Growth inhibition of human multiple myeloma cells by an oncolytic adenovirus carrying the CD40 ligand transgene.
OBJECTIVE
The growth-inhibitory activity of recombinant CD40 ligand (CD40L) is well documented in human multiple myeloma (MM). We examined MM-targeted delivery of CD40L by a conditional replicative oncolytic adenovirus, AdEHCD40L.


METHODS
The growth-regulatory activity of AdEHCD40L was determined in vitro and in vivo. Differential analysis with AdEHCD40L and parental virus (AdEHNull)-infected cultures allowed the identification of cellular and molecular pathways modulated by the CD40L transgene.


RESULTS
Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ. AdEHCD40L inhibited MM cell growth more effectively than AdEHNull. This enhanced growth-inhibitory activity was abrogated by cotreatment with a CD40L antibody. Chemoresistant MM lines (MR20 and LR5) were similarly susceptible to AdEHCD40L treatment. AdEHCD40L induced apoptosis and S-phase cell cycle blockade while uniquely up-regulating the previously described proapoptotic elements tumor necrosis factor-related apoptosis-inducing ligand, Fas, and IL-8. Intratumoral injections of AdEHCD40L reduced the growth of severe combined immunodeficient/hu RPMI 8226 xenografts by >50% compared with 28% reduction by AdEHNull. Adenoviral hexon and CD40L were detected in AdEHCD40L-treated tumors at day 35 after infection primarily in necrotic areas, suggesting viral replicative activity.


CONCLUSIONS
These findings show that CD40L acts in concert with viral oncolysis to produce MM growth inhibition through activation of cellular apoptosis. The direct growth-inhibitory activity of AdEHCD40L, together with the well-known immune-potentiating features of CD40L, may be clinically applicable for the experimental treatment of MM or plasma cell leukemia.
Fernandes
Margret S
MS
Cancer Immunology Research Laboratory, Baylor Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA.
Gomes
Erica M
EM
Butcher
Lindsay D
LD
Hernandez-Alcoceba
Reuben
R
Chang
Dongkun
D
Kansopon
Joe
J
Newman
Joseph
J
Stone
Marvin J
MJ
Tong
Alex W
AW
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000821:virology; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D040901:Proteomics; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D016207:Cytokines; D023201:CD40 Ligand