Encapsulated Stem Cells Loaded with Hyaluronidase-expressing Oncolytic Virus for Brain Tumor Therapy

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2014 Oct 30

PMID 25352242

Citations 57

Authors

Jordi Martinez-Quintanilla

Derek He

Hiroaki Wakimoto

Ramon Alemany

Khalid Shah

Affiliations

Soon will be listed here.

Abstract

Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications.

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References

Shuster S, Frost G, Csoka A, Formby B, Stern R . Hyaluronidase reduces human breast cancer xenografts in SCID mice. Int J Cancer. 2002; 102(2):192-7. DOI: 10.1002/ijc.10668. View

Guedan S, Rojas J, Gros A, Mercade E, Cascallo M, Alemany R . Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther. 2010; 18(7):1275-83. PMC: 2911260. DOI: 10.1038/mt.2010.79. View

Ganesh S, Gonzalez-Edick M, Gibbons D, Van Roey M, Jooss K . Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models. Clin Cancer Res. 2008; 14(12):3933-41. DOI: 10.1158/1078-0432.CCR-07-4732. View

Prestwich G . Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J Control Release. 2011; 155(2):193-9. PMC: 3716467. DOI: 10.1016/j.jconrel.2011.04.007. View

Lang F, Bruner J, Fuller G, Aldape K, Prados M, Chang S . Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003; 21(13):2508-18. DOI: 10.1200/JCO.2003.21.13.2508. View

Baumgartner G . The impact of extracellular matrix on chemoresistance of solid tumors--experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy. Cancer Lett. 1998; 131(1):1-2. View

Kranzler J, Tyler M, Sonabend A, Ulasov I, Lesniak M . Stem cells as delivery vehicles for oncolytic adenoviral virotherapy. Curr Gene Ther. 2009; 9(5):389-95. PMC: 2790537. DOI: 10.2174/156652309789753347. View

Potter W, Kalil R, Kao W . Biomimetic material systems for neural progenitor cell-based therapy. Front Biosci. 2007; 13:806-21. DOI: 10.2741/2721. View

Markert J, Liechty P, Wang W, Gaston S, Braz E, Karrasch M . Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther. 2008; 17(1):199-207. PMC: 2834981. DOI: 10.1038/mt.2008.228. View

10.

Wakimoto H, Kesari S, Farrell C, Curry Jr W, Zaupa C, Aghi M . Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res. 2009; 69(8):3472-81. PMC: 2785462. DOI: 10.1158/0008-5472.CAN-08-3886. View

11.

Chiocca E, Abbed K, Tatter S, Louis D, Hochberg F, Barker F . A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther. 2004; 10(5):958-66. DOI: 10.1016/j.ymthe.2004.07.021. View

12.

Sasportas L, Kasmieh R, Wakimoto H, Hingtgen S, van de Water J, Mohapatra G . Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci U S A. 2009; 106(12):4822-7. PMC: 2660771. DOI: 10.1073/pnas.0806647106. View

13.

Rojas J, Guedan S, Searle P, Martinez-Quintanilla J, Gil-Hoyos R, Alcayaga-Miranda F . Minimal RB-responsive E1A promoter modification to attain potency, selectivity, and transgene-arming capacity in oncolytic adenoviruses. Mol Ther. 2010; 18(11):1960-71. PMC: 2990517. DOI: 10.1038/mt.2010.173. View

14.

Ma W, Fitzgerald W, Liu Q, OShaughnessy T, Maric D, Lin H . CNS stem and progenitor cell differentiation into functional neuronal circuits in three-dimensional collagen gels. Exp Neurol. 2004; 190(2):276-88. DOI: 10.1016/j.expneurol.2003.10.016. View

15.

Pluen A, Boucher Y, Ramanujan S, McKee T, Gohongi T, Di Tomaso E . Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc Natl Acad Sci U S A. 2001; 98(8):4628-33. PMC: 31885. DOI: 10.1073/pnas.081626898. View

16.

Abumaree M, Al Jumah M, Pace R, Kalionis B . Immunosuppressive properties of mesenchymal stem cells. Stem Cell Rev Rep. 2011; 8(2):375-92. DOI: 10.1007/s12015-011-9312-0. View

17.

Kauer T, Figueiredo J, Hingtgen S, Shah K . Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. Nat Neurosci. 2011; 15(2):197-204. PMC: 3601490. DOI: 10.1038/nn.3019. View

18.

Hansen K, Muller F, Messing M, Zeigler F, Loring J, Lamszus K . A 3-dimensional extracellular matrix as a delivery system for the transplantation of glioma-targeting neural stem/progenitor cells. Neuro Oncol. 2010; 12(7):645-54. PMC: 2940655. DOI: 10.1093/neuonc/noq002. View

19.

Lee D, Ahn Y, Kim S, Wang K, Cho B, Phi J . Targeting rat brainstem glioma using human neural stem cells and human mesenchymal stem cells. Clin Cancer Res. 2009; 15(15):4925-34. DOI: 10.1158/1078-0432.CCR-08-3076. View

20.

Stuckey D, Hingtgen S, Karakas N, Rich B, Shah K . Engineering toxin-resistant therapeutic stem cells to treat brain tumors. Stem Cells. 2014; 33(2):589-600. PMC: 4305025. DOI: 10.1002/stem.1874. View