Under Pressure: Elevated Blood Pressure Enhances Targeting of Tumors by Oncolytic Viruses
Authors: Leonard W Seymour, Kerry D Fisher
Journal: Molecular Therapy (2016)

In this issue of Molecular Therapy, Miller et al. provide a timely and well-constructed demonstration of the influence that murine blood pressure can have on the efficacious delivery to tumors of systemically injected oncolytic viruses.1Miller A Nace R Ayala-Breton CC Steele M Bailey K Peng KW et al.Perfusion pressure is a critical determinant of the intratumoral extravasation of oncolytic viruses.Mol Ther. 2016; 24: 306-317Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The authors compared tumor delivery of vesicular stomatitis virus in mice with blood pressure elevated through exercise or depressed through the use of inhaled anesthesia (isoflurane). Under these contrasting conditions, levels of tumor infection (monitored longitudinally in living animals by daily high-resolution tomographic SPECT/CT imaging of the virally encoded sodium iodide symporter reporter transgene) were elevated as much as twofold in the exercise-treated mice compared to those treated under anesthesia. This enhanced delivery of the virus correlated with significantly improved anticancer activity of vesicular stomatitis virus in exercise-treated mice and also allowed over 100-fold greater recovery of infectious virus from tumors. These dramatic consequences reflecting different treatment strategies with the same agent (and dose) emphasize the need for standardized animal handling and anesthesia protocols, and may help explain variations often seen between similar agents used in different laboratories. The findings have implications far beyond the world of oncolytic virotherapy and potentially influence intravenous delivery of any macromolecular agent to systemic targets, including antibodies and other protein drugs. Systemic tumor targeting of macromolecular drugs and viruses has long been an important pharmacological goal that underpins treatment of metastatic cancer. The enhanced permeability and retention (EPR) effect of tumor vasculature2Matsumura Y Maeda H A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.Cancer Res. 1986; 46: 6387-6392PubMed Google Scholar has been widely described in animal tumor models, and to some extent in clinical disease, and has often been exploited to achieve selective delivery of macromolecular drugs to distant and disseminated disease.3Maeda H Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity.Adv Drug Deliv Rev. 2015; 91: 3-6Crossref PubMed Scopus (803) Google Scholar,4Seymour LW Passive tumor targeting of soluble macromolecules and drug conjugates.Crit Rev Ther Drug Carrier Syst. 1992; 9: 135-187PubMed Google Scholar,5Green NK Hale A Cawood R Illingworth S Herbert C Hermiston T et al.Tropism ablation and stealthing of oncolytic adenovirus enhances systemic delivery to tumors and improves virotherapy of cancer.Nanomedicine (Lond). 2012; 7: 1683-1695Crossref PubMed Scopus (21) Google Scholar,6Prabhakar U Maeda H Jain RK Sevick-Muraca EM Zamboni W Farokhzad OC et al.Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology.Cancer Res. 2013; 73: 2412-2417Crossref PubMed Scopus (1104) Google Scholar The EPR effect relies on the relatively high permeability of tumor-associated vasculature, allowing extravasation of fluid containing macromolecules and viruses that in most normal tissues remain in the bloodstream. The permeability of tumor vasculature is elevated by locally secreted permeabilizing factors (notably vascular endothelial growth factor, originally known as vascular permeability factor)7Senger DR Galli SJ Dvorak AM Perruzzi CA Harvey VS Dvorak HF Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.Science. 1983; 219: 983-985Crossref PubMed Scopus (3396) Google Scholar. This enhanced permeability is compounded by elevated interstitial hydrostatic pressure in tumors with concomitant poor interstitial fluid flow and lymphatic drainage. As a result, much of the extravasated fluid shunts through the perivascular tissues to re-enter the bloodstream in postcapillary venules. During this process many of the contained macromolecules become deposited in the perivascular tissues, producing the EPR effect. Many factors, including the differential pressure between the bloodstream and the perivascular tumor tissues, could predictably influence the level of extravasation of fluid (containing proteins and/or viruses) into tumor tissue. Accordingly, the findings by Miller et al. make intuitive sense in demonstrating a considerably higher level of tumor extravasation when comparing animals with mean arterial pressures of approximately 50 mm Hg (under isoflurane anesthesia) and 160 mm Hg (with exercise). As the authors note, blood pressure has previously been manipulated to increase the extravasation of drugs and macromolecules into tumors—although pharmacological interventions can more easily produce changes in blood pressure than can subjecting patients to enforced exercise.8Suzuki M Hori K Abe I Saito S Sato H A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II.J Natl Cancer Inst. 1981; 67: 663-669PubMed Google Scholar,9Li CJ Miyamoto Y Kojima Y Maeda H Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure.Br J Cancer. 1993; 67: 975-980Crossref PubMed Scopus (101) Google Scholar Perhaps the most elegant example was in a series of cancer patients who were treated with angiotensin II to elevate blood pressure and improve intra-arterial delivery of the macromolecular therapeutic SMANCS (styrene-maleic acid/anhydride copolymer-neocarzinostatin) in pioneering work led by Hiroshi Maeda in Japan in the 1980s and '90s.10Nagamitsu A Greish K Maeda H Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors.Jpn J Clin Oncol. 2009; 39: 756-766Crossref PubMed Scopus (148) Google Scholar In recent years, the main focus of this concept has been on promoting extravasation of therapeutics into tumors by decreasing the interstitial pressure in the tumors,11Azzi S Hebda JK Gavard J Vascular permeability and drug delivery in cancers.Front Oncol. 2013; 3: 211Crossref PubMed Scopus (203) Google Scholar and clearly both approaches should enhance fluid convection and drug delivery by increasing the pressure differences across the tumor vasculature. In addition to measuring effects on tumor delivery, Miller et al. used a sophisticated SPECT/CT analysis of the distances between infected tumor cells. Under anesthesia, tumors showed the largest infection "voids" and the most "patchy" infection patterns, whereas animals treated after exercise showed the most homogeneous distribution of infection. This is a very important finding because it suggests a qualitative improvement, not just a quantitative one, in the patterns of virus delivery under elevated blood pressure conditions. This finding is consistent with the concept that elevated arterial pressure can open up areas of the tumor vasculature that are normally only transiently perfused, and thereby access more regions of the tumor for infection. As mentioned above, the authors showed an approximately twofold rise in transgene expression by elevating blood pressure, whereas production of infectious virus particles increased 100-fold. One explanation for this could be that elevating the pressure enabled the viruses to infect a much larger number of tumor cells, spread through the tissue, giving rise to a much greater number of infectious progeny virus particles. Vascular normalization, using agents such as avastin, can decrease the permeability of tumor-associated vasculature, thereby reducing tumor interstitial fluid pressure.12Tong RT Boucher Y Kozin SV Winkler F Hicklin DJ Jain RK Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors.Cancer Res. 2004; 64: 3731-3736Crossref PubMed Scopus (984) Google Scholar Although this therapy can improve interstitial fluid convection and delivery of low-molecular-weight anticancer agents,13Goel S Duda DG Xu L Munn LL Boucher Y Fukumura D et al.Normalization of the vasculature for treatment of cancer and other diseases.Physiol Rev. 2011; 91: 1071-1121Crossref PubMed Scopus (1108) Google Scholar its inhibition of the EPR effect is unlikely to promote better delivery of macromolecules and virus particles. Most anesthetics depress cardiovascular functions and mediate a range of physiological effects.14Constantinides C Mean R Janssen BJ Effects of isoflurane anesthesia on the cardiovascular function of the C57BL/6 mouse.ILAR J. 2011; 52: e21-e31PubMed Google Scholar All inhalational anesthetics (except nitrous oxide) cause a fall in blood pressure, although isoflurane appears to have a greater effect than most through decreasing systemic vascular resistance coupled with vasodilation of the coronary artery. It follows that the use of isoflurane is likely to be counterproductive in studies of systemic targeting of drugs and viruses to tumors, and it would probably be optimal to avoid the use of all forms of anesthetic in order to maximize systemic delivery. It should, of course, be possible to enhance delivery further by elevating blood pressure, through exercise or hypertensive agents, and all these approaches can be considered in both preclinical and clinical models. However, the crucial message of this important study is that inhaled anesthetics should not be used for systemic delivery of oncolytic viruses.