Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

Our plain-English summary of Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma, by L. Cordier Kellerman, L. Valeyrie, N. Fernandez, et al (Cancer Gene Therapy, 2003).

The study

• Authors: L. Cordier Kellerman, L. Valeyrie, N. Fernandez, P. Opolon, J.C. Sabourin, E. Maubec, P. Le Roy, A. Kane, A. Legrand, M.A. Abina, V. Descamps, H. Haddada
• Journal: Cancer Gene Therapy
• Published: 2003;10(6):481-90
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a lethal tumor linked with a prior exposure to asbestos in which limited progress has been made so far using conventional therapies. MM is an example of a "nonimmunogenic" tumor characterized by a fibrous stroma and an absence of infiltrating T lymphocytes. High levels of transforming growth factor-beta (TGF-beta) produced by mesothelioma cells have been related to the immune tolerance towards the tumor. In order to evaluate the effect of local delivery of cytokines such as interferon gamma (IFN-gamma) by gene transfer, we characterized and used a murine model, AK7, which appeared very similar to human mesothelioma. AK7 cells expressed low levels of major histocompatibility class I and class II antigens and secreted high levels of latent TGF-beta. The TGF-beta pathway in AK7 cells is operative but inefficient because endogenous TGF-beta is predominantly inactive. Treatment of pre-established AK7 tumors by direct intratumoral injection of an adenovirus vector expressing murine IFN-gamma, Ad.mIFN-gamma, led to significant tumor regression. Peripheral tumor infiltration by CD4+ and CD8+ T lymphocytes in the treated tumors appeared to be because of the induction of an immune response. Tumor relapse was observed, which could be due to local TGF-beta secretion by remaining tumor cells.

In plain English

This was a laboratory and animal study, not a study of people. The authors created a mouse mesothelioma cell line, called AK7, from a mouse that had received 41 weekly injections of crocidolite asbestos fibers into the abdomen. They grew AK7 tumors under the skin of mice and tested a gene therapy: a modified virus carrying the mouse interferon gamma gene, injected directly into the tumors. In the 12 treated mice with normal immune systems, tumors shrank during the first 10 days and stayed stable for at least a month. Three of the 12 had no tumor that could be felt, but tumors came back in tumor-free mice about two months after treatment. In nude mice, which lack a thymus, treated tumors only stopped growing until about day 20 and then grew again. Treated tumors had more CD4+ and CD8+ immune cells at their edges. In lab dishes, 60% of treated cells died within 48 hours, compared with 10% with a control virus. The authors concluded that local interferon gamma had antitumor activity in this model. They noted that the immune reaction was not enough to produce an efficient memory response, since tumors relapsed.

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 experiment with in vitro (cell culture) work: a mouse mesothelioma cell line was characterized and used to test gene transfer of interferon gamma by an adenovirus vector
• Who was studied: AK7 mouse mesothelioma cells, grown as tumors under the skin of female C57BL/6 mice (normal immune system) and C57BL/6 nude mice. For the main treatment experiment in C57BL/6 mice: 12 given the interferon gamma vector, 8 given a control vector (Ad.bgal), 8 given PBS. Nude mice: six animals per group in a representative experiment. Work done at the Institut Gustave Roussy, France.
• Exposure: Crocidolite asbestos was used only to create the cell line (41 weekly intraperitoneal injections into one C57BL/6 mouse). The treatment tested was intratumoral injection of 10^9 PFU of an adenovirus vector expressing murine interferon gamma (Ad.mIFN-g), compared with a control vector expressing beta-galactosidase (Ad.bgal) or PBS.
• Main results:
  • In C57BL/6 mice, tumors injected with the interferon gamma vector shrank during the first 10 days. Tumors given the control vector stabilized and then kept growing.
  • In C57BL/6 mice treated with the interferon gamma vector, tumor size stayed stable for at least 1 month, and 3 of 12 mice had no palpable tumor (Student's t-test; the printed P value is garbled by OCR).
  • Tumors relapsed in the tumor-free mice 2 months after treatment with the interferon gamma vector.
  • In nude mice, tumors treated with the interferon gamma vector stopped growing until day 20 and then grew again. Tumors given PBS or the control vector kept growing.
  • Tumors treated with the interferon gamma vector had numerous clusters of CD4+ and CD8+ T cells at the tumor's edge. Tumors given the control vector had few T cells.
  • In cell culture, 60% of AK7 cells were dead 48 hours after infection with the interferon gamma vector, compared with 10% with the control vector. Caspase 3 cleavage indicated apoptosis.
  • After infection with the interferon gamma vector, 44% of AK7 cells were positive for MHC class I, compared with 14% of control cells. MHC class II was only slightly increased.
  • Two of three mice given the interferon gamma vector intravenously died at day 7. Injection into the tumor caused no deaths and no detectable interferon gamma in the blood.
  • Untreated AK7 cells released IL-6 (850 pg per 10^6 cells per 48 h) and TGF-beta1 (1076 pg per 10^6 cells per 48 h). Active TGF-beta1 was about 4% of the total.
  • Injecting irradiated AK7 cells did not protect mice against a later challenge with live tumor cells.
• The authors' conclusion: The authors concluded that local interferon gamma showed effective antitumor activity and caused regression of a highly aggressive mouse malignant mesothelioma resembling human mesotheliomas with poor prognosis. They suggested it may work partly by inhibiting TGF-beta signaling.
• Limitations the authors state:
  • The authors state that the immune (lymphocyte) reaction was not enough to produce an efficient memory response, since tumors relapsed.
  • The authors note that complete remission was difficult to obtain, and suggest combined treatments may be more effective.

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, Transforming Growth Factor-beta (TGF-β), Mesothelioma, Cytokine.

Related studies

• Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma — I. Mohiuddin, X. Cao, et al. (2001)
• Cytokine gene therapy or infusion as treatment for solid human cancer — B.W. Robinson, S.A. Mukherjee, et al. (1998)
• Asbestos fibers and interferon-gamma up-regulate nitric oxide production in rat alveolar macrophages — G. Thomas, T. Ando, et al. (1994)
• In vitro effects of recombinant human interferon gamma on human mesothelioma cell lines — L. Zeng, A. Buard, et al. (1993)
• 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)

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