Abstract
Cancer is often conceptualized as principally a cellular process, one initiated by genetic mutations in a progenitor cell that result in dysregulated cell proliferation. Accordingly, investigations into mechanisms of treatment resistance to cancer therapies often revolve around the biologic barriers to the therapies. However, there is a growing appreciation for the unique biomechanical properties for tumors and the role they play in treatment resistance for conventional, molecularly targeted, and immune-mediated cancer therapies. This understanding has inspired the development of pharmacologic and interventional approaches to overcome these barriers. Of particular promise are perfusion-enhanced drug delivery (PEDD) approaches that potentially allow for comprehensive tumor coverage with increased delivery pressure and prevention of reflux to drive therapeutics into the tumor parenchyma. In this review, we summarize the key features of the tumor microenvironment that drive tumor progression and impose barriers to anti-cancer therapies. We highlight the rationale and application of pharmacologic approaches and interventional drug delivery devices designed to overcome these impediments. We additionally contextualize these concepts by illustrating their application to the treatment of uveal melanoma liver metastases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
All data will be made available upon reasonable request.
References
Nia HT, Munn LL, Jain RK. Physical traits of cancer. Science 2020;370:eaaz0868.
Noble R, Burri D, Sueur CL, Lemant J, Viossat Y, Kather JN, et al. Spatial structure governs the mode of tumour evolution. Nat Ecol Evol. 2022;6:207–17.
Huang A, Pressnall MM, Lu R, Huayamares SG, Griffin JD, Groer C, et al. Human intratumoral therapy: linking drug properties and tumor transport of drugs in clinical trials. J Control Release. 2020;326:203–21.
Zanotelli MR, Reinhart-King CA. Biomechanics in Oncology. Adv Exp Med Biol. 2018;1092:91–112.
Khawar IA, Kim JH, Kuh HJ. Improving drug delivery to solid tumors: priming the tumor microenvironment. J Control Release. 2015;201:78–89.
Sheth RA, Hesketh R, Kong DS, Wicky S, Oklu R. Barriers to drug delivery in interventional oncology. J Vasc Int Radiol. 2013;24:1201–7. http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=23735316&retmode=ref&cmd=prlinks.
Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516.
Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2012;21:418–29.
Wang-Gillam A. Targeting stroma: a tale of caution. J Clin Oncol. 2019;37:JCO.19.00056.
Bazan-Peregrino M, Garcia-Carbonero R, Laquente B, Álvarez R, Mato-Berciano A, Gimenez-Alejandre M, et al. VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects. J Immunother Cancer. 2021;9:e003254.
Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol: Offic J Am Soc Clin Oncol. 2013;31:2205–18. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.46.3653.
Mpekris F, Baish JW, Stylianopoulos T, Jain RK. Role of vascular normalization in benefit from metronomic chemotherapy. Proc Natl Acad Sci. 2017;114:1994–9.
Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21:541–57.
Qu S, Worlikar T, Felsted AE, Ganguly A, Beems MV, Hubbard R, et al. Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer. 2020;8:e000200.
Bilusic M, Gulley JL. Editorial: Local Immunotherapy: A Way to Convert Tumors From “Cold” to “Hot”. J Natl Cancer Inst. 2017;109:djx132.
Murthy V, Minehart J, Sterman DH. Local immunotherapy of cancer: innovative approaches to harnessing tumor-specific immune responses. J Natl Cancer Inst. 2017;109. https://doi.org/10.1093/jnci/djx097.
Andtbacka RHI, Ross M, Puzanov I, Milhem M, Collichio F, Delman KA, et al. Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. Ann Surg Oncol. 2016;23:4169–77.
Munoz NM, Williams M, Dixon K, Dupuis C, McWatters A, Avritscher R, et al. Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy. J Immunother Cancer. 2021;9:e001800. https://jitc.bmj.com/lookup/doi/10.1136/jitc-2020-001800.
Sheth RA, Murthy R, Hong DS, Patel S, Overman MJ, Diab A, et al. Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer. JAMA Network Open. 2020;3:e207911–e207911. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2768765.
Lohr F, Huang Q, Hu K, Dewhirst MW, Li CY. Systemic vector leakage and transgene expression by intratumorally injected recombinant adenovirus vectors. Clin Cancer Res Off J Am Assoc Cancer Res. 2001;7:3625–8.
Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, Baere Tde, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29:2163–74.
Mehta AM, Sonabend AM, Bruce JN. Convection-Enhanced Delivery. Neurotherapeutics 2017;14:358–71.
Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, et al. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg. 2005;103:923–9.
Sillay KA, McClatchy SG, Shepherd BA, Venable GT, Fuehrer TS. Image-guided Convection-enhanced Delivery into Agarose Gel Models of the Brain. J Vis Exp. 2014;e51466. https://doi.org/10.3791/5146.
Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro-Oncol. 2010;12:871–81.
Hu J, Albadawi H, Chong BW, Deipolyi AR, Sheth RA, Khademhosseini A, et al. Advances in Biomaterials and Technologies for Vascular Embolization. Adv Mater (Deerfield Beach, Fla). 2019;31:e1901071. https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201901071.
Rose SC, Narsinh KH, Newton IG. Quantification of Blood Pressure Changes in the Vascular Compartment When Using an Anti-Reflux Catheter during Chemoembolization versus Radioembolization: a retrospective case series. J Vasc Inter Radio. 2017;28:103–10.
Fischman AM, Ward TJ, Patel RS, Arepally A, Kim E, Nowakowski FS, et al. Prospective, Randomized Study of Coil Embolization versus Surefire Infusion System during Yttrium-90 Radioembolization with Resin Microspheres. J Vasc Inter Radio. 2014;25:1709–16.
Pasciak AS, McElmurray JH, Bourgeois AC, Heidel RE, Bradley YC. The Impact of an Antireflux Catheter on Target Volume Particulate Distribution in Liver-Directed Embolotherapy: a pilot study. J Vasc Inter Radio. 2015;26:660–9.
d’Abadie P, Belgium D of NM Saint Luc University Hospital and King Albert II Cancer Institute, Brussels, Walrand S, Goffette P, Amini N, van Maanen A, et al. Antireflux catheter improves tumor targeting in liver radioembolization with resin microspheres. Diagn Inter Radio. 2021;27:768–73.
Arepally A, Chomas J, Katz SC, Jaroch D, Kolli KP, Prince E, et al. Pressure-Enabled Drug Delivery Approach in the Pancreas with Retrograde Venous Infusion of Lipiodol with Ex Vivo Analysis. Cardiovasc Inter Rad. 2021;44:141–9.
Adusumilli PS, Zauderer MG, Riviere I, Solomon SB, Rusch VW, O’Cearbhaill RE, et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 2021;11:candisc.0407.2021.
Chai LF, Hardaway JC, Heatherton KR, O’Connell KP, LaPorte JP, Guha P, et al. Regional Delivery of CAR-T Effectively Controls Tumor Growth in Colorectal Liver Metastasis Model. J Surg Res. 2022;272:37–50.
Szeligo BM, Ivey AD, Boone BA. Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases. Cancers 2021;13:3426.
Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015;64:817–29.
Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27:152–64.
Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2019;29:561–8.
Meijer TS, Burgmans MC, Leede EM de, Geus-Oei LF de, Boekestijn B, Handgraaf HJM, et al. Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study. Ann Surg Oncol. 2021;28:1130–41.
Author information
Authors and Affiliations
Contributions
RAS and SP conceived, wrote, and edited the paper.
Corresponding author
Ethics declarations
Competing interests
RAS reports receiving consulting fees from Trisalus and Medtronic as well as research support from Boston Scientific. All other authors report no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pavuluri, S., Sheth, R.A. Overcoming biophysical barriers with innovative therapeutic delivery approaches. Cancer Gene Ther 29, 1847–1853 (2022). https://doi.org/10.1038/s41417-022-00529-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41417-022-00529-3