Deliver Tumor Antigens Research Articles

Tumor Microenvironment-Derived Exosomes: A Double-Edged Sword for Advanced T Cell-Based Immunotherapy.

The tumor microenvironment (TME) plays a crucial role in cancer progression and immune evasion, partially mediated by the activity of the TME-derived exosomes. These extracellular vesicles are pivotal in shaping immune responses through the transfer of proteins, lipids, and nucleic acids between cells, facilitating a complex interplay that promotes tumor growth and metastasis. This review delves into the dual roles of exosomes in the TME, highlighting both their immunosuppressive functions and their emerging therapeutic potential. Exosomes can inhibit T cell function and promote tumor immune escape by carrying immune-modulatory molecules, such as PD-L1, yet they also hold promise for cancer therapy as vehicles for delivering tumor antigens and costimulatory signals. Additionally, the review discusses the intricate crosstalk mediated by exosomes among various cell types within the TME, influencing both cancer progression and responses to immunotherapies. Moreover, this highlights current challenges and future directions. Collectively, elucidating the detailed mechanisms by which TME-derived exosomes mediate T cell function offers a promising avenue for revolutionizing cancer treatment. Understanding these interactions allows for the development of targeted therapies that manipulate exosomal pathways to enhance the immune system's response to tumors.

Biologically Self-Assembled Tumor Cell-Derived Cancer Nanovaccines as an All-in-One Platform for Cancer Immunotherapy.

Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer α-mangostin (αM) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (αM-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, αM-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, αM-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.

Harnessing Nanotechnology: Emerging Strategies for Multiple Myeloma Therapy.

Advances in nanotechnology have provided novel avenues for the diagnosis and treatment of multiple myeloma (MM), a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. This review elucidates the potential of nanotechnology to revolutionize myeloma therapy, focusing on nanoparticle-based drug delivery systems, nanoscale imaging techniques, and nano-immunotherapy. Nanoparticle-based drug delivery systems offer enhanced drug targeting, reduced systemic toxicity, and improved therapeutic efficacy. We discuss the latest developments in nanocarriers, such as liposomes, polymeric nanoparticles, and inorganic nanoparticles, used for the delivery of chemotherapeutic agents, siRNA, and miRNA in MM treatment. We delve into nanoscale imaging techniques which provide spatial multi-omic data, offering a holistic view of the tumor microenvironment. This spatial resolution can help decipher the complex interplay between cancer cells and their surrounding environment, facilitating the development of highly targeted therapies. Lastly, we explore the burgeoning field of nano-immunotherapy, which employs nanoparticles to modulate the immune system for myeloma treatment. Specifically, we consider how nanoparticles can be used to deliver tumor antigens to antigen-presenting cells, thus enhancing the body's immune response against myeloma cells. In conclusion, nanotechnology holds great promise for improving the prognosis and quality of life of MM patients. However, several challenges remain, including the need for further preclinical and clinical trials to assess the safety and efficacy of these emerging strategies. Future research should also focus on developing personalized nanomedicine approaches, which could tailor treatments to individual patients based on their genetic and molecular profiles.

Click-Chemistry-Mediated Cell Membrane Glycopolymer Engineering to Potentiate Dendritic Cell Vaccines.

Dendritic cell vaccine (DCV) holds great potential in tumor immunotherapy owing to its potent ability in eliciting tumor-specific immune responses. Aiming at engineering enhanced DCV, we report the first effort to construct a glycopolymer-engineered DC vaccine (G-DCV) via metabolicglycoengineering and copper-free click-chemistry. Model G-DCV was prepared by firstly delivering tumor antigens, ovalbumin (OVA) into dendritic cells (DC) with fluoroalkane-grafted polyethyleneimines, followed by conjugating glycopolymers with a terminal group of dibenzocyclooctyne (DBCO) onto dendritic cells. Compared to unmodified DCV, our G-DCV could induce stronger T cell activation due to the enhanced adhesion between DCs and T cells. Notably, such G-DCV could more effectively inhibit the growth of the mouse B16-OVA (expressing OVA antigen) tumor model after adoptive transfer. Moreover, by combination with an immune checkpoint inhibitor, G-DCV showed further increased anti-tumor effects in treating different tumor models. Thus, our work provides a novel strategy to enhance the therapeutic effectiveness of DC vaccines.

Click‐Chemistry‐Mediated Cell Membrane Glycopolymer Engineering to Potentiate Dendritic Cell Vaccines

AbstractDendritic cell vaccine (DCV) holds great potential in tumor immunotherapy owing to its potent ability in eliciting tumor‐specific immune responses. Aiming at engineering enhanced DCV, we report the first effort to construct a glycopolymer‐engineered DC vaccine (G‐DCV) via metabolicglycoengineering and copper‐free click‐chemistry. Model G‐DCV was prepared by firstly delivering tumor antigens, ovalbumin (OVA) into dendritic cells (DC) with fluoroalkane‐grafted polyethyleneimines, followed by conjugating glycopolymers with a terminal group of dibenzocyclooctyne (DBCO) onto dendritic cells. Compared to unmodified DCV, our G‐DCV could induce stronger T cell activation due to the enhanced adhesion between DCs and T cells. Notably, such G‐DCV could more effectively inhibit the growth of the mouse B16‐OVA (expressing OVA antigen) tumor model after adoptive transfer. Moreover, by combination with an immune checkpoint inhibitor, G‐DCV showed further increased anti‐tumor effects in treating different tumor models. Thus, our work provides a novel strategy to enhance the therapeutic effectiveness of DC vaccines.

Skin-Grafting and Dendritic Cell "Boosted" Humanized Mouse Models Allow the Pre-Clinical Evaluation of Therapeutic Cancer Vaccines.

Vaccines have been hailed as one of the most remarkable medical advancements in human history, and their potential for treating cancer by generating or expanding anti-tumor T cells has garnered significant interest in recent years. However, the limited efficacy of therapeutic cancer vaccines in clinical trials can be partially attributed to the inadequacy of current preclinical mouse models in recapitulating the complexities of the human immune system. In this study, we developed two innovative humanized mouse models to assess the immunogenicity and therapeutic effectiveness of vaccines targeting human papillomavirus (HPV16) antigens and delivering tumor antigens to human CD141+ dendritic cells (DCs). Both models were based on the transference of human peripheral blood mononuclear cells (PBMCs) into immunocompromised HLA-A*02-NSG mice (NSG-A2), where the use of fresh PBMCs boosted the engraftment of human cells up to 80%. The dynamics of immune cells in the PBMC-hu-NSG-A2 mice demonstrated that T cells constituted the vast majority of engrafted cells, which progressively expanded over time and retained their responsiveness to ex vivo stimulation. Using the PBMC-hu-NSG-A2 system, we generated a hyperplastic skin graft model expressing the HPV16-E7 oncogene. Remarkably, human cells populated the skin grafts, and upon vaccination with a DNA vaccine encoding an HPV16-E6/E7 protein, rapid rejection targeted to the E7-expressing skin was detected, underscoring the capacity of the model to mount a vaccine-specific response. To overcome the decline in DC numbers observed over time in PBMC-hu-NSG-A2 animals, we augmented the abundance of CD141+ DCs, the specific targets of our tailored nanoemulsions (TNEs), by transferring additional autologous PBMCs pre-treated in vitro with the growth factor Flt3-L. The Flt3-L treatment bolstered CD141+ DC numbers, leading to potent antigen-specific CD4+ and CD8+ T cell responses in vivo, which caused the regression of pre-established triple-negative breast cancer and melanoma tumors following CD141+ DC-targeting TNE vaccination. Notably, using HLA-A*02-matching PBMCs for humanizing NSG-A2 mice resulted in a delayed onset of graft-versus-host disease and enhanced the efficacy of the TNE vaccination compared with the parental NSG strain. In conclusion, we successfully established two humanized mouse models that exhibited strong antigen-specific responses and demonstrated tumor regression following vaccination. These models serve as valuable platforms for assessing the efficacy of therapeutic cancer vaccines targeting HPV16-dysplastic skin and diverse tumor antigens specifically delivered to CD141+ DCs.

Fused Cytomembrane-Camouflaged Nanoparticles for Tumor-Specific Immunotherapy.

Tumor immunotherapy is commonly hindered by inefficient delivery and presentation of tumor antigens as well as immunosuppressive tumor microenvironment. To overcome these barriers, a tumor-specific nanovaccine capable of delivering tumor antigens and adjuvants to antigen-presenting cells and modulating the immune microenvironment to elicit strong antitumor immunity is reported. This nanovaccine, named FCM@4RM, is designed by coating the nanocore (FCM) with a bioreconstituted cytomembrane (4RM). The 4RM, which is derived from fused cells of tumorous 4T1 cells and RAW264.7 macrophages, enables effective antigen presentation and stimulation of effector T cells. FCM is self-assembled from Fe(II), unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG), and metformin (MET). CpG, as the stimulator of toll-like receptor 9, induces the production of pro-inflammatory cytokine and the maturation of cytotoxic T lymphocytes (CTLs), thereby enhancing antitumor immunity. Meanwhile, MET functions as the programmed cell death ligand 1 inhibitor and can restore the immune responses of T cells against tumor cells. Therefore, FCM@4RM exhibits high targeting capabilities toward homologous tumors that develop from 4T1 cells. This work offers a paradigm for developing a nanovaccine that systematically regulates multiple immune-related processes to achieve optimal antitumor immunotherapy.

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.

Tumor-derived microparticles-based nanomaterial as platform for delivery of tumor antigens to enhance immunogenicity

BackgroundTumor‐derived microparticles (TMPs) are not only carriers for tumor antigens but also can be used as good delivery platform. Therefore, for such an excellent delivery platform, we considered modifying TMPs with lipopolysaccharide (LPS) and polyethyleneimine (PEI) to synthesize TMPs-PEI-LPS for the delivery of tumor antigen and investigated its delivery efficiency, histocompatibility and anti-tumor effect. ResultWe investigated the bioactivity of TMPs-PEI-LPS with dendritic cells and their potential for therapeutic application to treat lung cancer in mice models bearing Lewis lung carcinoma cells. Both in vitro and in vivo assays demonstrated successful TMPs-PEI-LPS induced the uptake and maturity of dendritic cells. TMPs-PEI-LPS exhibited certain immunostimulation activity and anti-tumor effects on inhibiting tumor growth in vivo. Notably, TMPs-PEI-LPS were safe and non-toxic in vivo study. ConclusionThese results indicated that TMPs-PEI-LPS are promising platforms for delivering tumor antigens to enhance immunogenicity.

Therapeutic Vaccination for HPV-Mediated Cancers.

The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers. Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise. Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.

Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years. Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells (APCs) to stimulate a strong immune response to against tumors, representing a potentially therapeutic and prophylactic effect with the long-term anti-cancer benefits. Nevertheless, the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection, immunogenicity, lymph nodes (LNs) targeting ability, lysosomal escape ability, immune evasion, etc. Nanotechnology, aiming to overcome these barriers, has been utilized in cancer vaccine development for decades. Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy. In this review, we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design. In addition, the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

Recent Advances in Cancer Vaccines: Challenges, Achievements, and Futuristic Prospects.

Cancer is a chronic disease, and it can be lethal due to limited therapeutic options. The conventional treatment options for cancer have numerous challenges, such as a low blood circulation time as well as poor solubility of anticancer drugs. Therapeutic cancer vaccines emerged to try to improve anticancer drugs' efficiency and to deliver them to the target site. Cancer vaccines are considered a viable therapeutic technique for most solid tumors. Vaccines boost antitumor immunity by delivering tumor antigens, nucleic acids, entire cells, and peptides. Cancer vaccines are designed to induce long-term antitumor memory, causing tumor regression, eradicate minimal residual illness, and prevent non-specific or unpleasant effects. These vaccines can assist in the elimination of cancer cells from various organs or organ systems in the body, with minimal risk of tumor recurrence or metastasis. Vaccines and antigens for anticancer therapy are discussed in this review, including current vaccine adjuvants and mechanisms of action for various types of vaccines, such as DNA- or mRNA-based cancer vaccines. Potential applications of these vaccines focusing on their clinical use for better therapeutic efficacy are also discussed along with the latest research available in this field.

Salmonella as a Promising Curative Tool against Cancer.

Bacteria-mediated cancer therapy has become a topic of interest under the broad umbrella of oncotherapy. Among many bacterial species, Salmonella remains at the forefront due to its ability to localize and proliferate inside tumor microenvironments and often suppress tumor growth. Salmonella Typhimurium is one of the most promising mediators, with engineering plasticity and cancer specificity. It can be used to deliver toxins that induce cell death in cancer cells specifically, and also as a cancer-specific instrument for immunotherapy by delivering tumor antigens and exposing the tumor environment to the host immune system. Salmonella can be used to deliver prodrug converting enzymes unambiguously against cancer. Though positive responses in Salmonella-mediated cancer treatments are still at a preliminary level, they have paved the way for developing combinatorial therapy with conventional chemotherapy, radiotherapy, and surgery, and can be used synergistically to combat multi-drug resistant and higher-stage cancers. With this background, Salmonella-mediated cancer therapy was approved for clinical trials by U.S. Food and Drug Administration, but the results were not satisfactory and more pre-clinical investigation is needed. This review summarizes the recent advancements in Salmonella-mediated oncotherapy in the fight against cancer. The present article emphasizes the demand for Salmonella mutants with high stringency toward cancer and with amenable elements of safety by virulence deletions.

“Cytokine-microfactories” recruit DCs and deliver tumor antigens via gap junctions for immunotherapy

The majority (~80%) of patients with cancer do not derive clinical benefit from current immunotherapy, largely due to attenuation of immune responses imposed by robust immunosuppression at tumor sites. Here, a cell-based tumor antigen delivery strategy was developed to boost tumor-specific immunity. Notably, the platform constructing ferric oxide nanoparticle-trained macrophages loading tumor antigens (MFe-N) acquired an immunostimulatory program and functioned as the tumoritropic “cytokine-microfactories” to sustainably produce high levels of multiple therapeutic cytokines (GM-CSF, TNFα, and MIP-1α), which are important in activation of immune cells with antitumor potential. Indeed, MFe-N markedly enhanced recruitment of the professional antigen-presenting cells, dendritic cells (DCs), to the tumor sites of an established B16F10 mouse melanoma model. Subsequently, MFe-N effectively delivered tumor antigens to DCs by gap junction-mediated cell-to-cell transmission. And this trafficking was critical for DC maturation to augment antitumor T-cell responses. Simultaneously, the “cytokine-microfactories” elicited high production of the tumoricidal effectors, and in turn blunted the pro-angiogenic activity of tumor-associated macrophages, resulting in conversion of the tumor-supporting milieu to a tumoricidal function that favored infiltration of antitumor T-cells. The findings provided a novel “cytokine-microfactories” harnessing effective delivery of tumor antigens and production of therapeutic cytokines to robustly promote antigen presentation and reshape the tumor immune milieu for priming antitumor immunity. This can enhance existing T-cell mediated immunotherapeutic potency and extend the curative potential immunotherapy to a broader range of patients.

Theragnostic Glycol Chitosan-Conjugated Gold Nanoparticles for Photoacoustic Imaging of Regional Lymph Nodes and Delivering Tumor Antigen to Lymph Nodes.

Lymph node mapping is important in cancer immunotherapy because the morphology of lymph nodes is one of the crucial evaluation criteria of immune responses. We developed new theragnostic glycol-chitosan-coated gold nanoparticles (GC-AuNPs), which highlighted lymph nodes in ultrasound-guided photoacoustic (US/PA) imaging. Moreover, the ovalbumin epitope was conjugated GC-AuNPs (OVA-GC-AuNPs) for delivering tumor antigen to lymph node resident macrophage. In vitro studies proved the vigorous endocytosis activity of J774A.1 macrophage and consequent strong photoacoustic signals from them. The macrophages also presented a tumor antigen when OVA-GC-AuNPs were used for cellular uptake. After the lingual injection of GC-AuNPs into healthy mice, cervical lymph nodes were visible in a US/PA imaging system with high contrast. Three-dimensional analysis of lymph nodes revealed that the accumulation of GC-AuNPs in the lymph node increased as the post-injection time passed. Histological analysis showed GC-AuNPs or OVA-GC-AuNPs located in subcapsular and medullar sinuses where macrophages are abundant. Our new theragnostic GC-AuNPs present a superior performance in US/PA imaging of lymph nodes without targeting moieties or complex surface modification. Simultaneously, GC-AuNPs were able to deliver tumor antigens to cause macrophages to present the OVA epitope at targeted lymph nodes, which would be valuable for cancer immunotherapy.

Nanoparticle-mediated tumor vaccines for personalized therapy: preparing tumor antigens in vivo or ex vivo?

Tumor vaccines, focusing on tailoring individual tumor antigens, have gained much attention in personalized tumor therapy. Recently, breakthroughs have been made in the development of tumor vaccines thanks to the progress in nanotechnology. We will summarize nanoparticle-mediated tumor vaccines for personalized therapy in this review. ROS/heat generating nanoparticles and molecules could induce immunogenic cell death and tumor antigen release in vivo. This strategy often includes chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, magneto-thermal therapy, etc. On the other hand, ex vivo technologies have been applied for processing of tumor cells/tissues to form effective tumor antigens, in which nanotechnology has shown very good prospects in delivering tumor antigens. In in vivo and ex vivo strategies, nanotechnology also could improve the immune effect through enhancing the uptake by targeting cells, reducing therapeutic drugs/agents, further encapsulating immuno-modulatory molecules or combining with other therapy treatments. Thus, therapeutic vaccines based on nanoparticles have the potential to enhance the immune response and reduce the side effects.

Engineered Nanoparticles for Cancer Vaccination and Immunotherapy.

The immune system has evolved over time to protect the host from foreign microorganisms. Activation of the immune system is predicated on a distinction between self and nonself. Unfortunately, cancer is characterized by genetic alterations in the host's cells, leading to uncontrolled cellular proliferation and evasion of immune surveillance. Cancer immunotherapy aims to educate the host's immune system to not only recognize but also attack and kill mutated cancer cells. While immune checkpoint blockers have been proven to be effective against multiple types of advanced cancer, the overall patient response rate still remains below 30%. Therefore, there is an urgent need to improve current cancer immunotherapies. In this Account, we present an overview of our recent progress on nanoparticle-based strategies for improving cancer vaccines and immunotherapies. We also present other complementary strategies to give a well-rounded snapshot of the field of combination cancer immunotherapy. The versatility and tunability of nanoparticles make them promising platforms for addressing individual challenges posed by various cancers. For example, nanoparticles can deliver cargo materials to specific cells, such as vaccines delivered to antigen-presenting cells for strong immune activation. Nanoparticles also allow for stimuli-responsive delivery of various therapeutics to cancer cells, thus forming the basis for combination cancer immunotherapy. Here, we focus on nanoparticle platforms engineered to deliver tumor antigens, whole tumor cells, and chemotherapeutic or phototherapeutic agents in a manner to effectively and safely trigger the host's immune system against tumor cells. For each work, we discuss the nanoparticle platform developed, synthesis chemistry, and in vivo applications. Nanovaccines offer a unique platform for codelivery of personalized tumor neoantigens and adjuvants and elicitation of robust immune responses against aggressive tumors. Nanovaccines either delivering whole tumor cell lysate or formed from tumor cell lysate may increase the repertoire of tumor antigens as immune targets while exploiting immunogenic cell death to prime antitumor immune responses. We also discuss how antigen- and whole tumor cell-based approaches may open the door for personalized cancer vaccination and immunotherapy. On the other hand, chemotherapy, phototherapy, and radiotherapy are more standardized cancer therapies, and nanoparticle-based approaches may promote their ability to initiate T cell activation against tumor cells and improve antitumor efficacy with minimal toxicity. Finally, building on the recent progress in nanoparticle-based cancer immunotherapy, the field should set the ultimate goal to be clinical translation and clinical efficacy. We will discuss regulatory, analytical, and manufacturing hurdles that should be addressed to expedite the clinical translation of nanomedicine-based cancer immunotherapy.

Mannose-Modified Multi-Walled Carbon Nanotubes as a Delivery Nanovector Optimizing the Antigen Presentation of Dendritic Cells.

Dendritic cells (DCs) based cancer immunotherapy is largely dependent on adequate antigen delivery and efficient induction of DCs maturation to produce sufficient antigen presentation and ultimately lead to substantial activation of tumor‐specific CD8+ T cells. Carbon nanotubes (CNTs) have attracted great attention in biomedicine because of their unique physicochemical properties. In order to effectively deliver tumor antigens to DCs and trigger a strong anti‐tumor immune response, herein, a specific DCs target delivery system was assembled by using multi‐walled carbon nanotubes modified with mannose which can specifically bind to the mannose receptor on DCs membrane. Ovalbumin (OVA) as a model antigen, could be adsorbed on the surface of mannose modified multi‐walled carbon nanotubes (Man‐MWCNTs) with a large drug loading content. This nanotube‐antigen complex showed low cytotoxicity to DCs and was efficiently engulfed by DCs to induce DCs maturation and cytokine release in vitro, indicating that it could be a potent antigen‐adjuvant nanovector of efficient antigen delivery for therapeutic purpose.

Strategies for developing and optimizing cancer vaccines.

With the spotlight on cancer immunotherapy and the expanding use of immune checkpoint inhibitors, strategies to improve the response rate and duration of current cancer immunotherapeutics are highly sought. In that sense, investigators around the globe have been putting spurs on the development of effective cancer vaccines in humans after decades of efforts that led to limited clinical success. In more than three decades of research in pursuit of targeted and personalized immunotherapy, several platforms have been incorporated into the list of cancer vaccines from live viral or bacterial agents harboring antigens to synthetic peptides with the hope of stronger and durable immune responses that will tackle cancers better. Unlike adoptive cell therapy, cancer vaccines can take advantage of using a patient’s entire immune system that can include more than engineered receptors or ligands in developing antigen-specific responses. Advances in molecular technology also secured the use of genetically modified genes or proteins of interest to enhance the chance of stronger immune responses. The formulation of vaccines to increase chances of immune recognition such as nanoparticles for peptide delivery is another area of great interest. Studies indicate that cancer vaccines alone may elicit tumor-specific cellular or humoral responses in immunologic assays and even regression or shrinkage of the cancer in select trials, but novel strategies, especially in combination with other cancer therapies, are under study and are likely to be critical to achieve and optimize reliable objective responses and survival benefit. In this review, cancer vaccine platforms with different approaches to deliver tumor antigens and boost immunity are discussed with the intention of summarizing what we know and what we need to improve in the clinical trial setting.

Robust antitumor effects of SNA-based T cell therapy

Abstract The use of toll like receptor (TLR) agonists for immunotherapy remains under intense investigation. Activation of TLRs unleash the power of dendritic cells (DCs) to induce a robust antitumor CD8+ T cell response. However, the role of TLRs in CD8+ T cells has been largely overlooked. T cells do express endosomal TLR9, but it is not readily targetable in these non-phagocytic cells. Using the novel delivery platform of spherical nucleic acids (SNAs), we have devised a way to efficiently activate endosomal TLR9 by CpG, while simultaneously delivering tumor antigens to intracellular compartments in T cells. Activation of TLR9 in CD8+ T cells endows them with special properties. First, T cells themselves express appreciable levels of co-stimulatory molecules after activation of CpG derived from SNAs, thereby functioning as antigen presenting cells to cross-prime antigen-specific CD8+ T cells. Second, SNA activated T cells act as chaperones (T chaperones) of SNA material. Through exosomal transfer, T chaperones shuttle CpG and antigen, mouse or human, to bystander DCs for further cross-presentation of antigen. Third, antigen specific T chaperones are highly cytotoxic and resist tumor induced immune suppression. These combined effects of adoptive therapy using tumor antigen specific T chaperones achieve tumor regression in aggressive melanoma models without irradiation or cytokine supplementation, which complicate T cell-based therapies. T chaperones represent a novel cell-based therapy that co-delivers adjuvant and antigen to efficiently boost antitumor CD8+ T cell activity, eliminating the need for viral manipulation and shortens the long, and costly, production time associated with other T cell therapies.