Long-term Immunological Memory Research Articles

Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity

Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.

Immunological studies of Burkholderia multivorans O-antigen oligosaccharide-rsScpA193 conjugates as potential candidates for vaccine development.

The Burkholderia cepacia complex (Bcc) is a group of phenotypically similar but genotypically diverse Gram-negative bacteria that pose a significant threat to public health worldwide. Due to the absence of effective therapies, the development of an effective vaccine against Bcc infections is urgently needed. Lipopolysaccharides (LPSs) O-antigens of B. multivorans (BM) are attractive immunogenic components and recognized as potential target antigens for vaccine development. In this study, we designed and prepared three BM oligosaccharide-based glycoconjugates rsScpA193-1-3 with rsScpA193 as a new carrier protein. We performed preliminarily immunological assessments to determine the immunogenicity of these glycoconjugates, alongside in vitro evaluations of their capacity to bind BM cells and trigger long-term immunological memory. Our findings revealed that these synthesized conjugates, especially rsScpA193-1, which exhibited stronger immunogenicity and better recognition to trisaccharide 1 and nonasaccharide 3 than the other two groups. Moreover, rsScpA193-1 could effectively bind to BM cells in vitro and successfully induce long-lasting immunological memory. Therefore, trisaccharide 1 was identified as an effective antigenic target, and the conjugate rsScpA193-1 may represent a promising candidate for BM vaccine development. Overall, our study presented the first exploitation of immunogenicity of BM oligosaccharide-protein conjugates and significantly paved the way for Bcc vaccine development.

Recent Advances in the Translational Application of Immunotherapy with Pulsed Dendritic Cell-Derived Exosomes (DEX)

This article explores recent advances in immunotherapy using exosomes derived from dendritic cells (DEXs), highlighting their potential as an innovative option in cancer treatment. DEXs have demonstrated the ability to activate robust and sustainable immune responses, overcoming the limitations of conventional therapies. Their low toxicity profile and capacity to induce long-term immunological memory position them as a viable alternative, especially for patients who do not respond to traditional treatments. The article analyzes the mechanisms of action of DEXs and details their optimized production using advanced pulsing techniques. Clinical trials in melanoma, lung cancer, and other resistant tumors underscore their efficacy and the potential for combining them with conventional treatments, thereby improving tolerance and increasing effectiveness by minimizing adverse reactions. Additionally, the article reviews the epicutaneous administration of DEXs, a strategy that enhances immune response while improving patient experience. The adaptability of DEXs to different types and stages of cancer makes them a fundamental tool in personalized oncology. The question is no longer whether this therapy is effective, but rather when and which low-cost implementation option will be chosen for clinical use, consolidating DEXs as an innovative and validated therapeutic line integrated into protocols that promote more precise and safer treatments with greater effectiveness.

Recent development of nanomaterials-based PDT to improve immunogenic cell death.

Photodynamic therapy (PDT) is a clinically approved therapeutic modality for treating oncological and non-oncological disorders. PDT has proclaimed multiple benefits over further traditional cancer therapies including its minimal systemic toxicity and selective ability to eliminate irradiated tumors. In PDT, a photosensitizing substance localizes in tumor tissues and becomes active when exposed to a particular wavelength of laser light. This produces reactive oxygen species (ROS), which induce neoplastic cells to die and lead to the regression of tumors. The contributions of ROS to PDT-induced tumor destruction are described by three basic processes including direct or indirect cell death, vascular destruction,and immunogenic cell death. However, the efficiency of PDT is significantly limited by the inherent nature and tumor microenvironment. Combining immunotherapy with PDT has recently been shown to improve tumor immunogenicity while decreasing immunoregulatory repression, thereby gently modifying the anticancer immune response with long-term immunological memory effects. This review highlights the fundamental ideas, essential elements, and mechanisms of PDT as well as nanomaterial-based PDT to boost tumor immunogenicity. Moreover, the synergistic use of immunotherapy in combination with PDT to enhance immune responses against tumors is emphasized.

Effectiveness and Safety of mRNA Vaccines in the Therapy of Glioblastoma.

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy.

Manganese-coordinated nanoparticle with high drug-loading capacity and synergistic photo-/immuno-therapy for cancer treatments

Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with “cold” and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.

An Engineered Self-biomineralized Oncolytic Adenovirus Induces Effective Antitumor Immunity and Synergizes With Immune Checkpoint Blockade.

Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunologic response against the agents limit the therapeutic potential of oADVs. In this study, we present a combined method with a rational design for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiologic conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackievirus and adenovirus receptor (CAR)-negative cancer cells wherein protecting them against neutralization by preexisting neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunologic memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and increased the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a "cold" to "hot" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.

The avidity of virus-specific antibodies obtained from <i>in vitro</i> stimulated memory b cells does not change one month after booster with Sputnik V or Comirnaty

The protective properties of long-term immunological memory after vaccination against COVID-19 are characterized by the neutralizing activity of serum antibodies and antibodies secreted by memory B cells upon repeated encounter with the antigen. Somatic hypermutations occurring in the immunoglobulin genes of memory B cells are one of the mechanisms for increasing the affinity of antibodies. At the moment, the effect of booster vaccination against COVID-19 with vector vaccines, on the maturation of memory B cells remains poorly understood. The purpose of this work was to determine how COVID-19 booster affects the affinity of RBD-specific IgG antibodies secreted by memory B cells. B lymphocytes were isolated from peripheral mononuclear blood cells of volunteers who had been revaccinated against COVID-19 with Sputnik V or Comirnaty. B cells were stimulated in vitro with CD40L expressed on the surface of A549 feeder cells and IL-21. Supernatants were concentrated 8-fold using centrifugal concentrators. In the obtained supernatants from stimulated memory B cells, the level of IgG antibodies specific to wild-type RBD was determined by enzyme-linked immunosorbent assay (ELISA). To determine the avidity index, ELISA with 7M urea was provided. It was shown that despite a general increase in the amount of antigen-specific IgG antibodies obtained from stimulated memory B cells, there was no change in the avidity of these antibodies one month after booster in both groups of donors. The obtained results contribute to the understanding of the mechanisms of memory B cell maturation after booster vaccinations against COVID-19 and may be useful for deciding on the strategy of booster vaccination.

Formation of immunological memory of salmonella antigens in cows using different phenotypes of T-lymphocyte populations

The study aimed to investigate the formation of immunological memory to Salmonella antigens in cows using different phenotypes of T-lymphocyte populations. The study was conducted on farms in Kazakhstan and Latvia. As part of the study, blood samples were collected from cows vaccinated against Salmonella to analyse T-lymphocyte phenotypes. A comparative study of different phenotypes of T-cell populations, including CD4+, CD8+, γδ T-cells and effector T-cells (CD45RA+ and CD45RA-), was conducted to assess their role in the formation of immunological memory. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to quantify T-cell populations and levels of specific antibodies. The main results showed that vaccination causes a significant increase in the population of CD4+ and CD8+ T-lymphocytes, which correlates with an increase in the level of specific antibodies to Salmonella antigens. The γδ T-cell population also showed significant activation, indicating their potential role in the formation of an immune response to Salmonella. Particular attention was devoted to effector cells of T-lymphocytes: CD45RA+ cells were actively involved in the primary immune response to Salmonella antigens, while CD45RA cells showed high activity during repeated exposure to the antigen, indicating their key role in maintaining longterm immunological memory. Comparative analysis of data from Kazakhstan and Latvia showed similar trends, indicating the universality of the observed immunological mechanisms. These findings highlight the importance of including different T-cell phenotypes in vaccination programmes to ensure more effective immunological memory in cows. Thus, this study provides valuable data on the role of different T-lymphocyte populations in the formation of immunological memory to Salmonella antigens in cows, which may contribute to the development of more effective vaccine programmes and improve the health and productivity of livestock in the regions of Kazakhstan and Latvia

Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism

BackgroundTrained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. AimThis study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. MethodsCompared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. ConclusionsThis novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

Near-infrared photoimmunotherapy targeting PD-L1: Improved efficacy by preconditioning the tumor microenvironment.

Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer therapy that employs antibody-IRDye700DX conjugates (AbPCs) and near-infrared (NIR) light at a wavelength of 689 nm, the excitation wavelength of IR700. Administered intravenously, injected AbPCs bind specifically to cells expressing the target antigen, whereupon NIR light exposure causes rapid, selective killing. This process induces an anticancer T cell response, leading to sustained anticancer host immune response. Programmed cell death ligand-1 (PD-L1) is a major inhibitory immune checkpoint molecule expressed in various cancers. In this study, we first assessed the efficacy of PD-L1-targeted NIR-PIT (αPD-L1-PIT) in immune-competent tumor mouse models. αPD-L1-PIT showed a significant therapeutic effect on the tumor models with high PD-L1 expression. Furthermore, αPD-L1-PIT induced an abscopal effect on distant tumors and long-term immunological memory. In contrast, αPD-L1-PIT was not as effective for tumor models with low PD-L1 expression. To improve the efficacy of PD-L1-targeted NIR-PIT, PEGylated interferon-gamma (IFNγ) was administered with αPD-L1-PIT. The combination therapy improved the treatment efficacy by increasing PD-L1 expression leading to more efficient cell killing by αPD-L1-PIT. Furthermore, the PEGylated IFNγ led to a CD8+ T cell-dominant tumor microenvironment (TME) with an enhanced anticancer T cell response after αPD-L1-PIT. As a result, even so-called cold tumors exhibited complete responses after αPD-L1-PIT. Thus, combination therapy of PEGylated IFNγ and PD-L1-targeted NIR-PIT has the potential to be an important future strategy for cancer immunotherapy.

Abstract LB118: HM16390, a novel long-acting IL-2 analog with fine-tuned binding affinities to IL-2 receptor subunits for favorable safety profile, exhibits potent tumor killing effect in the various tumor syngeneic models

Abstract Although recombinant human IL-2 (rhIL-2, aldesleukin) produced approximately a 15% objective response rate in patients with renal cell carcinoma (RCC) and metastatic melanoma, its IL-2Rα (CD25)-biased binding and short half-life (t1/2 in human: 13-85 min) require a high dose and frequent dosing interval, leading to systemic toxicity such as vascular leak syndrome (VLS) and cytokine release syndrome (CRS). To overcome this limitation, various research groups are developing engineered IL-2 muteins with abolished CD25 binding affinity. While such IL-2 muteins may reduce CD25-mediated toxicity, there is a risk of a lopsided immune response. Furthermore, concomitantly reduced affinity to IL-2Rβ (CD122) may cause insufficient anti-tumor activity. We are developing HM16390, a long-acting IL-2 analog with a significantly increased binding affinity to CD122 for potent tumor killing effect. Simultaneously, optimal binding property to CD25 was introduced for a suppression of uncontrolled systemic immune response via peripheral Treg expansion. From these novel sequence modifications, HM16390 exhibited approximately 14-fold potent activity in human NK and CD8+ T cells compared to rhIL-2 and comparable activity with rhIL-2 in human Tregs (EC50 of STAT5 phosphorylation) without undesired release of cytokines associated with CRS. In B16F10 mouse model, HM16390 has a longer-lasting PK property (t1/2: 14.2~26.0 hr) after single subcutaneous (SC) administration. CD8+ T cells were significantly increased in peripheral blood along with a transient increase of peripheral Tregs, suggesting that HM16390 not only has a significant effect on expansion of CD8+ T cells but can simultaneously modulate exaggerated peripheral immune response. It is also noteworthy that, unlike in the peripheral, Tregs were drastically reduced in the tumor immune microenvironment, and CD8+ T cells were significantly increased. Next, in orthotopic model of mouse RCC (RENCA-luc cell implantation), across treatment groups, 40%(n=4/10) to 80%(n=8/10) of animals achieved complete tumor regression in dose-dependent manner after once weekly SC injection of HM16390 for 4 weeks. Furthermore, tumor nodules were not observed in lung and kidney after intravenous (IV) rechallenge of RENCA cells in the mice cured by HM16390 for at least 4 months after drug discontinuation. This indicates a long-term immunological memory response of generated memory cells by treatment of HM16390. In conclusion, HM16390 demonstrates potent and durable anti-tumor activity in various murine tumor models via its enhanced CD122 binding affinity, and incorporated optimal CD25 binding affinity may alleviate systemic toxicity by immunomodulatory role of peripheral Tregs. Citation Format: Sol-Bi Shin, Jinyoung Kim, Jaehyuk Choi, Seongju Jeong, Yunjae Kim, Jooyun Byun, Sungmin Bae, Daejin Kim, In Young Choi. HM16390, a novel long-acting IL-2 analog with fine-tuned binding affinities to IL-2 receptor subunits for favorable safety profile, exhibits potent tumor killing effect in the various tumor syngeneic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB118.

Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint molecule responsible for delivering inhibitory signals that suppress immune activation. Due to its inhibitory role in the immune response, TIGIT has emerged as a potential therapeutic target for various malignancies, with several clinical trials exploring the use of anti-TIGIT blocking antibodies with anti-PD-(L)1 therapies. Recent reports have indicated elevated expression of 4-1BB within intra-tumoral Tregs. Therefore, we hypothesized that a dual targeting approach involving both TIGIT and 4-1BB could effectively enhance intra-tumoral immunity. ABL112, a First-in-Class bispecific antibody targeting TIGIT and 4-1BB, demonstrated the induction of T cell activation by blocking the TIGIT signaling and TIGIT dependent 4-1BB clustering. By having intact Fc, ABL112 bound to FcγRI and its crosslinking with 4-1BB also induced 4-1BB activation. ABL112 selectively depleted Treg cells but not other T cells in vitro, potentially through antibody-dependent cell-mediated cytotoxicity. ABL112 demonstrated superior efficacy in tumor regression compared to anti-TIGIT monoclonal antibody across various mouse tumor models. Additionally, combining ABL112 with pembrolizumab significantly inhibited tumor growth better than combining anti-TIGIT monoclonal antibody with pembrolizumab. According to immune cell depletion assay, ABL112-mediated tumor suppressive activity was predominantly driven by CD8+ T cells, with a partial tumor reduction by CD4+ T cell or NK cell depletion. Mice with complete remission (CR) were further protected from the tumor re-challenge after 3 months of cessation of ABL112 treatment, and the proportion of tumor-specific memory T cells in the blood increased, suggesting long-term immunological memory has been established. In conclusion, ABL112 exhibited potent in vitro and in vivo anti-tumor activity through multiple mode of action including TIGIT inhibition and 4-1BB activation. These results strongly suggest that ABL112 is an innovative and promising therapeutic option with the combination of anti-PD-(L)1 therapies for cancer patients. Citation Format: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won. A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5303.

Measles-specific antibodies loss after a single dose of MMR vaccine in children with oligo-articular JIA on methotrexate treatment: a single-center case-controlled study.

Novel treatments have revolutionized the care and outcome of patients with juvenile idiopathic arthritis (JIA). Patients with rheumatic diseases are susceptible to infections, including vaccine preventable ones, due to waning immunity, failing immune system and immunosuppressive treatment received. However, data regarding long-term immunological memory and response to specific vaccines are limited. Assessment of the impact of methotrexate (MTX) treatment on measles-specific-IgG titers, in children with oligo-JIA previously vaccinated with Measles Mumps Rubella (MMR) vaccine (1 dose); by evaluating the persistence of antibodies produced after measles vaccination while on immunomodulating treatment at 0, 12 and 24months. Single-center controlled study including 54 oligo-JIA patients and 26 healthy controls. Seroprotection rates and measles-specific-IgG titers were measured by ELISA and were expressed as GMCs (Geometric Mean Concentrations).The two groups had similar demographic characteristics, vaccination history and immunization status. Seroprotection rates were adequate for both groups. Nonetheless, measles GMCs were significantly lower in the oligo-JIA compared to the control group at one (p = 0.039) and two years' follow-up (p = 0.021). Children with oligo-JIA on MTX treatment appeared to have lower measles-specific-IgG titers. Further studies are required to assess the long-term immunity conveyed by immunizations given at an early stage in children with rheumatic diseases on synthetic Disease Modifying Antirheumatic Drugs (sDMARDs) and to assess the need for booster doses to subjects at risk.

A Programmable Peptidic Hydrogel Adjuvant for Personalized Immunotherapy in Resected Stage Tumors.

Adjuvant treatment after surgical resection usually plays an important role in delaying disease recurrence. Immunotherapy displays encouraging results in increasing patients' chances of staying cancer-free after surgery, as reported by recent clinical trials. However, the clinical outcomes of current immunotherapy need to be improved due to the limited responses, patient heterogeneity, nontargeted distribution, and immune-related adverse effects. This work describes a programmable hydrogel adjuvant for personalized immunotherapy after surgical resection. By filling the hydrogel in the cavity, this system aims to address the limited secretion of granzyme B (GrB) during immunotherapy and improve the low immunotherapy responses typically observed, while minimizing immune-related side effects. The TLR7/8 agonist imidazoquinoline (IMDQ) is linked to the self-assembling peptide backbone through a GrB-responsive linkage. Its release could enhance the activation and function of immune cells, which will lead to increased secretion of GrB and enhance the effectiveness of immunotherapy together. The hydrogel adjuvant recruits immune cells, initiates dendritic cell maturation, and induces M1 polarized macrophages to reverse the immunosuppressive tumor microenvironment in situ. In multiple murine tumor models, the hydrogel adjuvant suppresses tumor growth, increases animal survival and long-term immunological memory, and protects mice against tumor rechallenge, leading to effective prophylactic and therapeutic responses. This work provides a potential chemical strategy to overcome the limitations associated with immunotherapy.

Tumor Microenvironment-Activatable Nanosystem Capable of Overcoming Multiple Therapeutic Obstacles for Augmenting Immuno/Metal-Ion Therapy.

Abnormal tumor microenvironment (TME) imposes barriers to nanomedicine penetration into tumors and evolves tumor-supportive nature to provide tumor cell protection, seriously weakening the action of antitumor nanomedicines and posing significant challenges to their development. Here, we engineer a TME-activatable size-switchable core-satellite nanosystem (Mn-TI-Ag@HA) capable of increasing the effective dose of therapeutic agents in deep-seated tumors while reversing tumor-supportive microenvironment for augmenting immuno/metal-ion therapy. When activated by TME, the nanosystem disintegrates, allowing ultrasmall-sized Ag nanoparticles to become unbound and penetrate deep into solid tumors. Simultaneously, the nanosystem produces O2 and releases TGF-β inhibitors in situ to drive macrophage M2-to-M1 polarization, increasing intratumoral H2O2 concentration, and ultimately augmenting metal-ion therapy by accelerating hypertoxic Ag+ production. The nanosystem can overcome multiple obstacles that aid in tumor resistance to nanomedicine, demonstrating effective tumor penetration, TME regulation, and tumor inhibition effects. It can provoke long-term immunological memory effects against tumor rechallenge when combined with immune checkpoint inhibitor anti-PD-1. This work provides a paradigm for designing efficient antitumor nanomedicines.

The Modification of H3K4me3 Enhanced the Expression of CgTLR3 in Hemocytes to Increase CgIL17-1 Production in the Immune Priming of Crassostrea gigas.

Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5'-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming.

Palmitic acid-capped MIL-101-Al as a nano-adjuvant to amplify immune responses against Pseudomonas aeruginosa.

As a highly contagious opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa) is one of the main causes of healthcare-associated infections. The drug-resistant nature of P. aeruginosa can render antibiotic treatments ineffective, leading to a high morbidity and mortality. Higher specificity and reduced toxicity are features of immunotherapy, which can generate robust immune responses and preserve long-term immunological memory to completely eradicate infections. In this study, we developed a type of P. aeruginosa vaccine based on a metal-organic framework. Specifically, MIL-101-Al nanoparticles were synthesized to encapsulate antigens derived from the bacterial lysate (BL) of PAO1, a drug-resistant P. aeruginosa, and the adjuvant unmethylated cytosine-phosphate-guanine oligonucleotide (CpG), which were then modified with palmitic acid (PAA) to obtain MIL-BC@PAA. The stability and biocompatibility were significantly increased by capping with PAA. Moreover, MIL-BC@PAA showed significantly enhanced uptake by antigen presenting cells (APCs), and promoted their maturation. Importantly, immunity studies revealed the greatly elicited antigen-specific humoral and cellular responses, and a protection rate of about 70% was observed in P. aeruginosa-challenged mice. Overall, these results demonstrate the promising potential of MIL-BC@PAA as an ideal nanovaccine for P. aeruginosa vaccination.

PERSPECTIVE FOR APPLYING ANTITUMOR VACCINES

One of the promising areas in immunotherapy are tumour-specific vaccines based on immunocompromised cells. DC-based personalized neoantigenic cellular vaccines have promising antitumor effects in clinical practice. Dendritic cell-based vaccines have a number of advantages, one example being the ability to engage both innate and adaptive immunity, as well as to develop long-term immunological memory against tumor recurrence. DCs are the most professional and consistent antigens and are more effective in activating resting T cells. The review provides the most up-to-date information on cancer vaccines, as well as an analysis of the types of cancer vaccines from domestic and foreign sources. The conclusion of this brief review is the wide variety of types of tumor-specific vaccines and their rapid improvement.