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Shedding Light on Tumor Targeting by Adenovirus
editorial
© The American Society of Gene Therapy
doi:10.1038/sj.mt.6300158
See page 921
Shedding Light on Tumor Targeting by Adenovirus
A
substantial challenge for gene therapists is achieving sufficient levels of gene delivery in target tissue to elicit an acceptable therapeutic effect. Localized gene transfer in vivo is often not a viable or even preferred option, for example, in cancer gene therapy targeted to disseminated metastases. In such scenarios, injection of the therapeutic vector into the bloodstream is the only viable route but is compromised by the relatively poor tumor targeting capacity of currently available vectors. The development and optimization of more effective vectors is a key area of development in the cancer gene therapy field. Of particular interest are systems based on oncolytic measles virus, herpesvirus, and adenovirus (Ad). In this issue of Molecular Therapy, Mocanu and colleagues1 use longitudinal bioluminescence imaging to define the transduction kinetics of adenoviruses. Elegant use of imaging defined tumor and off-target transduction mediated by adenoviruses transcriptionally controlled for Epstein-Barr virus (EBV)–positive xenografts in SCID mice after intravenous delivery. As expected, tumor transgene levels were higher using EBV-targeted transcriptional control than with the relatively weak but “constitutive” simian virus 40 promoter. Because liver transduction was significant, the authors pursued several pharmacological interventions to improve tumor-specific virus control. STI571 (Glivec) administration reduced tumor interstitial fluid pressure, diminished activation of the plateletderived growth factor–β receptor, and, interestingly, improved the tumor-to-liver transduction ratio. Hence, combinatorial approaches may offer improved tumor targeting by Ad. Unfortunately, the effect of STI571 on tumor burden after intravascular administration of conditionally replicating EBV-targeted adenoviruses was not evaluated in this study. The authors chose intratumoral injection of virus in conjunction with STI571 to evaluate efficacy, although STI571 did not modulate tumor growth despite enhancing initial tumor transgene levels. Molecular Therapy vol. 15 no. 5 may 2007
In spite of its shortcomings, this study highlights several important issues. First, instilling transcriptional control of Ad vectors is a logical strategy for improving selectivity. However, transcriptional control does not influence Ad biodistribution per se. Assessment of vector biodistribution is critical in defining site-selective targeting of any gene-delivery system. For adenoviruses this should not be accomplished solely by assessment of vector and transgene at late time points but should also involve assessment of virus-uptake kinetics at very early time points after injection, ideally involving systematic analysis of liver, splenic, and target-tissue uptake. Because Ad interaction with the host is highly dynamic, early analysis will provide essential information on the possibility that any modifications in protocol design could have an impact on native vector tropism and on target-tissue homing. In the case of oncolytic therapy this is particularly relevant in that off-target vector replication may be a critical determinant of therapeutic index. Second, marginal improvements in Ad targeting, at either the transductional or transcriptional level, or indeed both, are unlikely to have any significant impact on efficacy. Third, it is imperative to determine the effect of drug interventions on transcriptional activity of promoters, because this will influence interpretation and potential translation aspects of any combinatorial approach to the clinic. Several other approaches exist to improve Ad-mediated delivery to tumors after intravascular injection. Targeting strategies include fiber/ serotype swapping, as well as use of peptideand antibody-based targeting regimens (see review2). Ascertaining the most effective targeting regimen is difficult and requires careful consideration. Thus far, switching to CD46-utilizing adenoviruses offers a high-affinity alternative virus–receptor interaction,3 potentially allowing the targeting of CD46-overexpressing tumors in vivo. At present there is an incomplete understanding of the complex mechanisms that govern in vivo Ad biodistribution when delivered via the 841
© The American Society of Gene Therapy
editorial
intravascular route. Important aspects include blood-cell interactions, binding of Ad to plasma proteins, and the affinity of interaction with cellular receptor mechanism(s) at target sites. Approaches to understanding and modifying these interactions may further improve tumor delivery. Hence, highly efficient and selective tumor targeting via intravascular injection remains a formidable challenge. Approaches to improving delivery with pharmacological enhancement of tumor-virus uptake with additional transcriptional control, as documented by Mocanu et al.,1 perhaps in conjunction with vector
842
engineering strategies, may further improve the efficacy of cancer gene therapy.
Andrew H Baker Associate Editor
REFERENCES 1. 2. 3.
Mocanu, JD, Yip, KW, Alajez, NM, Shi, W, Li, J-H, Lunt, SJ et al. (2007). Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy. Mol Ther 15: 921–929. Nicklin, SA, Wu, E, Nemerow, G and Baker, AH (2005). The influence of adenovirus fiber structure and function on vector development for gene therapy. Mol Ther 12: 384–393. Gaggar, A, Shayakhmetov, DM and Lieber, A (2003). CD46 is a cellular receptor for group B adenoviruses. Nat Med 9: 1–5.
www.moleculartherapy.org vol. 15 no. 5 may 2007
© The American Society of Gene Therapy
doi:10.1038/sj.mt.6300158
See page 921
Shedding Light on Tumor Targeting by Adenovirus
A
substantial challenge for gene therapists is achieving sufficient levels of gene delivery in target tissue to elicit an acceptable therapeutic effect. Localized gene transfer in vivo is often not a viable or even preferred option, for example, in cancer gene therapy targeted to disseminated metastases. In such scenarios, injection of the therapeutic vector into the bloodstream is the only viable route but is compromised by the relatively poor tumor targeting capacity of currently available vectors. The development and optimization of more effective vectors is a key area of development in the cancer gene therapy field. Of particular interest are systems based on oncolytic measles virus, herpesvirus, and adenovirus (Ad). In this issue of Molecular Therapy, Mocanu and colleagues1 use longitudinal bioluminescence imaging to define the transduction kinetics of adenoviruses. Elegant use of imaging defined tumor and off-target transduction mediated by adenoviruses transcriptionally controlled for Epstein-Barr virus (EBV)–positive xenografts in SCID mice after intravenous delivery. As expected, tumor transgene levels were higher using EBV-targeted transcriptional control than with the relatively weak but “constitutive” simian virus 40 promoter. Because liver transduction was significant, the authors pursued several pharmacological interventions to improve tumor-specific virus control. STI571 (Glivec) administration reduced tumor interstitial fluid pressure, diminished activation of the plateletderived growth factor–β receptor, and, interestingly, improved the tumor-to-liver transduction ratio. Hence, combinatorial approaches may offer improved tumor targeting by Ad. Unfortunately, the effect of STI571 on tumor burden after intravascular administration of conditionally replicating EBV-targeted adenoviruses was not evaluated in this study. The authors chose intratumoral injection of virus in conjunction with STI571 to evaluate efficacy, although STI571 did not modulate tumor growth despite enhancing initial tumor transgene levels. Molecular Therapy vol. 15 no. 5 may 2007
In spite of its shortcomings, this study highlights several important issues. First, instilling transcriptional control of Ad vectors is a logical strategy for improving selectivity. However, transcriptional control does not influence Ad biodistribution per se. Assessment of vector biodistribution is critical in defining site-selective targeting of any gene-delivery system. For adenoviruses this should not be accomplished solely by assessment of vector and transgene at late time points but should also involve assessment of virus-uptake kinetics at very early time points after injection, ideally involving systematic analysis of liver, splenic, and target-tissue uptake. Because Ad interaction with the host is highly dynamic, early analysis will provide essential information on the possibility that any modifications in protocol design could have an impact on native vector tropism and on target-tissue homing. In the case of oncolytic therapy this is particularly relevant in that off-target vector replication may be a critical determinant of therapeutic index. Second, marginal improvements in Ad targeting, at either the transductional or transcriptional level, or indeed both, are unlikely to have any significant impact on efficacy. Third, it is imperative to determine the effect of drug interventions on transcriptional activity of promoters, because this will influence interpretation and potential translation aspects of any combinatorial approach to the clinic. Several other approaches exist to improve Ad-mediated delivery to tumors after intravascular injection. Targeting strategies include fiber/ serotype swapping, as well as use of peptideand antibody-based targeting regimens (see review2). Ascertaining the most effective targeting regimen is difficult and requires careful consideration. Thus far, switching to CD46-utilizing adenoviruses offers a high-affinity alternative virus–receptor interaction,3 potentially allowing the targeting of CD46-overexpressing tumors in vivo. At present there is an incomplete understanding of the complex mechanisms that govern in vivo Ad biodistribution when delivered via the 841
© The American Society of Gene Therapy
editorial
intravascular route. Important aspects include blood-cell interactions, binding of Ad to plasma proteins, and the affinity of interaction with cellular receptor mechanism(s) at target sites. Approaches to understanding and modifying these interactions may further improve tumor delivery. Hence, highly efficient and selective tumor targeting via intravascular injection remains a formidable challenge. Approaches to improving delivery with pharmacological enhancement of tumor-virus uptake with additional transcriptional control, as documented by Mocanu et al.,1 perhaps in conjunction with vector
842
engineering strategies, may further improve the efficacy of cancer gene therapy.
Andrew H Baker Associate Editor
REFERENCES 1. 2. 3.
Mocanu, JD, Yip, KW, Alajez, NM, Shi, W, Li, J-H, Lunt, SJ et al. (2007). Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy. Mol Ther 15: 921–929. Nicklin, SA, Wu, E, Nemerow, G and Baker, AH (2005). The influence of adenovirus fiber structure and function on vector development for gene therapy. Mol Ther 12: 384–393. Gaggar, A, Shayakhmetov, DM and Lieber, A (2003). CD46 is a cellular receptor for group B adenoviruses. Nat Med 9: 1–5.
www.moleculartherapy.org vol. 15 no. 5 may 2007