Antitumor Activity of an Oncolytic Adenoviral-CD40 Ligand (CD154) Transgene Construct in Human Breast Cancer Cells

• Published in: Clinical cancer research Vol. 15; no. 4; pp. 1317 - 1325
• Main Authors: GOMES, Erica M, RODRIGUES, Margret S, TONG, Alex W, PHADKE, Anagha P, BUTCHER, Lindsay D, STARLING, Cherry, CHEN, Salina, DONGKUN CHANG, HERNANDEZ-ALCOCEBA, Ruben, NEWMAN, Joseph T, STONE, Marvin J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-02-2009
• Subjects: Adenoviridae - genetics; Adenovirus E1A Proteins - analysis; Animals; Antineoplastic agents; Biological and medical sciences; breast cancer; Breast Neoplasms - pathology; Breast Neoplasms - therapy; CD40 ligand (CD154); CD40 Ligand - genetics; Cell Line, Tumor; conditional replicative oncolytic adenovirus; Female; Genetic Therapy - methods; Gynecology. Andrology. Obstetrics; Humans; hypoxia-inducing factor (HIF)-1; Mammary gland diseases; Medical sciences; Mice; Mice, SCID; Pharmacology. Drug treatments; Phenotype; Transgenes; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Human; Breast disease; Adenoviridae; Breast cancer; Malignant tumor; Transgene; Biological activity; Virus; Mammary gland diseases; Treatment; CD40 ligand; Gene therapy; Tumor cell; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1360

Purpose: CD40 ligand (CD40L, CD154) plays a central role in immunoregulation and also directly modulates epithelial cell growth and
differentiation. We previously showed that the CD40 receptor is commonly expressed in primary breast cancer tissues. In this
proof-of-principle study, we examined the breast cancer growth–regulatory activities of an oncolytic adenoviral construct
carrying the CD40L transgene (AdEHCD40L).
Experimental Design: In vitro and in vivo evaluations were carried out on AdEHCD40L to validate selective viral replication and CD40L transgene activity in hypoxia
inducing factor-1α and estrogen receptor–expressing human breast cancer cells.
Results: AdEHCD40L inhibited the in vitro growth of CD40 + human breast cancer lines (T-47D, MDA-MB-231, and BT-20) by up to 80% at a low multiplicity of infection of 1. Incorporation
of the CD40L transgene reduced the effective dose needed to achieve 50% growth inhibition (ED 50 ) by ∼10-fold. In contrast, viral and transgene expression of AdEHCD40L, as well its cytotoxicity, was markedly attenuated
in nonmalignant cells. Intratumoral injections with AdEHCD40L reduced preexisting MDA-MB-231 xenograft growth in severe combined
immunodeficient mice by >99% and was significantly more effective ( P < 0.003) than parental virus AdEH (69%) or the recombinant CD40L protein (49%). This enhanced antitumor activity correlated
with cell cycle blockade and increased apoptosis in AdEHCD40L-infected tumor cells.
Conclusions: These novel findings, together with the previously known immune-activating features of CD40L, support the potential applicability
of AdEHCD40L for experimental treatment of human breast cancer.