title: Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study.
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.
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA. poschwarz@yahoo.com
authors: P
authors: P
authors: Schwarzenberger
authors: P
authors: P
authors: Byrne
authors: R
authors: R
authors: Gaumer
authors: J
authors: J
authors: Norton
authors: L
authors: L
authors: Harrison
authors: A
authors: A
authors: Marrogi
authors: J K
authors: JK
authors: Kolls
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D016753:Interleukin-10 / Q000032:analysis / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D010995:Pleural Diseases / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D058408:Th1-Th2 Balance; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016753:Interleukin-10; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D015774:Ganciclovir