Biohybrid Vaccines for Improved Treatment of Aggressive Melanoma with Checkpoint Inhibitor.

Flavia Fontana,Jouni T Hirvonen,Cristian Capasso,Sara Feola,Jarno J Salonen,Ermei M Mäkilä,Manlio Fusciello,Christianne Groeneveldt,Jacopo Chiaro,Zehua Liu,Vincenzo Cerullo,Hélder A Santos

doi:10.1021/acsnano.8b09613

Flavia Fontana, Jouni T Hirvonen + Show 10 more

Open Access

https://doi.org/10.1021/acsnano.8b09613

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Abstract

Recent approaches in the treatment of cancer focus on involving the immune system to control the tumor growth. The administration of immunotherapies, like checkpoint inhibitors, has shown impressive results in the long term survival of patients. Cancer vaccines are being investigated as further tools to prime tumor-specific immunity. Biomaterials show potential as adjuvants in the formulation of vaccines, and biomimetic elements derived from the membrane of tumor cells may widen the range of antigens contained in the vaccine. Here, we show how mice presenting an aggressive melanoma tumor model treated twice with the complete nanovaccine formulation showed control on the tumor progression, while in a less aggressive model, the animals showed remission and control on the tumor progression, with a modification in the immunological profile of the tumor microenvironment. We also prove that co-administration of the nanovaccine together with a checkpoint inhibitor increases the efficacy of the treatment (87.5% of the animals responding, with 2 remissions) compared to the checkpoint inhibitor alone in the B16.OVA model. Our platform thereby shows potential applications as a cancer nanovaccine in combination with the standard clinical care treatment for melanoma cancers.

Highlights

The recent reports about the increase in the overall survival of cancer patients treated with immunotherapeutics, in particular checkpoint inhibitors, adoptive cell transfer, and chimeric antigen receptor T cells, rekindled the interest in the development of prophylactic and therapeutic cancer vaccines.[1−3] Biomaterials are currently being investigated for the formulation of micro- and nanoparticulate vaccines that enable the co-delivery of antigens and adjuvants.[4,5]
We have previously investigated the feasibility of this antigenic source in vitro, in a multistage delivery system composed of a core made of adjuvant biomaterials, which was further coated with a layer of cell membranes by extrusion through a polymeric membrane.[12]
(A) Cell viability (%) of JAWS II cells incubated with the tumor-membrane-coated Thermally oxidized PSi (TOPSi)@acetalated dextran (AcDEX) nanovaccine (NanoCCM) for 24 h and 48 h, as such or in the presence of two different concentrations of a murine anti-CTLA4 antibody

Summary

Introduction

The recent reports about the increase in the overall survival of cancer patients treated with immunotherapeutics, in particular checkpoint inhibitors, adoptive cell transfer, and chimeric antigen receptor T cells, rekindled the interest in the development of prophylactic and therapeutic cancer vaccines.[1−3] Biomaterials are currently being investigated for the formulation of micro- and nanoparticulate vaccines that enable the co-delivery of antigens and adjuvants.[4,5] Alternatively, biomaterials have been exploited in drug delivery systems for immune checkpoint inhibitors, including microneedles, scaffolds, micro- and nanoparticles, and platelets.[6−10] the materials themselves may present immunogenic properties leading to the stimulation of toll-like receptors and danger associated molecular pathways, and to the activation of antigen presenting cells (APCs).[11]. The immunosuppressive environment of the tumor microenvironment may reduce the potency of the immune response evoked by a therapeutic vaccination.[24] To tackle this problem, we hyphothesized that a biohybrid vaccination platform (Scheme 1) should synergize with checkpoint inhibitors, Scheme 1. The nanoparticles were enveloped by a layer of cancer cell membrane (CCM; autologous with the tumor model evaluated, B16.F10 or B16.OVA; white layer) We hypothesize that a combinatorial therapy between our nanovaccine and an anti-CTLA4 antibody can enhance the efficacy of the vaccination due to the mechanism of action of the checkpoint inhibitor on the central regulation of the T cell activation. We assessed the synergistic potential of the combinatorial therapy with the immune checkpoint inhibitor on the growth of established tumors and on the infiltration of activated immune cells in the tumor microenvironment

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