VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects
Miriam Bazan-Peregrino, Rocio Garcia-Carbonero, Berta Laquente, Rafael Álvarez, Ana Mato-Berciano, Marta Gimenez-Alejandre, Sara Morgado, Alba Rodríguez-García, Maria V Maliandi, M Carmen Riesco, Rafael Moreno, Mireia M Ginestà, Mercedes Perez-Carreras, Joan B Gornals, Susana Prados, Sofía Perea, Gabriel Capella, Ramon Alemany, Ramon Salazar, Emma Blasi, Carmen Blasco, Manel Cascallo, Manuel Hidalgo, Miriam Bazan-Peregrino, Rocio Garcia-Carbonero, Berta Laquente, Rafael Álvarez, Ana Mato-Berciano, Marta Gimenez-Alejandre, Sara Morgado, Alba Rodríguez-García, Maria V Maliandi, M Carmen Riesco, Rafael Moreno, Mireia M Ginestà, Mercedes Perez-Carreras, Joan B Gornals, Susana Prados, Sofía Perea, Gabriel Capella, Ramon Alemany, Ramon Salazar, Emma Blasi, Carmen Blasco, Manel Cascallo, Manuel Hidalgo
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer.
Methods: VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography.
Results: VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption.
Conclusions: VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma.
Trial registration number: EudraCT number: 2012-005556-42 and NCT02045589.
Keywords: gastrointestinal neoplasms; immunity; investigational; oncolytic viruses; therapies; tumor microenvironment.
Conflict of interest statement
Competing interests: MB-P, AM-B, MG-A, SM, MVM, EB, CB and MC are employees and RAlm and MH are consultants for VCN Biosciences. MC and RAlm are co-inventors of one patent application concerning the expression of hyaluronidase by oncolytic adenoviruses. MC, RAlm and GC have ownership interest in VCN Biosciences. MH is a founder and stock holder of Champions Oncology and Nelum Pharmaceuticals; he is a stock holder of Agenus, Pharmacyte, Highlight Pharmaceuticals, Oncomatrix, Inxmed and BMS; he is Board of Directors at BMS; he has received research support from Erytech, PanCan, TBA alliance and has received honorarium from Agenus, Oncomatrix, InxMed, Khar, Genechem, Cantargia, BMS, and royalties from Myriad and Kahr. RGC has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Mida-tech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Figures
References
- Korc M. Pancreatic cancer-associated stroma production. Am J Surg 2007;194:S84–6. 10.1016/j.amjsurg.2007.05.004
- Sun C, Ansari D, Andersson R, et al. . Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012;18:4944–58. 10.3748/wjg.v18.i35.4944
- Rasheed ZA, Matsui W, Maitra A. Pathology of pancreatic stroma in PDAC. In: Grippo PJ, Munshi HG, eds. Pancreatic cancer and tumor microenvironment. Trivandrum (India), 2012.
- Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016;22:2678–700. 10.3748/wjg.v22.i9.2678
- Chu GC, Kimmelman AC, Hezel AF, et al. . Stromal biology of pancreatic cancer. J Cell Biochem 2007;101:887–907. 10.1002/jcb.21209
- Erkan M, Reiser-Erkan C, Michalski CW, et al. . Tumor microenvironment and progression of pancreatic cancer. Exp Oncol 2010;32:128–31.
- Whatcott CJ, Han H, Posner RG, et al. . Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look. Cancer Discov 2011;1:291–6. 10.1158/-11-0136
- Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 2004;4:528–39. 10.1038/nrc1391
- Bertrand P, Girard N, Delpech B, et al. . Hyaluronan (hyaluronic acid) and hyaluronectin in the extracellular matrix of human breast carcinomas: comparison between invasive and non-invasive areas. Int J Cancer 1992;52:1–6. 10.1002/ijc.2910520102
- Seufferlein T, Ducreux M, Hidalgo M, et al. . More than a Gel & Hyaluronic Acid, a Central Component in the Microenvironment of Pancreatic Cancer. Eur Oncol Haematol 2018;14:40–4. 10.17925/EOH.2018.14.1.40
- Oettle H, Post S, Neuhaus P, et al. . Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267–77. 10.1001/jama.297.3.267
- Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer 2006;6:583–92. 10.1038/nrc1893
- Feig C, Gopinathan A, Neesse A, et al. . The pancreas cancer microenvironment. Clin Cancer Res 2012;18:4266–76. 10.1158/1078-0432.CCR-11-3114
- Nakazawa H, Yoshihara S, Kudo D, et al. . 4-Methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells. Cancer Chemother Pharmacol 2006;57:165–70. 10.1007/s00280-005-0016-5
- Provenzano PP, Cuevas C, Chang AE, et al. . Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418–29. 10.1016/j.ccr.2012.01.007
- Singha NC, Nekoroski T, Zhao C, et al. . Tumor-Associated hyaluronan limits efficacy of monoclonal antibody therapy. Mol Cancer Ther 2015;14:523–32. 10.1158/1535-7163.MCT-14-0580
- Hendifar A, Bullock A. Breaking the Barrier—PEGylated RecombinantHuman Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma. Oncol Hematol Rev 2017;13:107–11. 10.17925/OHR.2017.13.02.107
- Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, et al. . Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res 2015;21:1406–18. 10.1158/1078-0432.CCR-14-2213
- Guedan S, Rojas JJ, Gros A, et al. . Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther 2010;18:1275–83. 10.1038/mt.2010.79
- Vives M, Ginestà MM, Gracova K, et al. . Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int J Cancer 2013;133:2464–72. 10.1002/ijc.28259
- Janssen J, Schlörer E, Greiner L. EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis, and focal pancreatic lesions. Gastrointest Endosc 2007;65:971–8. 10.1016/j.gie.2006.12.057
- Iglesias-Garcia J, Lindkvist B, Lariño-Noia J, et al. . Endoscopic ultrasound elastography. Endosc Ultrasound 2012;1:8–16. 10.4103/2303-9027.117764
- Alvarez R, Musteanu M, Garcia-Garcia E, et al. . Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 2013;109:926–33. 10.1038/bjc.2013.415
- Hecht JR, Bedford R, Abbruzzese JL, et al. . A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003;9:555–61.
- Liang M, Oncorine LM. Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets 2018;18:171–6. 10.2174/1568009618666171129221503
- Conry RM, Westbrook B, McKee S, et al. . Talimogene laherparepvec: first in class oncolytic virotherapy. Hum Vaccin Immunother 2018;14:839–46. 10.1080/21645515.2017.1412896
- Garcia-Carbonero R, Gil Martín M, Alvarez Gallego R, et al. . Systemic administration of the hyaluronidase-expressing oncolytic adenovirus VCN-01 in patients with advanced or metastatic pancreatic cancer: first-in-human clinical trial. Annals Oncol 2019;30:v271–2. 10.1093/annonc/mdz247.037
- Thompson CB, Shepard HM, O'Connor PM, et al. . Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther 2010;9:3052–64. 10.1158/1535-7163.MCT-10-0470
- Jacobetz MA, Chan DS, Neesse A, et al. . Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62:112–20. 10.1136/gutjnl-2012-302529
- Cascallo M, Alonso MM, Rojas JJ, et al. . Systemic toxicity-efficacy profile of ICOVIR-5, a potent and selective oncolytic adenovirus based on the pRB pathway. Mol Ther 2007;15:1607–15. 10.1038/sj.mt.6300239
- de Sostoa J, Fajardo CA, Moreno R, et al. . Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J Immunother Cancer 2019;7:19. 10.1186/s40425-019-0505-4
- Toro Bejarano M, Merchan JR. Targeting tumor vasculature through oncolytic virotherapy: recent advances. Oncolytic Virother 2015;4:169–81. 10.2147/OV.S66045
- Bazan-Peregrino M, Sainson RCA, Carlisle RC, et al. . Combining virotherapy and angiotherapy for the treatment of breast cancer. Cancer Gene Ther 2013;20:461–8. 10.1038/cgt.2013.41
- Bockorny B, Semenisty V, Macarulla T, et al. . BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the combat trial. Nat Med 2020;26:878–85. 10.1038/s41591-020-0880-x
- Royal RE, Levy C, Turner K, et al. . Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828–33. 10.1097/CJI.0b013e3181eec14c
- O'Reilly EM, DY O, Dhani N. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol 2019.
- Pascual-Pasto G, Bazan-Peregrino M, Olaciregui NG, et al. . Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Sci Transl Med 2019;11. 10.1126/scitranslmed.aat9321. [Epub ahead of print: 23 01 2019].
- Ramanathan RK, McDonough SL, Philip PA, et al. . Phase Ib/II randomized study of Folfirinox plus PEGylated recombinant human hyaluronidase versus Folfirinox alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol 2019;37:1062–9. 10.1200/JCO.18.01295
- Tempero MA, Van Cutsem E, Sigal D, et al. . HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA). JCO 2020;38:638–38. 10.1200/JCO.2020.38.4_suppl.638
- Rhim AD, Oberstein PE, Thomas DH, Rhim Andrew D, Thomas Dafydd H, et al. . Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014;25:735–47. 10.1016/j.ccr.2014.04.021
Source: PubMed