Details

Autor(en) / Beteiligte

• FERNANDES, Margret S
• GOMES, Erica M
• BUTCHER, Lindsay D
• HERNANDEZ-ALCOCEBA, Reuben
• DONGKUN CHANG
• KANSOPON, Joe
• NEWMAN, Joseph
• STONE, Marvin J
• TONG, Alex W

Titel

Growth Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene

Ist Teil von

• Clinical cancer research, 2009-08, Vol.15 (15), p.4847-4856

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• Purpose: 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. Experimental Design: 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.