Gene-modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma

Our plain-English summary of Gene-modified PA1-STK cells home to tumor sites in patients with malignant pleural mesothelioma, by L.H. Harrison, P.O. Schwarzenberger, P.S. Byrne, et al (The Annals of Thoracic Surgery, 2000).

The study

• Authors: L.H. Harrison, P.O. Schwarzenberger, P.S. Byrne, A.J. Marrogi, J.K. Kolls, K.E. McCarthy
• Journal: The Annals of Thoracic Surgery
• Published: 2000;70(2):407-11
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma is an uncommon but lethal cancer of increasing incidence, particularly among patients with a history of exposure to asbestos. Although numerous treatments have been employed, including chemotherapy, radiation therapy, surgical resection, and combinations of the above, no satisfactory treatment yet exists, and affected patients will die of this disease, usually within 12 months. Gene-based therapies constitute a new approach that offers hope of improved control of these tumors while being associated with less morbidity than conventional chemotherapeutic or surgical regimens. We demonstrated that PA1-STK cells home in vivo to mesothelioma deposits, a phenomenon that is required for optimal exertion of this therapeutic concept.

Methods: Gene-modified ovarian cancer cells expressing the thymidine-kinase gene (PA1-STK) were radiolabeled with 99Tc and infused into the pleural space of 4 patients with malignant pleural mesothelioma, then scanned to determine distribution of the cells.

Results: PA1-STK cells recognized and adhered preferentially to mesothelioma lining the chest wall.

Conclusions: Cell-based "suicide gene" therapy utilizing the "bystander effect" with the gene-modified ovarian cancer cell line PA1-STK is feasible in human pleural mesothelioma. We have shown that this trafficking and homing of the therapeutic cells to the intrapleural tumor sites, a requirement for success with this novel therapeutic concept, is also valid in humans.

In plain English

This report came from a phase I clinical trial at Louisiana State University in New Orleans testing a gene-based treatment for malignant pleural mesothelioma. The treatment used ovarian cancer cells, called PA1-STK, altered to carry a herpes virus gene (thymidine kinase) that makes cells sensitive to the antiviral drug ganciclovir. The idea is that when these cells are killed, nearby tumor cells die too. The study did not examine asbestos exposure. In 4 patients, some of the cells were labeled with radioactive technetium, placed into the space around the lung through a catheter, and tracked with scans. Scans at 24 hours in all 4 patients, and at 48 hours in 1, showed the labeled cells gathered along surfaces matching tumor seen on CT. Labeled cells were absent from the free pleural fluid. The authors reported no harm in trial patients that they attributed to the treatment, though three needed catheters reinserted. The authors concluded the approach is feasible and that the cells home to tumor in humans. They noted the cells may reach only tumor near the surface, and the treatment needs an open pleural space.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I clinical trial (dose escalation) with a radionuclide imaging substudy of cell homing
• Who was studied: 4 patients with malignant pleural mesothelioma who received radiolabeled cells, treated at the Combined LSU-Tulane General Clinical Research Center at Charity Hospital, New Orleans. Dates of the study are not given.
• Exposure: Not an asbestos exposure study. The intervention was HSV-tk gene-modified ovarian cancer cells (PA1-STK), partly labeled with 99Tc and infused into the pleural space, followed by twice-daily intravenous ganciclovir (5 mg/kg).
• Main results:
  • In the 4 imaged patients, scans at 24 hours (and at 48 hours in 1 patient) showed radiolabeled cells along surfaces corresponding to tumor deposits seen on CT.
  • SPECT images confirmed labeled cells in areas of known tumor, with no radiolabeled cells in the free pleural fluid.
  • The authors stated the labeled cells were retained in the chest cavity for at least 24 hours.
  • In the trial, no bleeding or septic episodes were observed.
  • Three trial patients needed their pleural catheters reinserted.
  • One trial patient could not complete the full dose escalation because the pleural space fused between treatments.
• The authors' conclusion: The authors concluded that this cell-based suicide gene therapy is feasible in human pleural mesothelioma. They also concluded that the therapeutic cells travel to and home to intrapleural tumor sites in humans.
• Limitations the authors state:
  • Only tumor cells near the pleural surface are likely to bind the infused cells.
  • The fibrotic nature of mesothelioma may limit delivery of the cells to large parts of the tumor.
  • The approach needs a free pleural space, which patients with later-stage disease often lack.
  • Patients were not routinely imaged beyond 24 hours because the isotope decays quickly.
  • The actual number of adhering cells was not determined.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Malignant Mesothelioma, Chemotherapy, Surgical Resection, Mesothelioma, Ovarian Cancer.

Related studies

• Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model — E.S. Lambright, S.D. Force, et al. (2000)
• Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study — P. Schwarzenberger, P. Byrne, et al. (2011)
• Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer — H.C. Hwang, W.R. Smythe, et al. (1995)
• Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and — R. Hustinx, C.Y. Shiue, et al. (2001)
• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
• Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms — Z.G. Fridlender, J. Sun, et al. (2010)

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