Intradermal DNA vaccination combined with dual CTLA-4 and PD-1 blockade provides robust tumor immunity in murine melanoma.

Spela Kos,Ursa Lampreht Tratar,Gregor Sersa,Kevin Vanvarenberg,Gaelle Vandermeulen,Maja Cemazar,Bernard Ucakar,Alessandra Lopes,Veronique Preat,Fabrizio Mattei

doi:10.1371/journal.pone.0217762

Spela Kos, Ursa Lampreht Tratar + Show 8 more

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https://doi.org/10.1371/journal.pone.0217762

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Abstract

We aimed to explore whether the combination of intradermal DNA vaccination, to boost immune response against melanoma antigens, and immune checkpoint blockade, to alleviate immunosuppression, improves antitumor effectiveness in a murine B16F10 melanoma tumor model. Compared to single treatments, a combination of intradermal DNA vaccination (ovalbumin or gp100 plasmid adjuvanted with IL12 plasmid) and immune checkpoint CTLA-4/PD-1 blockade resulted in a significant delay in tumor growth and prolonged survival of treated mice. Strong activation of the immune response induced by combined treatment resulted in a significant antigen-specific immune response, with elevated production of antigen-specific IgG antibodies and increased intratumoral CD8+ infiltration. These results indicate a potential application of the combined DNA vaccination and immune checkpoint blockade, specifically, to enhance the efficacy of DNA vaccines and to overcome the resistance to immune checkpoint inhibitors in certain cancer types.

Highlights

In recent years, the field of cancer immunotherapy has considerably expanded with several new treatment options [1]
To test the research hypothesis that DNA vaccination and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)/PD-1 blockade may have complementary effects leading to a better control of tumor growth, mice were injected with B16F10-OVA tumor cells and received each individual treatment or a combination of them
At day 15, small tumor volumes were obtained in the groups treated with immune checkpoint inhibitors with or without the adjuvant plasmid coding for IL-12 and in the groups that combined DNA vaccination and inhibitors (Fig 1A and 1B)

Summary

Introduction

The field of cancer immunotherapy has considerably expanded with several new treatment options [1]. DNA vaccines hold a great promise in prevention and treatment of different types of cancer. DNA vaccines are promising for cancer immunotherapy since they induce a broad immune response [2] with activation of both cellular and humoral arms of the adaptive immune system [3]. The clinical ability of DNA vaccines is still limited due to the poor immune response initially observed in humans. In order to increase the immunogenicity of DNA vaccines, novel improvements have been incorporated to the DNA vaccine platform, such as plasmid optimization, delivery by in vivo gene electrotransfer and use of genetically encoded immune adjuvants [4].

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