Evaluation of MVA-5T4 As a Novel Immunotherapeutic Vaccine in Colorectal, Renal and Prostate Cancer

Amato, Robert J.; Stepankiw, Mika

doi:10.2217/fon.12.7

Cited by 13 publications

(12 citation statements)

References 25 publications

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“…MVA-5T4 (TroVax) is a vaccine based on a modified vaccinia virus engineered to express TPBG/5T4. 19 ABR-217620 (Anyara) consists of superantigen fused to a moiety of anti-5T4 antibody. 20 A1mcMMAF, also known as PF-06263507, is an antibody−drug conjugate (ADC) that consists of a microtubule disrupting agent, auristatin, conjugated to an anti-5T4 antibody.…”

Section: ■ Introductionmentioning

confidence: 99%

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Leal

Lin

et al. 2014

Mol. Pharmaceutics

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The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody-drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics.

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Section: ■ Introductionmentioning

confidence: 99%

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Leal

Lin

et al. 2014

Mol. Pharmaceutics

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“…Due to its viral replication potential being severely compromised, MVA has been used as a nonreplicating anti-cancer vector to deliver various transgenes rather than for replicating oncolytic virotherapy (Sutter and Moss, 1992;Carroll et al, 1997;Drexler et al, 1999). Currently, a modified version of the MVA strain is in clinical trials for treating various human cancers (Larocca Schlom, 2011;Amato et al, 2012;Gómez et al, 2013). Strain LC16m8 was developed in Japan in 1975, by passaging the Lister strain through primary rabbit kidney epithelial cells (PRK) at a low temperature (30°C) (Kenner et al, 2006).…”

Section: Origin Of Oncolytic Poxvirusesmentioning

confidence: 99%

“…SQPV was isolated from a grey squirrel (Sciurus carolinensis) in Maryland in 1953 and initially placed into the genus Leporipoxvirus by Kilham et al (1953); it was later thought to be a member of the genus Parapoxvirus (Housawi et al, 1998), but a sub- (Chen et al, 2001;Zhang et al, 2007;Kochneva et al, 2012;Chan and McFadden, 2014) Breast tumor model, Ovarian tumor model, etc (Hung et al, 2007;Zhang et al, 2007;Hiley et al, 2010;Gholami et al, 2014) Various solid tumors, Breast cancer (Gentschev et al, 2014;Mell et al, 2014) GLV-1h68*, GLV-1h99, GLV-1h108, VV-mIL2, VVhEA, VV-hup53, etc Wyeth Attenuated, transgenes inserted (Mastrangelo et al, 1999;Liu et al, 2014) Melanoma model, Bladder cancer model, etc (Mastrangelo et al, 1999;Gomella et al, 2001) Melanoma cancer, Liver cancer, etc (Mastrangelo et al, 1999;Park et al, 2008;Heo et al, 2013) JX-594* WR Attenuated, transgenes inserted (Gnant et al, 1999;McCart et al, 2001;Thorne et al, 2007;Parviainen et al, 2015) Colon cancer model. etc (Gnant et al, 1999;McCart et al, 2001;Autio et al, 2014) Various tumors (Zeh et al, 2015) JX-795, JX-963*, vvDD*, VV-TRAIL, etc MVA Severely attenuated, transgenes inserted (Sutter and Moss, 1992;Kochneva et al, 2012) Various cancer model (Drexler et al, 1999;Carroll et al, 1997) Various tumors (Larocca and Schlom, 2011;Amato et al, 2012;Gómez et al, 2013) MVA-5T4*, MVAhup53…”

Section: Origin Of Oncolytic Poxvirusesmentioning

confidence: 99%

“…However, it remains questionable as to whether MVA actually effectively induced protective immunity against smallpox, because these vaccinees could not be exposed to the real variola viruses. As mentioned above, MVA-based anticancer therapeutics are currently in clinical trials, but because viral replication competency is severely compromised, transgenes expressing MVA viruses are always used instead of the virus itself (Larocca and Schlom, 2011;Amato et al, 2012;Gómez et al, 2013). LC16m8 was produced by repeated passage of the Lister strain in cell culture and has a small plaque phenotype (Hashizume, 2004).…”

Section: Safety Of the Oncolytic Poxvirus Strainsmentioning

confidence: 99%

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Replicating poxviruses for human cancer therapy

Kim

2015

J Microbiol.

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Naturally occurring oncolytic viruses are live, replication-proficient viruses that specifically infect human cancer cells while sparing normal cell counterparts. Since the eradication of smallpox in the 1970s with the aid of vaccinia viruses, the vaccinia viruses and other genera of poxviruses have shown various degrees of safety and efficacy in pre-clinical or clinical application for human anti-cancer therapeutics. Furthermore, we have recently discovered that cellular tumor suppressor genes are important in determining poxviral oncolytic tropism. Since carcinogenesis is a multi-step process involving accumulation of both oncogene and tumor suppressor gene abnormalities, it is interesting that poxvirus can exploit abnormal cellular tumor suppressor signaling for its oncolytic specificity and efficacy. Many tumor suppressor genes such as p53, ATM, and RB are known to play important roles in genomic fidelity/maintenance. Thus, tumor suppressor gene abnormality could affect host genomic integrity and likely disrupt intact antiviral networks due to accumulation of genetic defects, which would in turn result in oncolytic virus susceptibility. This review outlines the characteristics of oncolytic poxvirus strains, including vaccinia, myxoma, and squirrelpox virus, recent progress in elucidating the molecular connection between oncogene/tumor suppressor gene abnormalities and poxviral oncolytic tropism, and the associated preclinical/clinical implications. I would also like to propose future directions in the utility of poxviruses for oncolytic virotherapy.

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“…Approximately 120,000 persons were vaccinated with MVA, primarily in West Germany and Turkey, as a part of smallpox eradication efforts and no significant safety concerns were identified in this context [31]. MVA has also been used as a vector for therapeutic cancer vaccine, advancing to phase III clinical trials in prostate cancer patients, and has been given to hematopoietic stem cell transplant (HSCT) recipients, with no significant safety concerns in either population [32] [33]. Interestingly, the route of administration of MVA has been shown to have a significant effect on immunogenicity, with similar responses to an intramuscular injection as to a 10-fold lower dose of intradermally administered MVA [34].…”

Section: Poxvirus Vectorsmentioning

confidence: 99%

Nonreplicating vectors in HIV vaccines

Johnson

Barouch²,

Baden³

2013

Current Opinion in HIV and AIDS

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Purpose of review We review the broad spectrum of nonreplicating viral vectors which have been studied extensively, from preclinical studies through clinical efficacy trials, and include some of our most promising HIV vaccine candidates. Recent findings The success of the RV144 trial, with an ALVAC (canarypox)-based regimen, contrasts with the failures of the Adenovirus 5-based regimens in the Step study, the Phambili study (HVTN 503), and the HVTN 505 study which was recently modified to halt vaccinations due to clinical futility. Summary The safety profile, immunogenicity, and variety of available candidates make the nonreplicating viral vectors attractive in HIV vaccine development. Building from the success of the RV144 study, further studies of Orthopoxvirus-based vaccines, including Vaccinia-based vaccines, are ongoing and planned for the future. Despite the failures of the Ad5-based vaccines in clinical efficacy trials, other adenovirus serotypes remain promising candidates, especially in prime-boost combination with other products, and with the potential use of mosaic inserts. Other nonreplicating viral vectors such as the rhabdoviruses, alphaviruses and the non-human adenoviruses, provide additional avenues for exploration.

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Evaluation of MVA-5T4 As a Novel Immunotherapeutic Vaccine in Colorectal, Renal and Prostate Cancer

Cited by 13 publications

References 25 publications

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

Replicating poxviruses for human cancer therapy

Nonreplicating vectors in HIV vaccines

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