Generic placeholder image

Current Gene Therapy


ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Research Article

Novel Combination Oncolytic Adenoviral Gene Therapy Armed with Dm-dNK and CD40L for Breast Cancer

Author(s): Qiuli Wang, Muwen Yang, Ye Zhang, Li Zhong and Xinyu Zheng*

Volume 19 , Issue 1 , 2019

Page: [54 - 65] Pages: 12

DOI: 10.2174/1566523219666190307094713

Price: $65


Background: Both Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) suicide gene therapy and exogenous CD40 ligand (CD40L)-CD40 interaction in cancer via conditionally replicating adenovirus can selectively kill tumors without damaging normal tissues.

Objective: To further improve the cancer killing effect, we investigated the therapeutic effect of combined cancer gene therapy based on a selective oncolytic adenovirus vector containing Dm-dNK suicide gene and exogenous CD40L on breast carcinoma cells in vitro and in vivo.

Methods: A series of conditionally replicating adenoviruses using adenovirus vector P74 were generated: P74-dNK, P74-CD40L (expressing Dm-dNK or CD40L respectively), and P74-dNK-CD40L (expressing combined Dm-dNK and CD40L). Breast cancer cell lines (MDA-MB-231, MCF-7) and non-tumor cell line (MRC5) were treated with adenovirus and cytotoxicity determined by MTT assay, and apoptosis assessed by flow cytometry after 72h. We also assessed in vivo cell killing efficiency using a mouse xenograft model with MDA-MB-231 cells.

Results and Discussion: Co-expression of Dm-dNK and CD40L reduced cell proliferation of MDAMB- 231 or MCF7 cancer cells, and induced more apoptosis in TERT and CD40 positive cancer cells, but not normal MRC5 cells. Significant reduction in tumor volume was also seen in combined treatment arms as compared to any single treatment.

Conclusion: Our data suggest enhanced, selective tumor cell killing using combined gene therapy with conditionally replicating adenovirus containing Dm-dNK suicide gene and exogenous CD40 ligation (CD40L-CD40).

Keywords: Suicide genetic therapy, CD40 ligand, breast neoplasms, adenoviridae, OVs, PCR.

Graphical Abstract
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67(6): 439-48.
Dong X, Qu W, Ma S, et al. Potent antitumoral effects of targeted promoter-driven oncolytic adenovirus armed with Dm-dNK for breast cancer in vitro and in vivo. Cancer Lett 2013; 328(1): 95-103.
Fountzilas C, Patel S, Mahalingam D. Review: Oncolytic virotherapy, updates and future directions. Oncotarget 2017; 8(60): 102617-39.
Tang M, Zu C, He A, Wang W, Chen B, Zheng X. Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo. Drug Des Devel Ther 2015; 9: 3301-12.
Pradere U, Garnier-Amblard EC, Coats SJ, Amblard F, Schinazi RF. Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem Rev 2014; 114(18): 9154-218.
De Clercq E. Antiviral drug discovery and development: Where chemistry meets with biomedicine. Antiviral Res 2005; 67(2): 56-75.
Toutirais O, Gervais A, Cabillic F, et al. Effects of CD40 binding on ovarian carcinoma cell growth and cytokine production in vitro. Clin Exp Immunol 2007; 149(2): 372-7.
Bereznaya NM, Chekhun VF. Expression of CD40 and CD40L on tumor cells: The role of their interaction and new approach to immunotherapy. Exp Oncol 2007; 29(1): 2-12.
Disis ML, Bernhard H, Jaffee EM. Use of tumour-responsive T cells as cancer treatment. Lancet 2009; 373(9664): 673-83.
Bourgeois C, Rocha B, Tanchot C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 2002; 297(5589): 2060-3.
Parameswaran S, Khalil M, Ahmed KA, Sharma RK, Xiang J. Enhanced protective immunity derived from dendritic cells with phagocytosis of CD40 ligand transgene-engineered apoptotic tumor cells via increased dendritic cell maturation. Tumori 2015; 101(6): 637-43.
Trella E, Raafat N, Mengus C, et al. CD40 ligand-expressing recombinant vaccinia virus promotes the generation of CD8(+) central memory T cells. Eur J Immunol 2016; 46(2): 420-31.
Zhou Y, Zhou SX, Gao L, Li XA. Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues. Cancer Immunol Immunother 2016; 65(8): 919-29.
Gomes EM, Rodrigues MS, Phadke AP, et al. Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells. Clin Cancer Res 2009; 15(4): 1317-25.
Loskog A, Maleka A, Mangsbo S, et al. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophos- phamide in metastatic melanoma patients. Br J Cancer 2016; 114(8): 872-80.
Ma S, Qu W, Mao L, et al. Antitumor effects of oncolytic adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase in colorectal cancer. Oncol Rep 2012; 27(5): 1443-50.
Zhou H, O’Neal W, Morral N, Beaud AL. Development of a complementing cell line and a system for construction of adenovirus vectors with E1 and E2a deleted. J Virol 1996; 70(10): 7030-8.
Zhu Z, Mao L, Zhao L, et al. Synergistic therapeutic effect in gastric cancer cells produced by oncolytic adenovirus encoding Drosophila melanogaster deoxyribonucleoside kinase. Cancer Biol Ther 2011; 11(10): 874-82.
Korniluk A, Kemona H, Dymicka-Piekarska V. Multifunctional CD40L: Pro- and anti-neoplastic activity. Tumour Biol 2014; 35(10): 9447-57.
Tai YT, Podar K, Gupta D, et al. CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells. Blood 2002; 99(4): 1419-27.
Tai YT, Podar K, Mitsiades N, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/ AKT/NF-kappa B signaling. Blood 2003; 101(7): 2762-9.
Li R, Chen WC, Pang XQ, Tian WY, Zhang XG. Influence of sCD40L on gastric cancer cell lines. Mol Biol Rep 2011; 38(8): 5459-64.
Zhou Y, He J, Gou LT, et al. Expression of CD40 and growth-inhibitory activity of CD40 agonist in ovarian carcinoma cells. Cancer Immunol Immunother 2012; 61(10): 1735-43.
He S, Zhao H, Fei M, et al. Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro. Oncol Rep 2012; 28(1): 262-8.
Cheng PH, Wechman SL, McMasters KM, Zhou HS. Oncolytic Replication of E1b-Deleted Adenoviruses. Viruses 2015; 7(11): 5767-79.
Rao XM, Tseng MT, Zheng X, et al. E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells. Cancer Gene Ther 2004; 11(9): 585-93.
Murugaiyan G, Agrawal R, Mishra GC, et al. Differential CD40/CD40L expression results in counteracting antitumor immune responses. J Immunol 2007; 178(4): 2047-55.
Eriksson E, Moreno R, Milenova I, et al. Activation of myeloid- and endothelial cells by CD40L gene therapy supports T cell expansion and migration into the tumor microenvironment. Gene Ther 2016.
Ghamande S, Hylander BL, Oflazoglu E, et al. Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. Cancer Res 2001; 61(20): 7556-62.
Kubo M, Satoh T, Tabata KI, et al. Enhanced central memory cluster of differentiation 8+ and tumor antigen-specific T cells in prostate cancer patients receiving repeated in situ adenovirus-mediated suicide gene therapy. Mol Clin Oncol 2015; 3(3): 515-21.
Wei MX, Bougnoux P, Sacre-Salem B, et al. Suicide gene therapy of chemically induced mammary tumor in rat: Efficacy and distant bystander effect. Cancer Res 1998; 58(16): 3529-32.
Zhu Z, Gorman MJ, McKenzie LD, et al. Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 2017; 214(10): 2843-57.
Ribacka C, Hemminki A. Virotherapy as an approach against cancer stem cells. Curr Gene Ther 2008; 8(2): 88-96.
Lv SQ, Ye ZL, Liu PY, et al. 11R-P53 and GM-CSF expressing oncolytic adenovirus target cancer stem cells with enhanced synergistic activity. J Cancer 2017; 8(2): 199-206.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy