or due to occult metastases from the primary tumor. Thus, the report by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar may suggest a dual function for JX-594 in treating both the pre-existing macroscopic and microscopic disease, as well as potentially inhibiting or delaying the transformation of premalignant clones of HCC. Although the data discussed are limited to three patients, the effect observed is of critical importance and requires more detailed analysis in subsequent controlled trials. Oncolytic viruses have been developed with the objective of exploiting tumor-selective replication of the virus followed by lysis of the tumor cell by mature virons and subsequent infection of additional tumor cells.13Kelley E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar Ongoing viral replication has been limited by the rapid development of neutralizing antibody against the virus. ONYX-015, an E1b-55K-deleted adenovirus, is the prototype of an oncolytic virus. It has been extensively studied in phase I/II/III clinical trials and has recently been approved in China for treatment of head and neck cancer by local injection.14Kirn DH The end of the beginning: oncolytic virotherapy achieves clinical proof-of-concept.Mol Ther. 2006; 13: 237-238Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,15Garber K China approves world's first oncolytic virus therapy for cancer treatment.J Natl Cancer Inst. 2006; 98: 298-300Crossref PubMed Scopus (335) Google Scholar Clinical studies demonstrated rapid induction of high titers of neutralizing antibody, and limited activity was observed in patients treated by intravenous administration of ONYX-015. The data presented by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar demonstrate secondary and tertiary peaks of viral genomes in the circulation of patients with repeated treatment despite the presence of high titers of neutralizing antibody. The capacity of JX-594 to replicate and infect cells even in the presence of high titers of neutralizing antibody, as indicated by the secondary and tertiary peaks of viral DNA in the circulation, suggests that JX-594 may eventually be suitable for systemic treatment of HCC and other malignancies. The increasing use of molecularly targeted agents has ushered in a new era for analysis of clinic response to therapy. Unlike that of traditional cytotoxic agents, the activity of many targeted agents is not reliably captured by traditional anatomic measurement of tumor size. An example is Gleevec (imatinib mesylate), a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors.16Druker BJ Current treatment approaches for chronic myelogenous leukemia.Cancer J. Sudbury, MA2001: S14-18Google Scholar,17Maki RG Recent advances in therapy for gastrointestinal stromal tumors.Curr Oncol Rep. 2007; 9: 165-169Crossref PubMed Scopus (14) Google Scholar Recent studies have demonstrated that measurement of tumor cell viability by uptake of radioactively labeled glucose—positron emission tomography (PET)—is highly predictive of response to therapy with Gleevec, whereas anatomic measurements of tumor size are less predictive and can even lead to an erroneous assessment of tumor progression among patients responding to the treatment.18Antoch G Kanja J Bauer S Kuehl H Renzing-Koehler K Schuette J et al.Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors.J Nucl Med. 2004; 45: 357-365PubMed Google Scholar,19Choi H Response evaluation of gastrointestinal stromal tumors.Oncologist. 2008; 13 (suppl. 2): 4-7Crossref PubMed Scopus (191) Google Scholar Similar results have been observed with ONYX-015, with which transient increases in tumor size were paradoxically associated with clinical responses and prolonged survival.20Sze DY Freeman SM Slonim SM Samuels SL Andrews JC Hicks M et al.Dr. Gary J. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival.J Vasc Interv Radiol. 2003; 14: 279-290Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,21Reid TR Freeman S Post L McCormick F Sze DY Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin.Cancer Gene Ther. 2005; 12: 673-681Crossref PubMed Scopus (83) Google Scholar The transient increases in tumor size following treatment with ONYX-015 were attributed to tumor-selective viral infection and subsequent inflammation localized to the tumor. The report by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar demonstrates extensive necrosis of the tumor masses following treatment with JX-594. The necrosis was confirmed by quantification of loss of metabolic activity within the tumor by PET scan as well as significant decreases in circulating markers of tumor activity, including α-fetoprotein (AFP) and VEGF. Extensive necrosis of the tumor masses can lead to delayed resorption of the measurable tumor mass and a prolonged time interval before the size of the tumor has decreased sufficiently to achieve a partial or complete response by size based criteria. Consequently, response to treatment, as determined by traditional size based criteria, may significantly lag metabolic response criteria as determined by PET scan and biochemical markers such as AFP and VEGF. In summary, HCC is a common cancer worldwide, with a rising incidence in the United States. Despite extensive study, the treatment options for patients with inoperable cancer are very limited and the overall prognosis for these patients is poor because of both the cancer and the underlying cirrhosis and related comorbidities. Although the study described by Liu et al.5Liu T-C Hwang T Park B-H Bell J Kirn DH The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma.Mol Ther. 2008; 16: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar is small, the reported clinical results coupled with the suppression of hepatitis B DNA pave the way for more detailed studies of this oncolytic vaccinia virus for the treatment of HCC.