Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Abstract

Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle‐filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen‐mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy‐to‐monitor and high‐yield antigen ligation at low concentrations. The protective effect of these constructs is investigated against a highly aggressive model for tumor immunotherapy. The results show that the nanovaccines lead to a higher‐level antigen‐specific cytotoxic T lymphocyte (CTL) effector and memory responses, which when combined with abrogation of the immunosuppressive programmed death‐ligand 1 (PD‐L1), provide 100% long‐term protection against repeated tumor challenge. This nanovaccine platform in combination with checkpoint inhibition of PD‐L1 represents a promising approach to improve the cancer immunotherapy of TLR4 agonists.

Understanding the Nano-bio Interfaces: Lipid-Coatings for Inorganic Nanoparticles as Promising Strategy for Biomedical Applications

“…Similarly, multifunctional SPIONs coated with a SLB of lipoid phosphatidylcholine (PC) and cholesterol, also conjugated with a near-infrared fluorescence agent and further functionalized with a tumoral hepatocytes-targeting polymer, showed an high stability in physiological conditions; in addition, they demonstrated prominent tumor-contrasted imaging performance both on fluorescent and T 2 -weighted magnetic resonance (MR) imaging modalities in a living body (Liang et al, 2017). More recently, SPIONs with a HLB composed by a PEG-modified POPC and a lipooligosaccharide (LOS) derived from the plant pathogen as TLR4 agonists, were designed and developed as a cancer vaccine platform (Traini et al, 2019). This approach allows to produce stable bacteria-mimicking nanostructures for the development of cancer immunotherapies (Figure 7), proposing a novel bioinspired kind of multifunctional lipid-coated NPs with improved biomedical properties.…”

“…Illustration of SPIONs coated with a HLB containing a bacterial lipooligosaccharide (LOS) in the external leaflet as bioinspired nanostructures for cancer immunotherapy [adapted with permission from (Traini et al, 2019). Copyright (2019) WILEY-VCH].…”

Biodegradable PLGA-b-PEG Nanoparticles Induce T Helper 2 (Th2) Immune Responses and Sustained Antibody Titers via TLR9 Stimulation

“…Emerging NP-based vaccines often include additional adjuvants into the formulation, which stimulate innate danger-signal receptors, such as Toll-like receptor (TLR) agonists [ 11 ]. The most widely used TLR agonists are ligands for extracellular TLR4, i.e., lipopolysaccharide (LPS) and its non-toxic derivative monosphosphoryl lipid A (MPL-A) [ 12 , 13 ], and those that target intracellular TLRs such as CpG, the ligand for TLR9 [ 14 , 15 , 16 ]. Ligands targeting intracellular TLRs are increasingly popular due to their ability to induce antibody responses, as well as T-cell responses which promote high affinity antibody production, modulate antibody isotypes, and promote long lasting immunity [ 17 ].…”

Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment

“…Some examples of utilization of nano-carriers targeting the TLR for immune cancer therapy are listed in Table 2 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 below.…”