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Efficacy of CD40 ligand gene therapy in malignant mesothelioma
Paul L Friedlander1, Christie L Delaune, Jennifer M Abadie
1Department of Otolaryngology and Biocommunication, Louisiana State University Health Sciences Center, New Orleans, USA.
Abstract:
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.
Insights
CD40 Ligand (CD40L) gene therapy effectively suppressed malignant mesothelioma tumors in mice. This therapy activated CD8+ T cells, leading to both local and distant tumor regression, supporting its potential for mesothelioma treatment.
Area of Science:
- Immunotherapy
- Oncology
- Gene Therapy
Background:
- CD40 Ligand (CD40L) gene therapy shows promise for melanoma and adenocarcinoma.
- The efficacy of CD40L gene therapy for thoracic malignancies like malignant mesothelioma is not well understood.
Purpose of the Study:
- To investigate the effectiveness of CD40 Ligand (CD40L) gene therapy in suppressing local and distant malignant mesothelioma tumors.
- To evaluate the role of CD8+ T cells in the antitumor response induced by AdCD40L in mesothelioma.
Main Methods:
- Utilized a recombinant adenovirus encoding murine CD40L (AdCD40L) in an immunocompetent murine mesothelioma model.
- Administered AdCD40L ex vivo to mesothelioma cells and via intratumoral inoculation into established tumors.
- Assessed tumor growth, T cell infiltration, and the impact of CD8+ T cell adoptive transfer and treatment of synchronous tumors.
Main Results:
- AdCD40L did not inhibit mesothelioma cell growth in vitro but significantly suppressed tumor formation in vivo.
- Intratumoral AdCD40L treatment increased intratumoral CD8+ T cell recruitment and led to regression of both treated and untreated synchronous tumors.
- Adoptive transfer of CD8+ T cells from treated mice conferred protection against mesothelioma tumor challenge.
Conclusions:
- AdCD40L gene therapy demonstrates significant antitumor activity against malignant mesothelioma in a murine model.
- The therapy induces tumor-specific CD8+ T cell responses, mediating both local and systemic antitumor effects.
- AdCD40L holds potential as a therapeutic strategy for malignant mesothelioma and warrants further clinical development.