Fowlpox-based survivin vaccination for malignant mesothelioma therapy

Our plain-English summary of Fowlpox-based survivin vaccination for malignant mesothelioma therapy, by P. Bertino, M. Panigada, E. Soprana, et al (International Journal of Cancer, 2013).

The study

• Authors: P. Bertino, M. Panigada, E. Soprana, V. Bianchi, S. Bertilaccio, F. Sanvito, A.H. Rose, H. Yang, G. Gaudino, P.R. Hoffmann, A. Siccardi, M. Carbone
• Journal: International Journal of Cancer
• Published: 2013;133(3):612-23
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Survivin protein is an attractive candidate for cancer immunotherapy since it is abundantly expressed in most common human cancers and mostly absent in normal adult tissues. Malignant mesothelioma (MM) is a deadly cancer associated with asbestos or erionite exposure for which no successful therapies are currently available. In this study, we evaluated the therapeutic efficacy of a novel survivin-based vaccine by subcutaneous or intraperitoneum injection of BALB/c mice with murine fiber-induced MM tumor cells followed by vaccination with recombinant Fowlpox virus replicons encoding survivin. Vaccination generated significant immune responses in both models, leading to delayed tumor growth and improved animal survival. Flow cytometry and immunofluorescence analyses of tumors from vaccinated mice showed CD8(+) T-cell infiltration, and real-time PCR demonstrated increased mRNA and protein levels of immunostimulatory cytokines. Analyses of survivin peptide-pulsed spleen and lymph node cells from vaccinated mice using ELISPOT and intracellular cytokine staining confirmed antigen-specific, interferon-γ-producing CD8(+) T-cell responses. In addition pentamer-based flow cytometry showed that vaccination generated survivin-specific CD8(+) T cells. Importantly, vaccination did not affect fertility or induce autoimmune abnormalities in mice. Our results demonstrate that vaccination with recombinant Fowlpox expressing survivin improves T-cell responses against aggressive MM tumors and may form the basis for promising clinical applications.

Copyright © 2013 UICC.

In plain English

This laboratory and animal study tested an experimental mesothelioma vaccine: Fowlpox virus engineered to carry the gene for survivin, a protein found in many cancers (FP-surv). It was compared with a control virus (FP-ctrl). The authors found survivin in seven human mesothelioma cell lines and in 17 human mesothelioma specimens. To obtain mouse tumors, they injected BALB/c mice in the abdomen with crocidolite asbestos, Turkish erionite or US erionite. About 70% of fiber-injected mice died of mesothelioma within 2 years, while control mice developed no tumors. Mesothelioma cells were then implanted under the skin or into the abdomen of other mice, which were vaccinated twice. Compared with controls, vaccinated mice had slower tumor growth, longer survival and more CD8+ T cells (a type of immune cell) in their tumors. Vaccination caused no signs of autoimmunity or reduced fertility in mice. The authors concluded the vaccine may serve as a basis for future treatment and/or prevention strategies for human mesothelioma. They said its effects need careful evaluation before translation to people.

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: mouse models of mesothelioma (tumor cells implanted under the skin or into the abdomen) treated with an experimental vaccine or a control virus. It was combined with laboratory analysis of human and mouse mesothelioma cells and tissue.
• Who was studied: Female BALB/c and C57BL/6 mice aged 4 to 8 weeks. Fiber-injection groups had 15 mice each, subcutaneous-model groups 6 mice each and abdominal-model groups 10 mice each. The study also used seven human mesothelioma cell lines and 17 human mesothelioma specimens.
• Exposure: Crocidolite asbestos, Turkish erionite or US erionite (4 mg, injected into the abdomen) were used to produce mesothelioma in mice, from which tumor cell lines were made. The treatment studied was two injections of the survivin vaccine (FP-surv) compared with a control Fowlpox virus (FP-ctrl).
• Main results:
  • In the 17 human mesothelioma specimens, tumor tissue showed moderate to strong expression of survivin and MHC-I.
  • In fiber-injected mice, mesothelioma began to appear 4 months after the first injection. Within 2 years about 70% of fiber-injected mice died of mesothelioma; control mice developed no tumors.
  • In the subcutaneous models (6 mice per group), vaccination with FP-surv delayed tumor growth and improved survival compared with control-vaccinated mice.
  • In mice given the slow-growing EKKH5 cells (from a Turkish erionite-induced tumor) under the skin, vaccination increased survival. Tumors disappeared completely in 2 of 6 animals.
  • In the abdominal (intraperitoneal) model (10 mice per group), FP-surv-vaccinated mice had significantly longer median survival than controls: p = 0.0004 for AB12 cells and p = 0.0027 for CRH5 cells.
  • In both abdominal models, 10% of FP-surv-vaccinated mice showed complete tumor remission. The authors did not show these data.
  • Tumors from FP-surv-vaccinated mice contained significantly more CD8+ T cells than tumors from unvaccinated controls, in both AB12 and CRH5 tumors.
  • Spleen and lymph node cells from FP-surv-vaccinated mice showed significantly higher levels of interferon-gamma-producing CD8+ T cells than cells from control-vaccinated mice.
  • In abdominal tumors (5 per group), vaccination significantly increased the genetic activity (mRNA) of interferon-gamma and IL-12 in AB12 tumors, and of interferon-gamma in CRH5 tumors.
  • Organs from vaccinated mice (5 per group) showed no inflammatory cell infiltration, tissue damage or other sign of autoimmunity.
  • Vaccinated mice had normal fertility rates and litters. Nine vaccinated females and three vaccinated males were bred.
• The authors' conclusion: The authors concluded that the vaccine may serve as a basis for designing future treatment and/or prevention strategies for human mesothelioma.
• Limitations the authors state:
  • The vaccine used the human survivin gene in mice, which the authors acknowledged may be considered controversial.
  • The immune response produced by the vaccine still needs careful evaluation before the results can be applied to vaccine development for human mesothelioma.
  • The link between CD8+ T cells and survival was a correlation. Further experiments would be needed for more direct evidence of these cells' role.
  • Functional immune studies were limited to interferon-gamma production.
  • Cytokine protein measurements did not fully agree with the mRNA results.
  • A contribution from increased natural killer cell activity could not be ruled out.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Immunotherapy, erionite, Cytokine.

Related studies

• Preclinical development of HIvax: Human survivin highly immunogenic vaccines — P.R. Hoffmann, M. Panigada, et al. (2015)
• Novel targeted therapies and vaccination strategies for mesothelioma — M. Bagia, A.K. Nowak (2011)
• WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer — L.M. Krug, T. Dao, et al. (2010)
• Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma — M. Meerang, K. Bérard, et al. (2016)
• BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients — J. Hmeljak, N. Erčulj, et al. (2011)
• Is survivin expression prognostic or predictive in malignant pleural mesothelioma? — J. Hmeljak, N. Erčulj, et al. (2013)

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