Poly(propylacrylic acid)-peptide nanoplexes as a platform for enhancing the immunogenicity of neoantigen cancer vaccines

Abstract

Cancer vaccines targeting patient-specific tumor neoantigens have recently emerged as a promising component of the rapidly expanding immunotherapeutic armamentarium. However, neoantigenic peptides typically elicit weak CD8 T cell responses, and so there is a need for universally applicable vaccine delivery strategies to enhance the immunogenicity of these peptides. Ideally, such vaccines could also be rapidly fabricated using chemically synthesized peptide antigens customized to an individual patient. Here, we describe a strategy for simple and rapid packaging of peptide antigens into pH-responsive nanoparticles with endosomal escape activity. Electrostatically-stabilized polyplex nanoparticles (nanoplexes) can be assembled instantaneously by mixing decalysine-modified antigenic peptides and poly(propylacrylic acid) (pPAA), a polyanion with pH-dependent, membrane destabilizing activity. These nanoplexes increase and prolong antigen uptake and presentation on MHC-I (major histocompatibility complex class I) molecules expressed by dendritic cells, resulting in enhanced activation of CD8 T cells. Using an intranasal immunization route, nanoplex vaccines inhibit formation of lung metastases in a murine melanoma model. Additionally, nanoplex vaccines strongly synergize with the adjuvant α-galactosylceramide (α-GalCer) in stimulating robust CD8 T cell responses, significantly increasing survival time in mice with established melanoma tumors. Collectively, these findings demonstrate that peptide/pPAA nanoplexes offer a facile and versatile platform for enhancing CD8 T cell responses to peptide antigens, with potential to complement ongoing advancements in the development of neoantigen-targeted cancer vaccines.

Immunomodulatory Nanosystems

“…[134] When the antigen-loaded micelles entered endosomal compartments, the acid environment protonated the carboxylate residues of PAA and increased the positive charge in DMAEMA residues. [133] The polyPAA/peptide nanoplexes showed extended retention in DC2.4 cells and enhanced presentation on MHCI. [134,186] The authors found that a majority of OVA delivered by pH-responsive micelles was able to retain within DC cells in vitro for nearly 1.5 h, while non-pH-responsive micelles showed more than 60% antigen exocytosis in 15 min.…”

“…[130,131] These clinical researches confirmed their great therapeutic potential as antitumor agents. [56,126,[132][133][134] In this section, we overview the recent developments in the use of engineered nanoparticles to enhance cancer immunotherapy. [67] To achieve precise and controlled drug delivery, smart nanoparticles with more complex structures and specific drug release properties are also being produced according to the hallmarks of TME, such as weak acidic pH (6.5-6.8), high level of glutathione and hydrogen peroxide (H 2 O 2 ), and disorder of proteinases production, such as matrix metalloproteinase-2 (MMP-2).…”

“…[67] To achieve precise and controlled drug delivery, smart nanoparticles with more complex structures and specific drug release properties are also being produced according to the hallmarks of TME, such as weak acidic pH (6.5-6.8), high level of glutathione and hydrogen peroxide (H 2 O 2 ), and disorder of proteinases production, such as matrix metalloproteinase-2 (MMP-2). HDL-mimicking nanodisc Patient-derived neoantigen and cholesterol-modified CpG -- [135] PLGA NP OVA, Pam3Csk4, and Poly(I:C) CD40 on DCs - [136] Chitosan nanoparticle Cell lysate from B16 melanoma Mannose receptor on DCs - [38] Lipo-CpG micelle CpG Albumin hitchhiking - [137] γPGA-based CNNP OVA and poly(I:C) -- [138] PLGA-based AC-NP --- [139] mBiNE CRT HER-2 on tumor cells - [140] T cell activation DMAEMA, PAA, and butyl methacrylate OVA -pH [134] polyPAA OVA -pH [133] CNT MHC1 peptide, anti-CD28, and PLGA NPs encapsulating IL-2 and magnetite -- [141] Magnetic nanocluster MHC1-OVA, anti-CD28, and leukocyte membrane fragments Magnetic navigation - [128] PD-1 receptor-expressing NV --- [142] PEG-PLA NP CTLA-4 siRNA -- [143] Platelet-derived microparticle Anti-PD-L1 Ab -- [144] PEG-PLGA NP Anti-PD-1 Ab and aOX40 -- [145] Super-paramagnetic iron oxide nanoparticle Anti-PD-L1 Ab, anti-CD3/anti-CD28 Ab, fucoidan, and dextran Magnetic navigation - [129] Regulation of TME PLGA NP core with lipid shell Imatinib Nrp1 receptor on Tregs - [43] CDNP consisting of CD and lysine R848 -- [146] NV derived from type 1 macrophage --- [147] Carboxyl-functionalied and aminofunctionalized polystyrene nanoparticle --- [148] Super-paramagnetic iron oxide --- [149] Ferumoxytol --- [150] HDL NP -Scavenger receptor B1 on MDSCs - [151] PEGylated LNC lmGem -- [152] LPH NP HMGA1 siRNA Sigma receptor on tumor cells - [153] LCP NP TGF-β siRNA, tumor antigen, and CpG -- [154] PEG-PLGA NP SD-208 PD-1 on T cells - [155] Nanoparticle assembled from DEAP molecule, PD-L1 antagonist, NGL919, and a substrate peptide of MMP-2 -pH and MMP-2 …”

Recent Advances in Polymeric Nanomedicines for Cancer Immunotherapy

“…Antigen release profile was modulated by exploiting endosomal escape mechanisms and enhancing delivery of antigenic cargo to the cytosol for processing, which induces enhanced and sustained MHC class I presentation of peptide antigen by DCs . Qiu et al have developed polyplex nanoparticles (nanoplexes) via simple mixing of decalysine‐modified antigenic peptides and poly(propylacrylic acid) (pPAA), a linear amphiphilic polyanion with a p K a value of 6.7 as a cytosolic antigen delivery carrier which has pH‐dependent membrane destabilizing activity ( Figure A) . To prepare electrostatically stabilized complexation between the peptide antigen and pPAA, peptides containing the mouse MHC class I (H‐2K b )‐restricted epitope, SIINFEKL, from ovalbumin (OVA) as a model antigen were modified with a cationic N‐terminal decalysine (K 10 ) tail (K 10 OVA).…”

“…F) B3Z T cell response after DC were treated with each formulation for 4 h at 10 × 10 −6 m peptide, followed by coculture with B3Z hybridoma T cells for 24 h. G) B3Z T cell response to DC2.4 cells at different peptide concentrations. Reproduced with permission . Copyright 2018, Elsevier.…”