Systemically Administered TLR7/8 Agonist and Antigen-Conjugated Nanogels Govern Immune Responses against Tumors

Abstract

The generation of specific humoral and cellular immune responses plays a pivotal role in the development of effective vaccines against tumors. Especially the presence of antigen-specific, cytotoxic T cells influences the outcome of therapeutic cancer vaccinations. Different strategies, ranging from delivering antigen-encoding mRNAs to peptides or full antigens, are accessible but often suffer from insufficient immunogenicity and require immune-boosting adjuvants as well as carrier platforms to ensure stability and adequate retention. Here, we introduce a pH-responsive nanogel platform as a two-component antitumor vaccine that is safe for intravenous application and elicits robust immune responses in vitro and in vivo . The underlying chemical design allows for straightforward covalent attachment of a model antigen (ovalbumin) and an immune adjuvant (imidazoquinoline-type TLR7/8 agonist) onto the same nanocarrier system. In addition to eliciting antigen-specific T and B cell responses that outperform mixtures of individual components, our two-component nanovaccine leads in prophylactic and therapeutic studies to an antigen-specific growth reduction of different tumors expressing ovalbumin intracellularly or on their surface. Regarding the versatile opportunities for functionalization, our nanogels are promising for the development of highly customized and potent nanovaccines.

Pairing Nanoparticles Geometry with TLR Agonists to Modulate Immune Responses for Vaccine Development

“…To explore this notion, TLR agonists, CpG, and imidazoquinoline derivatives were selected for our studies because they have a venerable history as vaccine adjuvants. , CpGs are synthetic oligodeoxynucleotides that trigger toll-like receptor 9 and activate innate immune responses by producing Th1-associated cytokines. , Although imidazoquinoline derivatives were identified as TLR 7/8 agonists, they induce pro-inflammatory cytokines such as TNF alpha and IL-12 . Both CpGs and imidazoquinoline have been extensively used as adjuvants in several vaccines. − However, to the best of our knowledge, they have never been studied together on a nanotechnology platform.…”

Bioengineered nanogels for cancer immunotherapy

“…More recently in 2022, the same group also developed a pH-responsive nanogel platform, using OVA and TLR7/8 agonists, which could be modularly modified into nanogels, resulting in two-component nanogels that effectively inhibited tumour growth in both preventive and therapeutic assays and thus, provided the opportunity to establish cancer-specific immunity. 257 It was found that the expression of CD80 and CD86 of DCs in the spleen was enhanced, and induced the activation of downstream T lymphocytes. This nanogel could effectively prevent systemic inflammation due to massive systemic immune activations compared to the off-target effects of small-molecular IMDQ (Fig.…”

Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels

“…In previous reports, we could demonstrate that various types of macromolecular carriers can spatiotemporally control the delivery of covalently attached IMDQ while omitting the drug's systemic inflammatory offtarget effects. [22,26,[85][86][87][88][89] Giving the fact that the empty nanogel NP(-) remained immunologically silent during the in vitro experiments, we therefore administered the IMDQ-nanogel NP(IMDQ) versus the soluble drug sIMDQ subcutaneously into the footpad of mice. We aimed for a focused delivery of the nanogels to the draining lymph nodes followed by a local activation of lymph node residing and infiltrating immune cells while excluding a systemic activation of immune system.…”