Published ahead of print on April 3, 2003, doi:10.1165/rcmb.2002-0226OC Am. J. Respir. Cell Mol. Biol., Volume 29, Number 3, September 2003, 321-330 A more recent version of this article appeared on September 1, 2003
Submitted on October 29, 2002 Efficacy of CD40 Ligand Gene Therapy in Malignant MesotheliomaPaul L Friedlander1,1 Medicine/Gene Therapy Program, LSU Health Sciences Center, New Orleans, LA, USA; Stanely S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, USA; Otolaryngology, LSU Health Sciences Center, New Orleans, LA, USA, 2 Medicine/Gene Therapy Program, LSU Health Sciences Center, New Orleans, LA, USA; Stanely S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, USA; Stanely S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, USA, 3 Medicine/Gene Therapy Program, LSU Health Sciences Center, New Orleans, LA, USA, 4 Medicine/Gene Therapy Program, LSU Health Sciences Center, New Orleans, LA, USA; Stanely S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, USA * To whom correspondence should be addressed. E-mail: jkolls{at}lsuhsc.edu.
Gene delivery of CD40 Ligand (CD40L) has shown promise in murine models of melanoma and adenocarcinoma; however, its potential for thoracic malignancies such as malignant mesothelioma remains unclear. In this study, we investigated the hypothesis that CD40L gene therapy would be effective in local and distant tumor suppression in mesothelioma using an immunocompetent murine model. Using a recombinant adenovirus encoding murine CD40L (AdCD40L), we demonstrated no suppression of in vitro cell growth for the AC29 (mesothelioma) cell line. However, inoculation of immunocompetent CBA/J mice with AC29 cells treated ex vivo with AdCD40L, resulted in significant suppression of tumor formation in vivo when compared to controls (p <.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar anti-tumor results and was associated with increased recruitment of intratumoral CD8+ T-cells. Adoptive transfer of CD8+ T cells from AdCD40L-treated tumor bearing mice conferred protection to naive mice given an AC29 tumor challenge. Finally, in mice with two synchronous tumors, treatment of one of the tumors with AdCD40L resulted in a regression of both tumors. These findings demonstrate the development of tumor specific CD8+ T cells by AdCD40L and support the further development of AdCD40L for the treatment of malignant mesothelioma.
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