Abstract
Mesothelioma is an incurable cancer of the pleura with a life expectancy of less than 1 year. On the basis of in vivo efficacy seen with the herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene-modified PA1STK cell line and ganciclovir (GCV) in a murine model of mesothelioma, a first in humans, clinical trial was designed for this therapeutic concept. The study was a phase I clinical trial using direct infusion of escalating doses of HSVtk suicide gene-modified PA1STK cells directly into tumor-associated pleural effusions followed by 7 days of intravenous GCV infusion. Therapeutic levels of GCV in both serum and pleura were achieved within 1 h, and GCV trough levels remained above the therapeutic threshold for the duration of GCV treatment. The treatment was well tolerated without any Grade 3 or 4 toxicity observed. Significant inductions of both Th1 and Th2 cytokines up to 20-fold over baseline were observed. No significant differences were seen between serum and pleura cytokine profiles, with the exception of interleukin-10, which was consistently elevated in the pleura specimens. No objective radiographic responses were observed. The data indicate significant immunological responses and validate the principal anti-tumor mechanisms observed in preclinical models of mesothelioma in a human clinical trial.
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Acknowledgements
We thank Dr Scott Freeman for providing the PA1STK cell line. The study was supported in part by the Tulane/LSU General Clinical Research grant 5M01RR005096.
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Schwarzenberger, P., Byrne, P., Gaumer, R. et al. Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study. Cancer Gene Ther 18, 906–912 (2011). https://doi.org/10.1038/cgt.2011.60
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DOI: https://doi.org/10.1038/cgt.2011.60