Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells.
OBJECTIVE
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).


METHODS
In vitro and in vivo evaluations were carried out on AdEHCD40L to validate selective viral replication and CD40L transgene activity in hypoxia inducing factor-1alpha 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 (ED50) by approximately 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.
Gomes
Erica M
EM
Cancer Immunology Research Laboratory and Department of Pathology, Baylor Sammons Cancer Center, Dallas, TX 75246, USA.
Rodrigues
Margret S
MS
Phadke
Anagha P
AP
Butcher
Lindsay D
LD
Starling
Cherry
C
Chen
Salina
S
Chang
Dongkun
D
Hernandez-Alcoceba
Ruben
R
Newman
Joseph T
JT
Stone
Marvin J
MJ
Tong
Alex W
AW
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000032:analysis; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D023201:CD40 Ligand / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D023201:CD40 Ligand