Targeting self- and neoepitopes with a modular self-adjuvanting cancer vaccine
Elodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, Madiha Derouazi
Elodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, Madiha Derouazi
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Research Article Oncology Vaccines

Targeting self- and neoepitopes with a modular self-adjuvanting cancer vaccine

Abstract

Induction of a potent CD4 and CD8 T cell response against tumor-specific and tumor-associated antigens is critical for eliminating tumor cells. Recent vaccination strategies have been hampered by an inefficacious and low-amplitude immune response. In this article, we describe a self-adjuvanted chimeric protein vaccine platform to address these challenges, characterized by a multidomain construction incorporating (a) a cell-penetrating peptide allowing internalization of several multiantigenic MHC-restricted peptides within (b) the multiantigenic domain and (c) a TLR2/4 agonist domain. Functionality of the resulting chimeric protein is based on the combined effect of the above-mentioned 3 different domains for simultaneous activation of antigen-presenting cells and antigen cross-presentation, leading to an efficacious multiantigenic and multiallelic cellular immune response. Helper and cytotoxic T cell responses were observed against model-, neo-, and self-antigens and were highly potent in several murine tumor models. The safety and the immunogenicity of a human vaccine candidate designed for colorectal cancer treatment was demonstrated in a nonhuman primate model. This therapeutic vaccine approach, which we believe to be newly engineered, is promising for the treatment of poorly infiltrated tumors that do not respond to currently marketed immunotherapies.

Authors

Elodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, Madiha Derouazi

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Figure 4

ATP125 is processed and presented by human DCs.

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ATP125 is processed and presented by human DCs. (A) Representative intra...
(A) Representative intracellular and extracellular anti-His staining of human DCs stimulated with 300 nM of ATP125. One experiment shown is representative of 3. (B) Identification of naturally presented HLA class I– and HLA class II–restricted peptides by ATP125-loaded human DCs using a mass spectrometry–based immunopeptidomics approach. The bold lines indicate regions of the recombinant protein containing HLA class I– or class II–presented peptides. (C) Human DCs were cultured overnight with 300 nM of ATP125 before cytometry analysis. Histograms of activation markers are shown. One experiment shown is representative of 3. (D) Heatmap of secreted cytokines/chemokines (pg/ml) by 24-hour activated human DCs (n = 3) or human PBMCs (n = 3) with 300 nM of ATP125, MPLA (TLR4 ligand), Pam3CSK4 (TLR2 ligand), or R848 (TLR7/8 ligand), equivalent volume of ATP125 buffer and control cells.