Mesenchymal Stem Cells Modified with a Single-chain Antibody Against EGFRvIII Successfully Inhibit the Growth of Human Xenograft Malignant Glioma

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Mar 23

PMID 20305783

Citations 36

Authors

Irina V Balyasnikova

Sherise D Ferguson

Sadhak Sengupta

Yu Han

Maciej S Lesniak

Affiliations

Soon will be listed here.

Abstract

Background: Glioblastoma multiforme is the most lethal brain tumor with limited therapeutic options. Antigens expressed on the surface of malignant cells are potential targets for antibody-mediated gene/drug delivery.

Principal Findings: In this study, we investigated the ability of genetically modified human mesenchymal stem cells (hMSCs) expressing a single-chain antibody (scFv) on their surface against a tumor specific antigen, EGFRvIII, to enhance the therapy of EGFRvIII expressing glioma cells in vivo. The growth of U87-EGFRvIII was specifically delayed in co-culture with hMSC-scFvEGFRvIII. A significant down-regulation was observed in the expression of pAkt in EGFRvIII expressing glioma cells upon culture with hMSC-scFvEGFRvIII vs. controls as well as in EGFRvIII expressing glioma cells from brain tumors co-injected with hMSC-scFvEGFRvIII in vivo. hMSC expressing scFvEGFRvIII also demonstrated several fold enhanced retention in EGFRvIII expressing flank and intracranial glioma xenografts vs. control hMSCs. The growth of U87-EGFRvIII flank xenografts was inhibited by 50% in the presence of hMSC-scFvEGFRvIII (p<0.05). Moreover, animals co-injected with U87-EGFRvIII and hMSC-scFvEGFRvIII intracranially showed significantly improved survival compared to animals injected with U87-EGFRvIII glioma cells alone or with control hMSCs. This survival was further improved when the same animals received an additional dosage of hMSC-scFvEGFRvIII two weeks after initial tumor implantation. Of note, EGFRvIII expressing brain tumors co-injected with hMSCs had a lower density of CD31 expressing blood vessels in comparison with control tumors, suggesting a possible role in tumor angiogenesis.

Conclusions/significance: The results presented in this study illustrate that genetically modified MSCs may function as a novel therapeutic vehicle for malignant brain tumors.

Citing Articles

A Systematic Review of Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Treatment for Glioblastoma.

Agosti E, Antonietti S, Ius T, Fontanella M, Zeppieri M, Panciani P Brain Sci. 2024; 14(11).

PMID: 39595821 PMC: 11591642. DOI: 10.3390/brainsci14111058.

The role of MSCs and CAR-MSCs in cellular immunotherapy.

Yan L, Li J, Zhang C Cell Commun Signal. 2023; 21(1):187.

PMID: 37528472 PMC: 10391838. DOI: 10.1186/s12964-023-01191-4.

Enhancing Anticancer Efficacy of Chemotherapeutics Using Targeting Ligand-Functionalized Synthetic Antigen Receptor-Mesenchymal Stem Cells.

Nethi S, Li X, Bhatnagar S, Prabha S Pharmaceutics. 2023; 15(6).

PMID: 37376189 PMC: 10304812. DOI: 10.3390/pharmaceutics15061742.

Multipurposing CARs: Same engine, different vehicles.

Hossian A, Hackett C, Brentjens R, Rafiq S Mol Ther. 2022; 30(4):1381-1395.

PMID: 35151842 PMC: 9077369. DOI: 10.1016/j.ymthe.2022.02.012.

Glioblastoma Multiforme-A Look at the Past and a Glance at the Future.

King J, Benhabbour S Pharmaceutics. 2021; 13(7).

PMID: 34371744 PMC: 8309001. DOI: 10.3390/pharmaceutics13071053.

References

Khakoo A, Pati S, Anderson S, Reid W, Elshal M, Rovira I . Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med. 2006; 203(5):1235-47. PMC: 2121206. DOI: 10.1084/jem.20051921. View

Huang P, Mukasa A, Bonavia R, Flynn R, Brewer Z, Cavenee W . Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci U S A. 2007; 104(31):12867-72. PMC: 1937558. DOI: 10.1073/pnas.0705158104. View

Lal A, Glazer C, Martinson H, Friedman H, Archer G, Sampson J . Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res. 2002; 62(12):3335-9. View

Patel D, Lahiji A, Patel S, Franklin M, Jimenez X, Hicklin D . Monoclonal antibody cetuximab binds to and down-regulates constitutively activated epidermal growth factor receptor vIII on the cell surface. Anticancer Res. 2007; 27(5A):3355-66. View

Wu J, Abe T, Inoue R, Fujiki M, Kobayashi H . IkappaBalphaM suppresses angiogenesis and tumorigenesis promoted by a constitutively active mutant EGFR in human glioma cells. Neurol Res. 2004; 26(7):785-91. DOI: 10.1179/016164104225014139. View

Luetzkendorf J, Mueller L, Mueller T, Caysa H, Nerger K, Schmoll H . Growth inhibition of colorectal carcinoma by lentiviral TRAIL-transgenic human mesenchymal stem cells requires their substantial intratumoral presence. J Cell Mol Med. 2009; 14(9):2292-304. PMC: 3822570. DOI: 10.1111/j.1582-4934.2009.00794.x. View

Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J . Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005; 65(8):3307-18. DOI: 10.1158/0008-5472.CAN-04-1874. View

Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain J . Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. 2009; 20(9):1596-1603. DOI: 10.1093/annonc/mdp032. View

Jost M, Huggett T, Kari C, Boise L, Rodeck U . Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem. 2000; 276(9):6320-6. DOI: 10.1074/jbc.M008210200. View

10.

Yang B, Wu X, Mao Y, Bao W, Gao L, Zhou P . Dual-targeted antitumor effects against brainstem glioma by intravenous delivery of tumor necrosis factor-related, apoptosis-inducing, ligand-engineered human mesenchymal stem cells. Neurosurgery. 2009; 65(3):610-24. DOI: 10.1227/01.NEU.0000350227.61132.A7. View

11.

Compte M, Cuesta A, Sanchez-Martin D, Alonso-Camino V, Vicario J, Sanz L . Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds. Stem Cells. 2008; 27(3):753-60. PMC: 2729675. DOI: 10.1634/stemcells.2008-0831. View

12.

Frederick L, Eley G, Wang X, James C . Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements. Neuro Oncol. 2001; 2(3):159-63. PMC: 1920493. DOI: 10.1093/neuonc/2.3.159. View

13.

Luwor R, Johns T, Murone C, Huang H, Cavenee W, Ritter G . Monoclonal antibody 806 inhibits the growth of tumor xenografts expressing either the de2-7 or amplified epidermal growth factor receptor (EGFR) but not wild-type EGFR. Cancer Res. 2001; 61(14):5355-61. View

14.

Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek A, Silberstein L . Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells. 2005; 24(4):1030-41. DOI: 10.1634/stemcells.2005-0319. View

15.

SUGAWA N, Ekstrand A, James C, Collins V . Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A. 1990; 87(21):8602-6. PMC: 55005. DOI: 10.1073/pnas.87.21.8602. View

16.

Gan H, Kaye A, Luwor R . The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci. 2009; 16(6):748-54. DOI: 10.1016/j.jocn.2008.12.005. View

17.

Kim S, Lim J, Park S, Jeong C, Oh J, Jeong M . Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer Res. 2008; 68(23):9614-23. DOI: 10.1158/0008-5472.CAN-08-0451. View

18.

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

19.

Moscatello D, Godwin A, Ramirez G, Gunn G, Zoltick P, Biegel J . Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995; 55(23):5536-9. View

20.

Boise L, Gonzalez-Garcia M, Postema C, Ding L, LINDSTEN T, Turka L . bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993; 74(4):597-608. DOI: 10.1016/0092-8674(93)90508-n. View