Development of a Cancer Vaccine Using In Vivo Click‐Chemistry‐Mediated Active Lymph Node Accumulation for Improved Immunotherapy

Abstract

antigens together with a strong adjuvant. Despite the promise of this approach, the clinical efficacy currently remains modest. One method to elicit a more robust and durable immune response against a particular cancer is by targeting tumor antigens and adjuvants to antigen presenting macrophages and dendritic cells (DCs). [2,3] These cells normally encounter antigens at the site of peripheral vaccination, then subsequently mature, enter the lymphatic vessels and migrate to lymph nodes (LNs) to prime effector lymphocytes. [4] Over the past decades, considerable efforts have been made to generate DC-based cancer vaccines by maturing isolated DCs with adjuvants (e.g., toll-like receptor (TLR), agonists, cytokines, and molecules that facilitate DC maturation) and equipping them with tumor antigens in vitro to improve the efficiency of these cells. [5,6] However, ex vivo cell culture is expensive and a limited amount of DCs migrate to the LNs for the activation of antigen-specific T cells. Other widely investigated strategies for allophycocyanin (APC) targeting in vivo are to fuse antigens with antibodies or ligands that target APC surface markers, such as TLRs, CD205, CD207, CD11c, and major histocompatibility complex (MHC) II, or to generate nanoformulations modified with such antibodies or ligands to deliver the antigens. [2,7] Such designs often target APCs in peripheral tissues, whereas the LN APCs are a more desirable target. LNs contain a high number of resident APCs, so delivery of antigens and adjuvants to the LN is likely to increase uptake by APCs, resulting in enhanced vaccine efficiency. [8,9] In addition, resident APCs in LNs are phenotypically immature and capable of internalizing antigens and particles. [10] Thus, LN-resident APCs may be ideal targets for immunotherapeutic drugs.Nanoformulations loaded with tumor-specific antigens and adjuvants have proven highly beneficial in boosting vaccine efficiency. [11][12][13] Those nanoformulations with diameters larger than 100 nm are primarily utilized for the delivery of antigens to peripheral APCs, which subsequently migrate to the lymph nodes to activate T cells. [14] Antigen peptide degradation, rapid MHC I turnover, and the disassociation of peptide antigen from MHC molecules may all occur during translocation to Due to their ability to elicit a potent immune reaction with low systemic toxicity, cancer vaccines represent a promising strategy for treating tumors. Considerable effort has been directed toward improving the in vivo efficacy of cancer vaccines, with direct lymph node (LN) targeting being the most promising approach. Here, a click-chemistry-based active LN accumulation system (ALAS) is developed by surface modification of lymphatic endothelial cells with an azide group, which provide targets for dibenzocyclooctyne (DBCO)-modified liposomes, to improve the delivery of encapsulated antigen and adjuvant to LNs. When loading with OVA 257-264 peptide and poly(I:C), the formulation elicits an enhanced CD8 + T cell response in vivo, resulting in ...

Rapid Surface Display of mRNA Antigens by Bacteria‐Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine

“…These results demonstrate that the OMV-LL vaccine nanocarriers can enter the draining lymph nodes and be efficiently captured by APCs, which is a prerequisite for subsequent immune stimulation. [35] To investigate the immune response stimulated by the OMV-based mRNA vaccine, we treated C57BL/6 mice with mRNA OVA , the mixture of natural OMVs and mRNA OVA (OMVs + mRNA OVA ), OMV-L-mRNA OVA , or OMV-LL-mRNA OVA . The draining lymph nodes were collected for the evaluation of DC activation.…”

Metal-free bioorthogonal click chemistry in cancer theranostics

“…27a). 226 Under the albumin hitchhiking mechanism, azide groups were anchored on LECs, forming N 3 -LECs. OVA 257-264 peptide (a model CD8 + T-cell epitope antigen) and poly(I:C) (a TLR agonist) were encapsulated in DBCO-conjugated liposomes (DL), generating DL-O/IC vaccine.…”

Engineering POLYTAC Nanoparticles for Bioorthogonal Click Reaction-Enforced Protein Degradation and Breast Cancer Therapy

“…In previous studies, we had explored intracellular acidity-activatable PDT for circumventing multidrug resistance of the breast tumor 34 . To explore the potential of the POLY-PROTAC NPs as a generalizable nanoplatform for combinatory therapy, we next sought to combine the bioorthogonal NPs for PDTenforced antitumor therapy (Fig.…”