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Oncolytic virotherapy for advanced liver tumours.

Chang JF, Chen PJ, Sze DY, Reid T, Bartlett D, Kirn DH, Liu TC - J. Cell. Mol. Med. (2008)

Bottom Line: Despite decades of research, effective novel therapies for these cancers are urgently needed.This platform can also exploit the advantage of multiple intrinsic anti-cancer therapeutic mechanisms, combining direct viral oncolysis with therapeutic transgene expression.Recent advances in pre-clinical and clinical studies are revealing the potential of this unique therapeutic class, in particular for liver cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO, USA.

ABSTRACT
Primary and metastatic neoplasms of the liver account for more than a million deaths per year worldwide. Despite decades of research, effective novel therapies for these cancers are urgently needed. Oncolytic virotherapeutics represent a novel class of pharmacophore that holds promise for the treatment of hepatic neoplasms. Cancer-specific replication is followed by oncolysis, virus spreading and infection of adjacent cancer cells. This process is then repeated. Virotherapeutics target multiple genetic pathways involved in carcino-genesis, and demonstrate activity against apoptosis-resistant tumour cells. This platform can also exploit the advantage of multiple intrinsic anti-cancer therapeutic mechanisms, combining direct viral oncolysis with therapeutic transgene expression. Recent advances in pre-clinical and clinical studies are revealing the potential of this unique therapeutic class, in particular for liver cancers. This review summarizes the available data on applying oncolytic virotherapeutics to hepatic neoplasms to date, and discusses the challenges and future directions for virotherapy.

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Related in: MedlinePlus

(A) Systemic JX-594 genome levels after intratumoural administration. Reproduced from [17]. (B) Mathematical modelling of oncolytic virus Onyx-015 replication after hepatic arterial infusion. Reproduced from [27].
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fig01: (A) Systemic JX-594 genome levels after intratumoural administration. Reproduced from [17]. (B) Mathematical modelling of oncolytic virus Onyx-015 replication after hepatic arterial infusion. Reproduced from [27].

Mentions: More recently, a clinical trial was conducted using oncolytic vaccinia virus JX-594 (TK-deleted/GM-CSF-expressing Wyeth strain vaccinia virus) in patients with liver tumours [17, 18]. The primary end-point is determination of MTD/MFD and safety. JX-594 was administered via direct IT injection. JX-594 was well tolerated at the MTD (3 × 109 pfu), with transient flu-like symptoms the most common AE. Transient asymptomatic hyperbilirubinemia at the highest dose level (3×109 pfu) was dose-limiting. Despite IT administration, JX-594 genomes were detected in peripheral venous circulation as soon as 15 min. after injection. Secondary and tertiary waves of JX-594 in the blood following replication were also detected (Fig. 1A). Interestingly, despite systemic exposure, there was no significant toxicity to liver or other organs (Fig. 2B). Viral replication was detected in distant tumour sites following JX-594 viremia. Antitumoural efficacy by response evaluation criteria in solid tumours (RECIST) criteria was demonstrated in 30% of evaluable patients, and in 80% when using the Choi criteria [17, 31]. Significant (>50%) reduction of serum tumour markers was also noted in several patients. Furthermore, the trial demonstrated the feasibility of re-dosing patients in the presence of neutralizing antibodies. Patients who developed new tumours after completing the initial JX-594 treatment course were given JX-594 into the new tumours. Despite the presence of high titres of neutralizing antibodies, these tumours responded to JX-594 administration similarly to the original tumours (Fig. 2A). This is consistent with previous reports that the presence of circulating neutralizing antibodies does not preclude the antitumoural efficacy of locally delivered oncolytic virus [5, 7]. Phase II study with IT JX-594 in HCC is underway.


Oncolytic virotherapy for advanced liver tumours.

Chang JF, Chen PJ, Sze DY, Reid T, Bartlett D, Kirn DH, Liu TC - J. Cell. Mol. Med. (2008)

(A) Systemic JX-594 genome levels after intratumoural administration. Reproduced from [17]. (B) Mathematical modelling of oncolytic virus Onyx-015 replication after hepatic arterial infusion. Reproduced from [27].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496138&req=5

fig01: (A) Systemic JX-594 genome levels after intratumoural administration. Reproduced from [17]. (B) Mathematical modelling of oncolytic virus Onyx-015 replication after hepatic arterial infusion. Reproduced from [27].
Mentions: More recently, a clinical trial was conducted using oncolytic vaccinia virus JX-594 (TK-deleted/GM-CSF-expressing Wyeth strain vaccinia virus) in patients with liver tumours [17, 18]. The primary end-point is determination of MTD/MFD and safety. JX-594 was administered via direct IT injection. JX-594 was well tolerated at the MTD (3 × 109 pfu), with transient flu-like symptoms the most common AE. Transient asymptomatic hyperbilirubinemia at the highest dose level (3×109 pfu) was dose-limiting. Despite IT administration, JX-594 genomes were detected in peripheral venous circulation as soon as 15 min. after injection. Secondary and tertiary waves of JX-594 in the blood following replication were also detected (Fig. 1A). Interestingly, despite systemic exposure, there was no significant toxicity to liver or other organs (Fig. 2B). Viral replication was detected in distant tumour sites following JX-594 viremia. Antitumoural efficacy by response evaluation criteria in solid tumours (RECIST) criteria was demonstrated in 30% of evaluable patients, and in 80% when using the Choi criteria [17, 31]. Significant (>50%) reduction of serum tumour markers was also noted in several patients. Furthermore, the trial demonstrated the feasibility of re-dosing patients in the presence of neutralizing antibodies. Patients who developed new tumours after completing the initial JX-594 treatment course were given JX-594 into the new tumours. Despite the presence of high titres of neutralizing antibodies, these tumours responded to JX-594 administration similarly to the original tumours (Fig. 2A). This is consistent with previous reports that the presence of circulating neutralizing antibodies does not preclude the antitumoural efficacy of locally delivered oncolytic virus [5, 7]. Phase II study with IT JX-594 in HCC is underway.

Bottom Line: Despite decades of research, effective novel therapies for these cancers are urgently needed.This platform can also exploit the advantage of multiple intrinsic anti-cancer therapeutic mechanisms, combining direct viral oncolysis with therapeutic transgene expression.Recent advances in pre-clinical and clinical studies are revealing the potential of this unique therapeutic class, in particular for liver cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO, USA.

ABSTRACT
Primary and metastatic neoplasms of the liver account for more than a million deaths per year worldwide. Despite decades of research, effective novel therapies for these cancers are urgently needed. Oncolytic virotherapeutics represent a novel class of pharmacophore that holds promise for the treatment of hepatic neoplasms. Cancer-specific replication is followed by oncolysis, virus spreading and infection of adjacent cancer cells. This process is then repeated. Virotherapeutics target multiple genetic pathways involved in carcino-genesis, and demonstrate activity against apoptosis-resistant tumour cells. This platform can also exploit the advantage of multiple intrinsic anti-cancer therapeutic mechanisms, combining direct viral oncolysis with therapeutic transgene expression. Recent advances in pre-clinical and clinical studies are revealing the potential of this unique therapeutic class, in particular for liver cancers. This review summarizes the available data on applying oncolytic virotherapeutics to hepatic neoplasms to date, and discusses the challenges and future directions for virotherapy.

Show MeSH
Related in: MedlinePlus