Cancer Nanovaccines Research Articles

Abstract 835: Translational nanotechnology-based cancer vaccine to re-educate host immune response against metastatic cancers

Abstract Sixty percent of melanoma patients present brain metastases, having low response rates to current systemic therapies, which do not prolong survival. New therapeutic options to address this clinical need are urgent. Here, we report the development of a polymeric nanoparticle as a cancer nanovaccine capable of selectively co-targeting toll-like receptor function and PD-L1 expression to improve antigen presentation and subsequent effector immune cell function within brain microenvironment. Mannose-poly(lactic-co-glycolic acid)/poly(lactic acid) (man-PLGA/PLA) nanoparticles (NP) were prepared by a modified double emulsion solvent evaporation method, to deliver combinations of melanoma neoantigens, toll-like receptor ligands and regulators of the PD-1/PD-L1 axis. NP physicochemical properties were fully characterized, including size, surface charge and morphology. The amount of melanoma neoantigens and immune regulators entrapped within NP was determined by HPLC. Immature dendritic cells (DC) were used to evaluate the impact of NP on cell viability, and to assess NP uptake kinetics by flow cytometry. NP ability to target and trigger the activation of DC and T cells, was assessed in the lymph nodes and spleen of immunized mice. The NP anti-tumor immune-mediated effect was evaluated in vivo in two primary melanoma-bearing immunocompetent mouse models (B16F10 and B16MO5), and in a melanoma brain metastasis (MBM) mouse model (B16F10), which also included the immune profiling within tumor site by flow cytometry, before and after treatment.NP presented an average diameter of 180 nm, narrow polydispersity index, surface charge close to neutrality, spherical morphology, and high loadings of the neoantigens and immunoregulators. NP did not affect DC viability and were extensively internalized by immature DC. NP were preferentially taken-up in vivo by DC, increasing the expression of activation/maturation markers at DC surface, such as CD80 and CD86. NP elicited antigen-specific T-cell responses, by the significant increase in the expression of TNF-alpha and IFN-gamma (TH1-guided response). In vivo combination of NP with anti-PD-L1 induced a potent immune-mediated anti-tumor response in both primary and preclinical models of MBM, overcoming tumor development with an increased overall survival. This combination re-shaped immune and stroma cell populations in primary tumor and MBM microenvironment, which presented a marked infiltration of cytotoxic T cells that correlated with a decreased expression of PD-1 and PD-L1 within the TME. The synergy between our nanovaccine and anti-PD-L1 provide essential insights to devise alternative combinations regiments to improve the efficacy of immune checkpoint inhibitors in metastatic melanoma, thus opening new line for this unmet medical need. Citation Format: Barbara Carreira, Rita A. Acúrcio, Sabina Pozzi, Ron Kleiner, Liane I. Moura, Ana I. Matos, Daniela vaskovich, Carina Peres, Adelaide Fernandes, Sara Xapelli, Ronit Satchi-Fainaro, Helena F. Florindo. Translational nanotechnology-based cancer vaccine to re-educate host immune response against metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 835.

Nanovaccines for cancer immunotherapy: Focusing on complex formation between adjuvant and antigen.

As an interesting cancer immunotherapy approach, cancer vaccines have been developed to deliver tumor antigens and adjuvants to antigen-presenting cells (APCs). Although the safety and easy production shifted the vaccine designing platforms toward the subunit vaccines, their efficacy is limited due to inefficient vaccine delivery. Nanotechnology-based vaccines, called nanovaccines, address the delivery limitations through co-delivery of antigens and adjuvants into lymphoid organs and APCs and their intracellular release, leading to cross-presentation of antigens and induction of potent anti-tumor immune responses. Although the nanovaccines, either as encapsulating agents or biomimetic nanoparticles, exert the desired anti-tumor activities, there is evidence that the mixing formulation to form nanocomplexes between antigens and adjuvants based on the electrostatic interactions provokes high levels of immune responses owing to Ags' availability and faster release. Here, we summarized the various platforms for developing cancer vaccines and the advantages of using delivery systems. The cancer nanovaccines, including nanoparticle-based and biomimetic-based nanovaccines, are discussed in detail. Finally, we focused on the nanocomplexes formation between antigens and adjuvants as promising cancer nanovaccine platforms.

In Situ Separable Nanovaccines with Stealthy Bioadhesive Capability for Durable Cancer Immunotherapy.

Because of tumor heterogeneity and the immunosuppressive tumor microenvironment, most cancer vaccines typically do not elicit robust antitumor immunological responses in clinical trials. In this paper, we report findings about a bioadhesive nanoparticle (BNP)-based separable cancer vaccine, FeSHK@B-ovalbumin (OVA), to target multi-epitope antigens and exert effective cancer immunotherapy. After the FeSHK@B-OVA "nanorocket" initiates the "satellite-rocket separation" procedure in the acidic tumor microenvironment, the FeSHK@B "launch vehicle" can amplify intracellular oxidative stress persistently. This procedure allows for bioadhesiveness-mediated prolonged drug retention within the tumor tissue and triggers the immunogenic death of tumor cells that transforms the primary tumors into antigen depots, which acts synergistically with the OVA "satellite" to trigger robust antigen-specific antitumor immunity. The cooperation of these two immunostimulants not only efficiently inhibits the primary tumor growth and provokes durable antigen-specific immune activation in vivo but also activates a long-term and robust immune memory effect to resist tumor rechallenge and metastasis. These results highlight the enormous potential of FeSHK@B-OVA to serve as an excellent therapeutic and prophylactic cancer nanovaccine. By leveraging the antigen depots in situ and the synergistic effect among multi-epitope antigens, such a nanovaccine strategy with stealthy bioadhesion may offer a straightforward and efficient approach to developing various cancer vaccines for different types of tumors.

Development of a Cancer Nanovaccine to Induce Antigen-specific Immune Responses Based on Large-Sized Porous Silica Nanoparticles.

Cancer vaccine is one of the immunotherapeutic strategies aiming to effectively deliver cancer antigens to professional antigen-presenting cells such as dendritic cells (DCs), macrophages, and B cells to elicit a cancer-specific immune response. Despite the advantages of the cancer vaccine that can be applied to various cancer types, the clinical approach is limited due to the non-specific or adverse immune responses, stability, and safety issues. In this study, we report an injectable nanovaccine platform based on large-sized (∼350 nm) porous silica nanoparticles (PSNs). We found that large-sized PSNs, called PS3, facilitated the formation of an antigen supply depot at the site of injection so that a single injection of PSN-based nanovaccine elicited sufficient tumor-specific cell-mediated and humoral immune response. As a result, antigen-loaded PS3 induced successful tumor regression in prophylactic and therapeutic vaccination.

Facile preparation of a metal-phenolic network-based lymph node targeting nanovaccine for antitumor immunotherapy.

Cancer vaccines are being explored for enhanced cancer immunotherapy and prophylaxis. Some of their prevailing weaknesses, however, such as complicated preparation, poor biocompatibility, and failure to elicit strong cellular immune responses, have limited their further clinical applications. Here, we reported a multifunctional nanovaccine that was prepared in a quick and simple way. During the self-assembly of metal-phenolic networks (MPNs), the antigen ovalbumin (OVA) and immunoreactive chlorogenic acid (CHA) were simultaneously loaded. Owing to its dual pH and reduction sensitivities, the nanovaccine could deliver antigens into the cytoplasm of dendritic cells (DCs) and facilitate the cross-presentation of antigens. Moreover, the results of in vivo immunization assays demonstrated that the nanovaccine significantly excited the antigen presentation of DCs and provoked a robust cellular immune response with the restrained activation of regulatory T cells (Tregs), by targeting lymph nodes and executing the function of CHA. In vivo antitumor assays indicated that the nanovaccine with good biocompatibility afforded conspicuous cancer treatment and prevention effects. Overall, the nanovaccine presented in this study shows a promise for potentiating cancer immunotherapy by the lymph node-targeted delivery. STATEMENT OF SIGNIFICANCE: Cancer nanovaccines can be used for cancer immunotherapy. However, some existing shortcomings, such as cumbersome preparation, poor biocompatibility, and failure to elicit strong immune responses, limit the clinical application of cancer nanovaccines. This study developed a multifunctional nanovaccine that was readily prepared through the self-assembly of metal-phenolic networks. The nanovaccine with dual pH and reduction sensitivities could efficiently promote the antigen lysosome escape and cross-presentation. In vivo, it efficiently delivered antigen into lymph nodes and provoked strong cellular immune responses, and thus it showed significant cancer immunotherapy and prevention effect.

Orchestrated Cytosolic Delivery of Antigen and Adjuvant by Manganese Ion-Coordinated Nanovaccine for Enhanced Cancer Immunotherapy.

Cancer vaccines have received tremendous attention in cancer immunotherapy due to their capability to induce a tumor-specific immune response. However, their effectiveness is compromised by the insufficient spatiotemporal delivery of antigens and adjuvants in the subcellular level to induce a robust CD8+ T cell response. Herein, a cancer nanovaccine G5-pBA/OVA@Mn is prepared through multiple interactions of manganese ions (Mn2+), benzoic acid (BA)-modified fifth generation polyamidoamine (G5-PAMAM) dendrimer, and the model protein antigen ovalbumin (OVA). In the nanovaccine, Mn2+ not only exerts a structural function to assist OVA loading as well as its endosomal escape, but works as an adjuvant of stimulator of interferon genes (STING) pathway. These collaboratively facilitate the orchestrated codelivery of OVA antigen and Mn2+ into cell cytoplasm. Vaccination with G5-pBA/OVA@Mn not only shows a prophylactic effect, but also significantly inhibits growth against B16-OVA tumors, indicating its great potential for cancer immunotherapy.

Bacterial outer membrane vesicle-based cancer nanovaccines.

Tumor vaccines, a type of personalized tumor immunotherapy, have developed rapidly in recent decades. These vaccines evoke tumor antigen-specific T cells to achieve immune recognition and killing of tumor cells. Because the immunogenicity of tumor antigens alone is insufficient, immune adjuvants and nanocarriers are often required to enhance anti-tumor immune responses. At present, vaccine carrier development often integrates nanocarriers and immune adjuvants. Among them, outer membrane vesicles (OMVs) are receiving increasing attention as a delivery platform for tumor vaccines. OMVs are natural nanovesicles derived from Gram-negative bacteria, which have adjuvant function because they contain pathogen associated molecular patterns. Importantly, OMVs can be functionally modified by genetic engineering of bacteria, thus laying a foundation for applications as a delivery platform for tumor nanovaccines. This review summarizes 5 aspects of recent progress in, and future development of, OMV-based tumor nanovaccines: strain selection, heterogeneity, tumor antigen loading, immunogenicity and safety, and mass production of OMVs.

Unprecedented Chiral Nanovaccines for Significantly Enhanced Cancer Immunotherapy.

As a representative strategy for cancer immunotherapy, cancer nanovaccines have aroused enormous interest. Although various nanovaccines have been developed to promote immunogenicity and improve the therapeutic efficacy, chiral nanovaccines have been less explored as of yet. Chiral carbon dots (CDs) have similar size to proteins, abundant functional groups, and nanoscale chirality, which can not only carry and deliver antigens but also induce cellular and humoral immune responses and can play dual roles of nanovehicles and immune adjuvants. Herein, we demonstrate that the chiral nanovaccines (l/d-OVA) could be conveniently fabricated by utilizing chiral CDs as carriers and immune adjuvants and ovalbumin (OVA) as an antigen model. l/d-OVA nanovaccines could be effectively internalized by mouse bone-marrow-derived dendritic cells (BMDCs), boost BMDC maturation, efficiently cross-present to T cells, and suppress the growth of B16-OVA melanoma. This work illustrates the hopeful potential of chiral CDs as effective vectors for loading protein cargos and delivering them into cancer cells.

Nanovaccines for Cancer Prevention and Immunotherapy: An Update Review.

Simple SummaryCancer vaccines are a promising immunotherapy-based agents used in cancer therapy. However, monotherapy with these vaccines does not have the sufficient effectiveness in clinical settings. To overcome this challenge, researchers designed nanosystems that increase cancer vaccine efficacy and effectiveness by improving the vaccine's half-life and durability, inducing TME reprogram-ming, and enhancing the anti-tumor immunity with minimum toxicity. This review summarized the structure and different types of cancer nanovaccines and their mechanisms of action in cancer therapy. Moreover, the advantages and drawbacks of these vaccines are discussed.Cancer immunotherapy has received more and more attention from cancer researchers over the past few decades. Various methods such as cell therapy, immune checkpoint blockers, and cancer vaccines alone or in combination therapies have achieved relatively satisfactory results in cancer therapy. Among these immunotherapy-based methods, cancer vaccines alone have not yet had the necessary efficacy in the clinic. Therefore, nanomaterials have increased the efficacy and ef-fectiveness of cancer vaccines by increasing their half-life and durability, promoting tumor mi-croenvironment (TME) reprogramming, and enhancing their anti-tumor immunity with minimal toxicity. In this review, according to the latest studies, the structure and different types of nanovaccines, the mechanisms of these vaccines in cancer treatment, as well as the advantages and disadvantages of these nanovaccines are discussed.

Nanocarriers based on bacterial membrane materials for cancer vaccine delivery.

Here we present a protocol for the construction and use of two types of nanocarrier based on bacterial membrane materials for cancer vaccine delivery. Cancer vaccines induce tumor regression through triggering the specific T-cell responses against tumor neoantigens, a process that can be enhanced by nanocarrier delivery. Inspired by the body's natural immune defenses against bacterial invasion, we have developed two different types of nanocarrier based on bacterial membrane materials, which employ genetically engineered outer-membrane vesicles (OMVs), or hybrid membrane vesicles containing bacterial cytoplasmic membrane, respectively. The OMV-based nanocarriers can rapidly display different tumor antigens through the surface modified Plug-and-Display system, suitable for customized cancer vaccines when the tumor neoantigens can be identified. The hybrid membrane-based nanocarriers are prepared through fusion of the bacterial cytoplasmic membrane and the primary tumor cell membrane from surgically removed tumor tissues, possessing unique advantages as personalized cancer vaccines when the neoantigens are not readily available. Compared with chemically synthesized nanocarriers such as liposomes and polymer without intrinsic adjuvant properties, owing to the large amounts of pathogen-associated molecular patterns, the two nanocarriers can activate the antigen-presenting cells while delivering multiple antigens, thus inducing effective antigen presentation and robust adaptive immune activation. Excluding bacterial culture and tumor tissue collection, the preparation of OMV- and hybrid membrane-based nanocarriers takes ~8 h and 10 h for tumor vaccine construction, respectively. We also detail how to use these nanocarriers to create cancer nanovaccines and evaluate their immunostimulatory and antitumor effects.

Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy

The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment (TME). Here, we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes (TILs) using hybrid micelles (HM), which encapsulated colony stimulating factor 1 receptor (CSF1-R) inhibitor BLZ-945 and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG-919 in its core and displayed a model antigen ovalbumin (OVA) on its surface (denoted as BN@HM-OVA). The bioactive nanovaccine is coated with a polyethylene glycol (PEG) shell for extending nanoparticle circulation. The shell can be shed in response to the weakly acidic tumor microenvironment. The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs. We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells (DCs) and drugs transportation into M1-like tumor-associated macrophages (TAMs) and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME. Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment, leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models. Furthermore, combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition, based on the optimal timing and sequence of PD-1 blockade against T cell receptor. This research provides a new strategy for the development of efficient cancer immunotherapy.

Nano dimensions/adjuvants in COVID-19 vaccines.

A favorable outcome of the COVID-19 crisis might be achieved with massive vaccination. The proposed vaccines contain several different vaccine active principles (VAP), such as inactivated virus, antigen, mRNA, and DNA, which are associated with either standard adjuvants or nanomaterials (NM) such as liposomes in Moderna's and BioNTech/Pfizer's vaccines. COVID-19 vaccine adjuvants may be chosen among liposomes or other types of NM composed for example of graphene oxide, carbon nanotubes, micelles, exosomes, membrane vesicles, polymers, or metallic NM, taking inspiration from cancer nano-vaccines, whose adjuvants may share some of their properties with those of viral vaccines. The mechanisms of action of nano-adjuvants are based on the facilitation by NM of targeting certain regions of immune interest such as the mucus, lymph nodes, and zones of infection or blood irrigation, the possible modulation of the type of attachment of the VAP to NM, in particular VAP positioning on the NM external surface to favor VAP presentation to antigen presenting cells (APC) or VAP encapsulation within NM to prevent VAP degradation, and the possibility to adjust the nature of the immune response by tuning the physico-chemical properties of NM such as their size, surface charge, or composition. The use of NM as adjuvants or the presence of nano-dimensions in COVID-19 vaccines does not only have the potential to improve the vaccine benefit/risk ratio, but also to reduce the dose of vaccine necessary to reach full efficacy. It could therefore ease the overall spread of COVID-19 vaccines within a sufficiently large portion of the world population to exit the current crisis.

Immunotherapy and Prevention of Cancer by Nanovaccines Loaded with Whole‐Cell Components of Tumor Tissues or Cells (Adv. Mater. 43/2021)

Cancer Nanovaccines In article number 2104849, Mi Liu and co-workers demonstrate a simple and universal method to prepare therapeutic and preventive cancer nanovaccines based on tumor tissues/cells. Such nanovaccines show both potent preventive and potent therapeutic efficacy in lung cancer, melanoma, and breast cancer. This universal method can be applied to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.

Recombinant cancer nanovaccine for targeting tumor-associated macrophage and remodeling tumor microenvironment

The efficient cancer vaccines require the codelivery of potent antigens and highly immunostimulatory adjuvants to the same antigen-presenting cells (APCs) to initiate a robust immune response. In this work, a clinically used trichosanthin served as an adjuvant to prepare a minimalist “all-in-one” vaccine that was a recombinant protein (termed rTL) of trichosanthin and an antigen legumain peptide. rTL was further incorporated into a nanovaccine delivery system (LrTL) using a liposome-encapsulated technology. LrTL can trigger a robust cytotoxic T lymphocytes (CTL) response by activation of APCs that enhance immunostimulatory cytokine secretion (e.g., TNF-α, IL-12, and IFN-γ) and trigger T-cell immunity. By targeting tumor-associated macrophages (TAM), the nanovaccine carried out the anticancer immunity by eliminating TAM and thereby remodeling the tumor microenvironment. Subcutaneous immunization with the nanovaccine yielded a potent anti-tumor activity in several cancer models, including B16-F10, Lewis lung cancer (LLC), intracranial LLC xenograft, as well as CT-26 colon cancer. These findings demonstrate that the nanovaccine is a simple, safe, and robust strategy for cancer immunotherapy. The vaccination strategy offers a general applicability in various cancer types by targeting TAM and remodeling tumor microenvironment.

Radial porous SiO2 nanoflowers potentiate the effect of antigen/adjuvant in antitumor immunotherapy

Here, we reported a cancer nanovaccine based on SiO2 nanoflowers with a special radial pore structure, which greatly enhanced cross-presentation and induced the production of cytotoxic T lymphocyte cells secreting granzymes B and interferon-γ. The antigen ovalbumin was covalently conjugated onto the as-synthesized hierarchical SiO2 nanoflowers, and the adjuvant cytosine-phosphate-guanine was electrostatically adsorbed into their radial pore by simple mixing before use. The nanovaccine exhibited excellent storage stability without antigen release after 27 days of incubation, negligible cytotoxicity to dendritic cells, and a high antigen loading capacity of 430 ± 66 mg·g−1 support. Besides, the nanovaccine could be internalized by dendritic cells via multiple pathways. And the enhancement of antigen/adjuvant uptake and lysosome escape of antigen were observed. Noteworthy, in vitro culture of bone marrow-derived dendritic cells in the presence of nanovaccine proved the activation of dendritic cells and antigen cross-presentation as well as secretion of proinflammatory cytokines. Besides, in vivo study verified the targeting of nanovaccine to draining lymph nodes, the complete suppression of tumor in six out of ten mice, and the triggering of notable tumor growth delay. Overall, the present results indicated that the nanovaccine can be served as a potential therapeutic vaccine to treat cancer.

Emerging advances in cationic liposomal cancer nanovaccines: opportunities and challenges.

Advancements in the field of cancer therapeutics have witnessed a recent surge in the use of liposomes. The physicochemical characteristics of the liposomes and their components, including the lipid phase transition temperature, vesicular size and size distribution, surface properties, and route of administration, play a significant role in the modulation of the immune response as an adjuvant and for loaded antigen (Ag). Cationic liposomes, concerning their potential ability to amplify the immunogenicity of the loaded Ag/adjuvant, have received enormous interest as a promising vaccine delivery platform for cancer immunotherapy. In the present review, the physicochemical considerations for the development of Ag/adjuvant-loaded liposomes and the cationic liposomes' effectiveness for promoting cancer immunotherapy have been summarized.

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

Metal-Phenolic Network-Encapsulated Nanovaccine with pH and Reduction Dual Responsiveness for Enhanced Cancer Immunotherapy.

Cancer nanovaccines have been widely explored to enhance immunotherapy efficiency, in which the significant irritation of antigen-specific cytotoxic T cells (CTLs) is the critical point. In this study, we developed a pH and reduction dual-sensitive nanovaccine (PMSN@OVA-MPN) composed of two parts. The inner part was made up of polyethyleneimine (PEI)-modified mesoporous silica nanoparticles (MSNs) loaded with model antigen ovalbumin (OVA) and the outer part was made up of disulfide bond-involved metal-phenolic networks (MPNs) as a protective corona. In vitro release experiments proved that PMSN@OVA-MPN could intelligently release OVA in the presence of reductive glutathione, but not in neutral phosphate-buffered saline (PBS). Moreover, in vitro cell assays indicated that the nanovaccine promoted not only the OVA uptake efficiency by DC2.4 cells but also antigen lysosome escape due to the proton sponge effect of PEI. Furthermore, in vivo animal experiments indicated that PMSN@OVA-MPN induced a large tumor-specific cellular immune response so as to effectively inhibit the growth of an existing tumor. Finally, the immune memory effect caused by the nanovaccine afforded conspicuous prophylaxis efficacy in neonatal tumors. Hence, the multifunctional vaccine delivery system prepared in this work exhibits a great application potential in cancer immunotherapy and offers a platform for the development of nanovaccines.

Nanovaccines integrating endogenous antigens and pathogenic adjuvants elicit potent antitumor immunity

Abstract Cancer nanovaccines have the ability to train the immune system to specifically recognize and eliminate tumor cells. However, the vaccine’s efficacy is hampered by limited access to draining lymph nodes, poor recognition and internalization by dendritic cells (DCs), as well as insufficient immunogenicity to elicit the DC maturation. To overcome these challenges, we developed potent vesicular cancer nanovaccines by fusing bacterial outer membrane vesicles (OMVs) and tumor cell membranes (TCMs), namely BTs. The bacteria-derived pathogenic adjuvants in BTs enabled DC targeting, promoted full maturation of DCs and antigen presentation by DCs. The TCMs in BTs assembled a multitude of diverse tumor endogenous antigens as training cues to generate multiantigenic antitumor immunity. Integrating the two components via a lipid bilayer assembly avoids the premature separation in the biological environment and enables the high spatial and temporal delivery of the antigens and adjuvants into the same DCs. Immunization with BTs containing as low as 1 μg of OMVs confers an excellent tumor prophylactic effect with ∼30 % of treated mice maintaining a tumor-free status for over 100 days. Moreover, the nanovaccines exhibit a remarkable therapeutic effect in treating established solid tumors and potentiate immune checkpoint blockade therapy. Overall, the BTs are promising as personalized cancer nanovaccines and carry no systemic side effects.

Lipidation Approaches Potentiate Adjuvant-Pulsed Immune Surveillance: A Design Rationale for Cancer Nanovaccine.

Adjuvant-pulsed peptide vaccines hold great promise for the prevention and treatment of different diseases including cancer. However, it has been difficult to maximize vaccine efficacy due to numerous obstacles including the unfavorable tolerability profile of adjuvants, instability of peptide antigens, limited cellular uptake, and fast diffusion from the injection site, as well as systemic adverse effects. Here we describe a robust lipidation approach for effective nanoparticle co-delivery of low-molecular weight immunomodulators (TLR7/8 agonists) and peptides (SIINFEKL) with a potent in vivo prophylactic effect. The lipidation approaches (C16-R848 and C16-SIINFEKL) increased their hydrophobicity that is intended not only to improve drug encapsulation efficiency but also to facilitate the membrane association, intracellular trafficking, and subcellular localization. The polymer–lipid hybrid nanoparticles (PLNs) are designed to sustain antigen/adjuvant levels with less systemic exposure. Our results demonstrated that a lipidated nanovaccine can induce effective immunity by enhancing the expansion and activation of antigen-specific CD8+ T cells. This adaptive immune response led to substantial tumor suppression with improved overall survival in a prophylactic setting. Our new methodology enhances the potential of nanovaccines for anti-tumor therapy.