Efficacy of CD40 ligand gene therapy in malignant mesothelioma.
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 with controls (P < 0.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar antitumor 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.
Friedlander
Paul L
PL
Department of Otolaryngology and Biocommunication, Louisiana State University Health Sciences Center, New Orleans, USA.
Delaune
Christie L
CL
Abadie
Jennifer M
JM
Toups
Marisa
M
LaCour
Jeffrey
J
Marrero
Luis
L
Zhong
Qiu
Q
Kolls
Jay K
JK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D039521:CD11c Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002469:Cell Separation; D003713:Dendritic Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008808:Mice, Inbred CBA; D008856:Microscopy, Fluorescence; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D039521:CD11c Antigen; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma