Pre-clinical development of Listeria-based nanovaccines as immunotherapies for solid tumours: insights from melanoma

Abstract

Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO 91-99 ), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO 91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO 91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO 91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO 91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO 91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

Clinical Experience and Recent Advances in the Development of Listeria-Based Tumor Immunotherapies

“…As development continues in safer and more effective live Lmbased vaccines, other groups have focused on utilizing specific products or proteins from Listeria monocytogenes to improve the immunogenicity of nanoparticle-based vaccine platforms (90,91). Much like Lm, nanoparticle-based vaccines, comprised of liposomes and/or metal particles, have the ability to selectively deliver cargo to professional antigen presenting cells, and accumulate within primary and metastatic tumors (92).…”

“…Much like Lm, nanoparticle-based vaccines, comprised of liposomes and/or metal particles, have the ability to selectively deliver cargo to professional antigen presenting cells, and accumulate within primary and metastatic tumors (92). In fact, a recently developed nanovaccine utilized the adjuvant properties of LLO to enhance the efficacy of a gold nanoparticle-based vaccine in preclinical development for metastatic melanoma (90). Gold nanoparticles are utilized in tumor nanovaccines due to their small size, ability to disseminate widely throughout the tissues, and ability to specifically accumulate at tumor sites (93).…”

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

“…A new approach of targeting different TME components using nanoparticles has been recently proposed [130]. In melanoma mouse models, nanoparticles were shown to potentiate the efficiency of PD-1 blockade [131][132][133], to reduce the tumor volume and to prolong mouse survival [134].…”

Moderne Aspekte der Immuntherapie mit Checkpoint-Inhibitoren bei Melanom

“…Kürzlich wurde ein neuer Ansatz vorgeschlagen, bei dem Nanopartikel eingesetzt werden, um verschiedene TME-Komponenten gezielt anzugreifen [130]. Murine Melanom-Modelle zeigten, dass Nanopartikel die Wirksamkeit der PD-1-Blockade erhöhen [131-133], zu einem Rückgang des Tumorvolumens führen und das Überleben der Mäuse verlängern [134].…”