Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer

Our plain-English summary of Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer, by H.C. Hwang, W.R. Smythe, A.A. Elshami, et al (American Journal of Respiratory Cell and Molecular Biology, 1995).

The study

• Authors: H.C. Hwang, W.R. Smythe, A.A. Elshami, J.C. Kucharczuk, K.M. Amin, J.P. Williams, L.A. Litzky, L.R. Kaiser, S.M. Albelda
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 1995;13(1):7-16
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Previous studies have shown adenoviral transfer of the herpes simplex virus thymidine kinase (HSVtk) gene followed by the anti-viral drug ganciclovir (GCV) can be used to successfully treat established human mesothelioma tumors growing within the peritoneal cavities of severe combined immune deficient (SCID) mice. These findings raised a number of questions important to the applicability, efficiency, and safety of this treatment strategy. In this report, we have further characterized the use of recombinant adenovirus carrying the HSVtk gene to treat mesothelioma and other localized malignancies. Our results indicate that the Ad.RSVtk/GCV system is effective in causing tumor regression in animals inoculated with another mesothelioma cell line and a lung cancer cell line and that animals with bulky disease can be successfully treated. Effects are seen at a wide range of virus doses and significant anti-tumor activity is present at doses of ganciclovir that are clinically achievable. Finally, this treatment approach appears safe, with limited dissemination of virus using a sensitive RT-PCR detection system. These studies further characterize the use of adenoviral transfer of the HSVtk gene to treat experimental mesothelioma and suggest that clinical trials using this approach may be feasible.

In plain English

This was a laboratory and mouse study of an experimental gene therapy for mesothelioma; it did not study asbestos exposure. The authors gave immune-deficient (SCID) mice with human tumors in the abdomen a modified adenovirus carrying a herpes simplex gene (Ad.RSVtk), then the drug ganciclovir. On a tumor score of 0 to 4, mice with the 1-45 mesothelioma line scored 0.375 when treated (4 mice) versus 4.0 in controls. Mice with Calu-6 lung adenocarcinoma scored 1.5 when treated (4 mice) versus 3.8 in controls (3). Mice treated after bulky tumors had grown for 14 days scored 1.9 (8 mice) versus 4.0 (7 controls); their tumors shrank but did not disappear. Lower virus doses also lowered scores. Under the skin, tumors grown from cells infected with the virus before implantation regressed lastingly with low-dose ganciclovir given for 14 days, but came back after a 7-day course. In two mice, the gene's messenger RNA was found in tumor, liver and kidney but not in brain, lung, heart, muscle or salivary glands. The authors concluded that clinical trials may be feasible.

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: Animal experiments in severe combined immunodeficient (SCID) mice carrying human tumor cells, plus laboratory cell-culture (in vitro) experiments
• Who was studied: SCID mice injected with human tumor cell lines, at the University of Pennsylvania. The lines were two human mesothelioma cell lines (REN, and one printed as 1-45) and the Calu-6 human lung adenocarcinoma line. Group sizes: 10 mice in the 1-45 peritoneal experiment, 7 in the Calu-6 experiment, 16 inoculated for the bulky-disease experiment, 35 in the virus-dose experiment, and 2 in the virus-spread analysis.
• Exposure: No asbestos exposure was studied. The intervention was a single abdominal injection of a replication-deficient adenovirus carrying the herpes simplex thymidine kinase gene (Ad.RSVtk), mainly at 5 x 10^9 pfu, with lower doses in a dose experiment. Two days later the mice received ganciclovir, mainly 250 mg/kg daily for 7 days. A separate subcutaneous (flank) model, using cells infected with the virus in the laboratory before injection, tested ganciclovir doses of 10, 50 and 250 mg/kg/day.
• Main results:
  • In mice with 1-45 mesothelioma in the abdomen, the mean tumor score (scale 0 to 4) was 0.375 in the Ad.RSVtk-treated group (4 mice), compared with 4.0 in the sham control group (3 mice) and 4.0 in the Ad.RSVlacZ control group (3 mice) (P less than 0.001). Two of the four treated mice had any tumor.
  • In mice with Calu-6 lung adenocarcinoma in the abdomen, the mean tumor score was 1.5 (standard error 0.46) in treated mice (4 mice), compared with 3.8 (standard error 0.17) in controls (3 mice) (P = 0.0086).
  • In mice treated 14 days after inoculation, when bulky mesothelioma had developed, the mean tumor score was 1.9 (standard error 0.30) in treated mice (8 mice), compared with 4.0 in controls (7 mice) (P = 0.0021). All treated mice still had small 2- to 4-mm nodules in the pancreatic mesentery.
  • In the virus-dose experiment (35 mice with REN mesothelioma), mean tumor scores were 4.0 in controls (8 mice). Treated groups scored 2.1 at 5 x 10^6 pfu (8 mice), 1.0 at 5 x 10^7 (8 mice), 0.42 at 5 x 10^8 (6 mice) and 0.60 at 5 x 10^9 (5 mice). The three highest doses were similar to each other and differed significantly from the control. The lowest dose had a partial but statistically significant effect.
  • In cell culture, 80% of mesothelioma cells infected at 1 pfu per cell were killed by ganciclovir, compared with non-infected cells. Substantial sensitivity remained at 10^-3 pfu per cell.
  • In flank tumors made from mesothelioma cells infected with Ad.RSVtk in the laboratory before injection, 7 days of low-dose ganciclovir (10 mg/kg/day) caused regression followed by tumor recurrence. No recurrence was seen with the high dose (250 mg/kg/day). Given for 14 days, doses of 10 and 50 mg/kg/day produced complete and long-lasting regression. This experiment did not test low-dose ganciclovir in the abdominal treatment model.
  • In two tumor-bearing mice examined two days after the virus injection, the gene's messenger RNA was detected in the tumor nodule, kidney and liver. Brain, salivary glands, lung, skeletal muscle and heart were negative.
• The authors' conclusion: The authors concluded that their results further characterize adenoviral transfer of this gene to treat experimental mesothelioma, and suggest that clinical trials using this approach may be feasible.
• Limitations the authors state:
  • The authors used an abdominal (peritoneal) model rather than a chest (pleural) model, because introducing cells into the pleural cavity of mice is difficult.
  • A single treatment did not completely eradicate bulky tumors.
  • The inflammatory response to the virus in an animal with a normal immune system remains to be determined.
  • Formal safety studies were still ongoing.
  • The significance of the gene activity found in the liver was unclear.
  • In the chest, the virus might spread through tumor vessels. The authors said a larger animal model is needed to study this.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Lung Cancer, Mesothelioma, Clinical Trial.

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