Gene therapy for malignant mesothelioma: current prospects and challenges

Our plain-English summary of Gene therapy for malignant mesothelioma: current prospects and challenges, by M. Tagawa, Y. Tada, H. Shimada, et al (Cancer Gene Therapy, 2013).

The study

• Authors: M. Tagawa, Y. Tada, H. Shimada, K. Hiroshima
• Journal: Cancer Gene Therapy
• Published: 2013;20(3):150-6
• Type of article: Review
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma, developed in the thoracic cavity, is resistant to current treatments. Suppression of the local tumor growth is beneficial to the patients since mesothelioma infrequently metastasizes to extrapleural organs. A majority of the tumors have a homologous genetic deletion at the INK4A/ARF locus that includes the p14ARF and the p16INK4A genes, and the genetic defect results in an inactivation of the p53-mediated pathways and in progression of cell cycle through pRb phosphorylation. Preclinical studies targeting the genetic abnormality with adenoviruses showed that restoration of the p53 pathways induced pRb dephosphorylation and subsequently produced anti-tumor effects. A number of preclinical studies with different genes and vector systems demonstrated the therapeutic efficacy and raised the possibility of gene therapy in clinical settings. An intrapleural administration of vectors has several advantages in transducing pleural mesothelioma but activates rapid antibody production which impedes further gene expression. There have been several clinical studies conducted for mesothelioma and these trials showed the feasibility of intrapleural administrations of adenovirus vectors. In this review we summarize major preclinical and clinical gene therapy for mesothelioma, and discuss the advantages of gene therapy in the context of stimulating host immune systems. Accumulating clinical data suggest that an intrapleural administration of viral vectors has distinct aspects which are not observed in other administration routes.

In plain English

This article was a review, not a new study. The authors summarized laboratory (preclinical) and clinical research on gene therapy for malignant mesothelioma, mainly pleural mesothelioma. It concerns treatment and did not study asbestos exposure. The laboratory work it covered used adenovirus vectors to restore the p14 and p16 genes, which are often lost in mesothelioma, to reactivate p53 pathways, or to block growth signals (NK4). It also covered tumor-killing (oncolytic) viruses. The review described five clinical trials using replication-incompetent adenovirus in pleural mesothelioma patients (four phase I, one pilot), plus one pilot study with vaccinia virus. According to the review, these trials showed that injecting adenovirus into the pleural cavity was safe and produced anti-tumor responses in some patients. Patients quickly made antibodies against the virus, however. The authors judged that clinical benefits were probably due to the immune response rather than direct killing of tumor cells. They noted that detailed data from some studies were unavailable. The authors concluded that gene therapy, perhaps along with immunotherapy, could be one candidate within combined treatments.

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: Review of preclinical and clinical gene therapy studies for mesothelioma
• Who was studied: Published laboratory studies and clinical trials of gene therapy in malignant mesothelioma. The clinical trials enrolled pleural mesothelioma patients, and four of the clinical studies were conducted at Pennsylvania University.
• Exposure: Not an exposure study. The treatments reviewed included adenovirus vectors carrying genes such as p14, p16, p53, NK4, herpes simplex virus thymidine kinase (HSV-TK, followed by the drug ganciclovir) and interferon genes, along with oncolytic viruses and a vaccinia virus vector.
• Main results:
  • The review cited data that about 70–80% of clinical specimens from mesothelioma patients lacked the genetic region containing the p16 and p14 genes, while most specimens had the normal (wild-type) p53 gene; adenovirus carrying p53 was used to reactivate p53 pathways.
  • In the review's summary, the clinical trials with replication-incompetent adenovirus showed that injection into the pleural cavity was safe and produced anti-tumor responses in some patients.
  • In the first Pennsylvania phase I trial (adenovirus carrying HSV-TK), antibody against the adenovirus was produced in all patients.
  • The same HSV-TK trial reported 3 long-surviving patients who received no chemotherapy afterwards.
  • In an interferon-alpha-2b trial, a second injection given 3 days after the first increased gene expression; neutralizing antibody had not yet formed by day 3.
  • The authors judged that the clinical benefits were probably due to host immune responses rather than direct killing of tumor cells.
• The authors' conclusion: The authors concluded that combined (multimodal) treatments are needed for mesothelioma, and that gene therapy, perhaps along with immunotherapy, can be one candidate.
• Limitations the authors state:
  • Detailed clinical data and outcomes were unavailable for the case studies that were not phase I trials.
  • It is unclear how much the activation of cytotoxic T cells and natural killer cells contributed to the clinical responses.
  • No clinical data with oncolytic viruses had been published at the time of the review.
  • Anti-tumor effects of adenovirus carrying p14 had not been demonstrated in living animals.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Metastasis, Pleural Mesothelioma.

Related studies

• Gene therapy for malignant pleural mesothelioma: present and future — Y. Tada, Y. Takiguchi, et al. (2008)
• Gene therapy for mesothelioma and lung cancer — A. Vachani, E. Moon, et al. (2010)
• Gene therapy for mesothelioma — A. Vachani, E. Moon, et al. (2011)
• Gene therapy for lung diseases: development in the vector biology and novel concepts for gene therapy applications — M. Suzuki, T. Matsuse, et al. (2001)
• Mesothelioma: an inviting but challenging target for gene therapy — R.G. Crystal (2010)
• Gene therapy for lung neoplasms — A. Vachani, E. Moon, et al. (2011)

Browse more research in Cancer Gene Therapy, or return to medical research.