Oncotarget

Research Papers:

Antitumor effect of an adeno-associated virus expressing apolipoprotein A-1 fused to interferon alpha in an interferon alpha-resistant murine tumor model

Marcos Vasquez _, Vladimir Paredes-Cervantes, Fernando Aranda, Nuria Ardaiz, Celia Gomar and Pedro Berraondo

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Oncotarget. 2017; 8:5247-5255. https://doi.org/10.18632/oncotarget.14127

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Abstract

Marcos Vasquez1, Vladimir Paredes-Cervantes1,2, Fernando Aranda1, Nuria Ardaiz1, Celia Gomar1, Pedro Berraondo1

1Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain

2Centro Médico Nacional La Raza, IMSS, México DF, Mexico

Correspondence to:

Pedro Berraondo, email: pberraondol@unav.es

Keywords: colorectal cancer, liver metastasis, cancer immunotherapy, T regulatory cells, PD-1

Received: June 09, 2016    Accepted: November 22, 2016    Published: December 23, 2016

ABSTRACT

Interferon alpha (IFNα) is a cytokine approved for the treatment of several types of cancer. However, the modest effect on overall survival and the high toxicity associated with the treatment has reduced the clinical use of this cytokine. In this study, we have developed a tumor model that reproduces this clinical setting. A high dose of an adeno-associated virus encoding IFNα (AAV-IFNα) was able to eradicate a liver metastases model of colon cancer but induced lethal pancytopenia. On the other hand, a safe dose of AAV-IFNα was not able to eliminate the liver metastases of colon cancer. In this IFNα-resistant tumor model, administration of an adeno-associated vector encoding apolipoprotein A-1 fused to IFNα was able to fully eradicate the tumor in 43% of mice without toxicity. This antitumor effect was limited by suboptimal long-term CD8+ T cell activation and the expansion of T regulatory cells. In contrast, IFNα upregulated suppressor molecules such as PD-1 and interleukin 10 on CD8+ T lymphocytes. In conclusion, we show that apolipoprotein A-1 fused to IFNα is a novel antitumor drug that differs from IFNα in the modulation of suppressor mechanisms of the immune response. These differential properties pave the way for rational combinations with other immunomodulatory drugs.


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