Oncolytic adenoviruses coated with MHC-I tumor epitopes increase the antitumor immunity and efficacy against melanoma

ABSTRACT

The stimulation of the immune system using oncolytic adenoviruses (OAds) has attracted significant interest and several studies suggested that OAds immunogenicity might be important for their efficacy. Therefore, we developed a versatile and rapid system to adsorb tumor-specific major histocompatibility complex class I (MHC-I) peptides onto the viral surface to drive the immune response toward the tumor epitopes. By studying the model epitope SIINFEKL, we demonstrated that the peptide-coated OAd (PeptiCRAd) retains its infectivity and the cross presentation of the modified-exogenous epitope on MHC-I is not hindered. We then showed that the SIINFEKL-targeting PeptiCRAd achieves a superior antitumor efficacy and increases the percentage of antitumor CD8⁺ T cells and mature epitope-specific dendritic cells in vivo. PeptiCRAds loaded with clinically relevant tumor epitopes derived from tyrosinase-related protein 2 (TRP-2) and human gp100 could reduce the growth of primary-treated tumors and secondary-untreated melanomas, promoting the expansion of antigen-specific T-cell populations. Finally, we tested PeptiCRAd in humanized mice bearing human melanomas. In this model, a PeptiCRAd targeting the human melanoma-associated antigen A1 (MAGE-A1) and expressing granulocyte and macrophage colony-stimulating factor (GM-CSF) was able to eradicate established tumors and increased the human MAGE-A1-specific CD8⁺ T cell population. Herein, we show that the immunogenicity of OAds plays a key role in their efficacy and it can be exploited to direct the immune response system toward exogenous tumor epitopes. This versatile and rapid system overcomes the immunodominance of the virus and elicits a tumor-specific immune response, making PeptiCRAd a promising approach for clinical testing.

KEYWORDS:

• Cancer vaccine
• humanized mice
• immunotherapy
• melanoma
• oncolytic adenovirus
• oncolytic vaccine
• tumor epitopes

Disclosure of potential conflicts of interest

Vincenzo Cerullo, Cristian Capasso, and Mari Hirvinen are co-inventors in patent application based on the present work.

Acknowledgments

We thank Dr Petri Ihalainen (Åbo Akademi University) for assistance with atomic field microscopy and Victor Cervera Carrascon for his precious technical help.

Funding

This research was supported by the three-year research grant (University of Helsinki), K. Albin Johansson Foundation, Foundation for the Finnish Cancer Institute, CDR and Division of Pharmaceutical Biosciences (University of Helsinki), and a TEKES-TUTL grant (Team Finland Network). C.C. was supported by the Drug Research Doctoral Program, M.H. was supported by the Finnish Cultural Foundation, and A.V. was supported by a CREME grant.