Immune Antibodies Research Articles

Monobiotinylated Proteins Tethered to Microspheres for Detection of Antigen-Specific Serum Antibodies.

Surface modified microspheres have been leveraged as a useful way to immobilize antigen for serological studies. The use of carboxyl modified microspheres for this purpose is well-established, but commonly associated with technical challenges. Streptavidin modified microspheres require little technical expertise and thus address some of the shortcomings of carboxyl microspheres. An additional feature of streptavidin microspheres is the use of mono-biotinylated proteins, which contain a single biotinylation motif at the C-terminus. However, the relative performance of streptavidin and carboxyl microspheres is unknown. Here, we performed a head-to-head comparison of streptavidin and carboxyl microspheres. We compared antigen binding, orientation, and staining quality and found that both microspheres perform similarly based on these defined parameters. We also evaluated the utility of streptavidin microspheres bound to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD), to reliably detect RBD-specific IgG1, IgG3, and IgA1 produced in individuals recently immunized with Pfizer/BioNTech mRNA coronavirus disease (COVID) vaccine as 'proof-of-concept'. We provide evidence that each of the antibody targets are detectable in serum using RBD-coated microspheres, Ig-specific 'detector' monoclonal antibodies (mAbs), and flow cytometry. We found that cross-reactivity of the detector mAbs can be minimized by antibody titration to improve differentiation between IgG1 and IgG3. We also coated streptavidin microspheres with SARS-CoV-2 delta variant RBD to determine if the streptavidin microsphere approach revealed any differences in binding of immune serum antibodies to wild-type (Wuhan) versus variant RBD (Delta). Overall, our results show that streptavidin microspheres loaded with mono-biotinylated antigen is a robust alternative to chemically cross-linking antigen to carboxyl microspheres for use in serological assays.

Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer.

Despite the clinical outcomes being extremely limited, blocking immune inhibitory checkpoint pathways has been in the spotlight as a promising strategy for treating gastrointestinal cancer. However, a distinct strategy for the successful treatment is obviously needed in the clinical settings. Myeloid cells, such as neutrophils, macrophages, dendritic cells, and mast cells, are the majority of cellular components in the human immune system, but have received relatively less attention for the practical implementation than T cells and NK cells in cancer therapy because of concentration of the interest in development of the immune checkpoint blocking antibody inhibitors (ICIs). Abnormality of myeloid cells must impact on the entire host, including immune responses, stromagenesis, and cancer cells, leading to refractory cancer. This implies that elimination and reprogramming of the tumor-supportive myeloid villains may be a breakthrough to efficiently induce potent anti-tumor immunity in cancer patients. In this review, we provide an overview of current situation of the IC-blocking therapy of gastrointestinal cancer, including gastric, colorectal, and esophageal cancers. Also, we highlight the possible oncoimmunological components involved in the mechanisms underlying the resistance to the ICI therapy, particularly focusing on myeloid cells, including unique subsets expressing IC molecules. A deeper understanding of the molecular and cellular determinants may facilitate its practical implementation of targeting myeloid villains, and improve the clinical outcomes in the ICI therapy of gastrointestinal cancer.

Study on autoimmune antibody of infertile women based on ultrasound images

Objective: to study the clinical value of reproductive immune autoantibody based on ultrasound image in the diagnosis of infertility. Methods: Eighty infertile women who were admitted to our hospital from June 2019 to May 2020 were included in the study. ELISA was used to detect the serum reproductive immunity antibodies of the patients, including anti-sperm antibody (AsAb), anti-endometrial antibody (EMAb), anti-ovarian antibody (AOAb) and anti-cardiolipin antibody (ACA). Results: the results of reproductive immune antibody test indexes of female infertility patients with different types were compared, and the difference was statistically significant (p < o. 05). conclusion: the detection of reproductive immune autoantibody in clinic can be used for the diagnosis of female infertility, and has important clinical value.

Study on autoimmune antibody of infertile women based on ultrasound images

Objective: to study the clinical value of reproductive immune autoantibody based on ultrasound image in the diagnosis of infertility. Methods: Eighty infertile women who were admitted to our hospital from June 2019 to May 2020 were included in the study. ELISA was used to detect the serum reproductive immunity antibodies of the patients, including anti-sperm antibody (AsAb), anti-endometrial antibody (EMAb), anti-ovarian antibody (AOAb) and anti-cardiolipin antibody (ACA). Results: the results of reproductive immune antibody test indexes of female infertility patients with different types were compared, and the difference was statistically significant (p < o. 05). conclusion: the detection of reproductive immune autoantibody in clinic can be used for the diagnosis of female infertility, and has important clinical value.

Process development and preclinical evaluation of a major Plasmodium falciparum blood stage vaccine candidate, Cysteine-Rich Protective Antigen (CyRPA).

Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) is an essential, highly conserved merozoite antigen that forms an important multi-protein complex (RH5/Ripr/CyRPA) necessary for erythrocyte invasion. CyRPA is a promising blood-stage vaccine target that has been shown to elicit potent strain-transcending parasite neutralizing antibodies. Recently, we demonstrated that naturally acquired immune anti-CyRPA antibodies are invasion-inhibitory and therefore a correlate of protection against malaria. Here, we describe a process for the large-scale production of tag-free CyRPA vaccine in E. coli and demonstrate its parasite neutralizing efficacy with commonly used adjuvants. CyRPA was purified from inclusion bodies using a one-step purification method with high purity (>90%). Biochemical and biophysical characterization showed that the purified tag-free CyRPA interacted with RH5, readily detected by a conformation-specific CyRPA monoclonal antibody and recognized by sera from malaria infected individuals thus indicating that the recombinant antigen was correctly folded and retained its native conformation. Tag-free CyRPA formulated with Freund’s adjuvant elicited highly potent parasite neutralizing antibodies achieving inhibition of >90% across diverse parasite strains. Importantly, we identified tag-free CyRPA/Alhydrogel formulation as most effective in inducing a highly immunogenic antibody response that exhibited efficacious, cross-strain in vitro parasite neutralization achieving ~80% at 10 mg/ml. Further, CyRPA/Alhydrogel vaccine induced anti-parasite cytokine response in mice. In summary, our study provides a simple, scalable, cost-effective process for the production of tag-free CyRPA that in combination with human-compatible adjuvant induces efficacious humoral and cell-mediated immune response.

Immune Evasion of SARS-CoV-2 Omicron Subvariants

Since the SARS-CoV-2 Omicron variant (B.1.1.529) was declared a variant of concern (VOC) by the WHO on 24 November 2021, it has caused another global surge of cases. With extensive mutations in its spike glycoprotein, Omicron gained substantial capabilities to evade the antiviral immunity provided by vaccination, hybrid immunity, or monoclonal antibodies. The Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4 and BA.5 extended this immune evasion capability by having additional unique mutations in their respective spike proteins. The ongoing Omicron wave and emergence of new Omicron subvariants leads to additional concerns regarding the efficacy of the current antiviral measurements. To have a better understanding of the Omicron subvariants, this review summarizes reports of the immune evasion of subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 as well as the molecular basis of immune evasion.

Norovirus Infection in Young Nicaraguan Children Induces Durable and Genotype-Specific Antibody Immunity.

There are significant challenges to the development of a pediatric norovirus vaccine, mainly due to the antigenic diversity among strains infecting young children. Characterizing human norovirus serotypes and understanding norovirus immunity in naïve children would provide key information for designing rational vaccine platforms. In this study, 26 Nicaraguan children experiencing their first norovirus acute gastroenteritis (AGE) episode during the first 18 months of life were investigated. We used a surrogate neutralization assay that measured antibodies blocking the binding of 13 different norovirus virus-like particles (VLPs) to histo-blood group antigens (HBGAs) in pre- and post-infection sera. To assess for asymptomatic norovirus infections, stools from asymptomatic children were collected monthly, screened for norovirus by RT-qPCR and genotyped by sequencing. Seroconversion of an HBGA-blocking antibody matched the infecting genotype in 25 (96%) of the 26 children. A subset of 13 (50%) and 4 (15%) of the 26 children experienced monotypic GII and GI seroconversion, respectively, strongly suggesting a type-specific response in naïve children, and 9 (35%) showed multitypic seroconversion. The most frequent pairing in multitypic seroconversion (8/12) were GII.4 Sydney and GII.12 noroviruses, both co-circulating at the time. Blocking antibody titers to these two genotypes did not correlate with each other, suggesting multiple exposure rather than cross-reactivity between genotypes. In addition, GII titers remained consistent for at least 19 months post-infection, demonstrating durable immunity. In conclusion, the first natural norovirus gastroenteritis episodes in these young children were dominated by a limited number of genotypes and induced responses of antibodies blocking binding of norovirus VLPs in a genotype-specific manner, suggesting that an effective pediatric norovirus vaccine likely needs to be multivalent and include globally dominant genotypes. The duration of protection from natural infections provides optimism for pediatric norovirus vaccines administered early in life.

Protective efficacy of intranasal inactivated pseudorabies vaccine is improved by combination adjuvant in mice.

Pseudorabies virus (PRV) not only causes great economic loss to the pig industry but also seriously threatens the biosafety of other mammals, including humans. Since 2011, PRV mutant strains have emerged widely in China, and the classical Bartha-K61 vaccine cannot confer complete protection for pigs. PRV mainly infects pigs via the respiratory tract. Intranasal immunization with PRV has received more attention because intranasal vaccination elicits systemic and mucosal immune responses. To induce systemic and mucosal immune responses against PRV, we developed a combination adjuvant as a delivery system for intranasal vaccine, which was formulated with MONTANIDE™ Gel 01 and CVCVA5. In comparison to naked antigen of inactivated PRV, single Gel 01 adjuvanted inactivated antigen and single CVCVA5 adjuvanted inactivated antigen, intranasal inactivated PRV vaccine formulated with the combination adjuvant induced greater mucosal IgA immunity and serum antibody responses (IgG, IgG1, and IgG2a). Furthermore, the production of the Th1-type cytokine IFN-γ and the Th2-type cytokine IL-4 indicated that the cellular and humoral responses to the intranasal vaccine were improved by the combination adjuvant. In addition, the intranasal vaccine formulated with the combination adjuvant induced long-term T lymphocyte memory with increased central (CD62L+CD44+) and effector (CD62L–CD44+) memory subsets of both CD4 and CD8 T cells in nasal-associated lymphoid tissue. Intranasal challenge with virulent PRV in mice showed that the protective efficacy of the intranasal PRV vaccine was improved by the combination adjuvant compared with the other single-adjuvanted vaccines. In summary, these data demonstrated that Gel 01 combined with the CVCVA5 adjuvant induced a synergistic effect to improve mucosal immunity and protective efficacy of the intranasally inactivated PRV vaccine in mice. It represents a promising vaccination approach against PRV infection.

Dynamics of anti-SARS-CoV-2 seroconversion in individual patients and at the population level.

The immune response and specific antibody production in COVID-19 are among the key factors that determine both prognostics for individual patients and the global perspective for controlling the pandemics. So called “dark figure”, that is, a part of population that has been infected but not registered by the health care system, make it difficult to estimate herd immunity and to predict pandemic trajectories. Here we present a follow up study of population screening for hidden herd immunity to SARS-CoV-2 in individuals who had never been positively diagnosed against SARS-CoV-2; the first screening was in May 2021, and the follow up in December 2021. We found that specific antibodies targeting SARS-CoV-2 detected in May as the “dark figure” cannot be considered important 7 months later due to their significant drop. On the other hand, among participants who at the first screening were negative for anti-SARS-CoV-2 IgG, and who have never been diagnosed for SARS-CoV-2 infection nor vaccinated, 26% were found positive for anti-SARS-CoV-2 IgG. This can be attributed to of the “dark figure” of the recent, fourth wave of the pandemic that occurred in Poland shortly before the study in December. Participants who were vaccinated between May and December demonstrated however higher levels of antibodies, than those who undergone mild or asymptomatic (thus unregistered) infection. Only 7% of these vaccinated participants demonstrated antibodies that resulted from infection (anti-NCP). The highest levels of protection were observed in the group that had been infected with SARS-CoV-2 before May 2021 and also fully vaccinated between May and December. These observations demonstrate that the hidden fraction of herd immunity is considerable, however its potential to suppress the pandemics is limited, highlighting the key role of vaccinations.

Investigational drugs for the treatment of thymic cancer: a focus on phase 1 and 2 clinical trials

Introduction Thymic epithelial tumors (TETs) are rare tumors of thymic epithelial cells. Treatment options for advanced disease patients who failed standard platinum-based chemotherapy are limited. Areas covered Phase I and II trials published in the last five years testing new systemic treatments for advanced TET patients are discussed, as well as ongoing trials. A PubMed database literature review was conducted for articles published between January 2016 and December 2021, and ongoing clinical trials were retrieved from ClinicalTrials.gov database. Expert opinion The most promising classes of new drugs in TET patients are angiogenesis inhibitors and immune checkpoint antibodies (ICIs). Sunitinib and Lenvatinib showed response rates of 26% and 38%, respectively, and ICIs showed durable responses in 20-25% in thymic carcinoma patients (TCs). Both approaches are mainly active in TCs, therefore new treatment options for thymomas is an unmet medical need. Two major new therapeutic strategies are ICIs combinations with other drugs and drugs that target pathways that are dysregulated in TETs. Future challenges include the development of preclinical models to help identify novel targets and test new treatment strategies, and randomized clinical trials to provide reliable evidence based on survival endpoints.

ICOS is upregulated on T cells following radiation and agonism combined with radiation results in enhanced tumor control

Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

Activated Charcoal Hemadsorption in Cerbera odollam Poisoning

Cerbera odollam belongs to the poisonous Apocynaceae family, grows in coastal salt swamps, creeks and along river banks found in South India. The poisonous part of the plant is the kernel containing the toxin cerberin which is a cardiac glycoside that produces symptoms and signs similar to acute digoxin poisoning. The treatment is mainly symptomatic as well as administration of digoxin immune fab antibodies. Digoxin immune fab antibodies bind with cardiac glycosides to reduce their active concentration. However, there could be various barriers in developing countries in regard to the administration of DigiFab antibodies such as availability and affordability. Activated charcoal, a cheaper alternative, reduces gastrointestinal absorption and enterohepatic recirculation. Although its role in C. odollam poisoning remains unclear, there have been various trials where multidose activated charcoal has been beneficial in glycoside poisoning. We present a case report of a young female with an alleged history of consumption of an unknown plant compound, identified as C. odollam presenting with acute-onset vomiting, altered mental status and laboratory parameters showed hyperkalemia and thrombocytopenia. Electrocardiogram (ECG) showed sinus bradycardia followed by inverted tick mark sign. Serum digoxin levels were raised (4.2 ng/ml). The patient was stabilized with supportive measures and hemadsorption with 300 g of cellulose-coated activated charcoal, which led to the reversal of the ECG and laboratory parameters to normal, leading to the complete recovery of the patient.

1231P Phase I study to evaluate the safety, tolerability, and efficacy of VCN-01 in combination with durvalumab (MEDI4736) in subjects with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC)

VCN-01 is an oncolytic adenovirus designed to replicate selectively in cancer cells. It expresses a matrix remodeling-enzyme hyaluronidase and increases immune check-point antibody uptake in preclinical models. It also induces a pro-inflammatory tumor environment after intravenous [i.v] administration in pancreatic cancer patients (pts). VCN-01 may help to overcome previous resistance to anti-PD(L)-1 therapies in pts with R/M HNSCC.

EP08.01-044 A Phase 2 Multi-Cohort Study of Tiragolumab, Atezolizumab and Bevacizumab in Advanced Non-Squamous Non-Small Cell Lung Cancer

Checkpoint inhibitor immunotherapy (CPI) offers durable, immune-mediated, anti-tumor responses for a subset of patients (pts) with advanced non-small cell lung cancer (NSCLC), but not all derive meaningful benefit. Two clinical unmet needs where CPI has fallen short include EGFR-mutated NSCLC, where CPI is minimally effective, and NSCLC with primary or acquired resistance to currently available CPI. Novel combination strategies have shown promise. Two agents that have demonstrated synergy with the anti-PD-L1 CPI atezolizumab in NSCLC are bevacizumab, a vascular endothelial growth factor (VEGF)-blocking antibody, and tiragolumab, a T-cell immunoglobulin and ITIM domain (TIGIT) immune checkpoint-blocking antibody.

Immune network operations in COVID-19

The immune system, whose nature lies in being a complex network of interactions, lends itself well to being represented and studied using graph theory. However, it should be noted that although the formalization of models of the immune system is relatively recent, the medical use of its signaling network structure has been carried out empirically for centuries in vaccinology, immunopathology, and clinical immunology, as evidenced by the development of effective vaccines, the management of transplant rejection, the management of allergies, and the treatment of certain types of cancer and autoimmune diseases. A network optimization analogy is proposed through the employment of the system dynamic formalism of causal loop diagrams (CLDs), where current network operations (also known as NetOps) in information technology (IT), are interpreted as immune NetOps in coronavirus disease 2019 (COVID-19) treatment. Traffic shaping corresponds to signaling pathway modulation by immunosuppressors. Data caching corresponds to the activation of innate immunity by application of Bacillus Calmette-Guerin (BCG) and other vaccines. Data compression corresponds with the activation of adaptative immune response by vaccination with the actual approved COVID-19 vaccines. Buffer tuning corresponds with concurrent activation of innate and adaptative or specialized immune cells and antibodies that attack and destroy foreign invaders by trained immunity-based vaccines to develop. The present study delineates some experimental extensions and future developments. Given the complex communication architecture of signal transduction in the immune system, it is apparent that multiple parallel pathways influencing and regulating each other are not the exception but the norm. Thus, the transition from empirical immune NetOps to analytical immune NetOps is a goal for the near future in biomedicine.

Effects of Antimicrobial Peptide Supplementation on Immune Response and Immune Organ Index in Broiler Chicks

Background: Misuse of antibiotics has led to bacterial antibiotic resistance and antibiotic residues in meat and egg. The aim of this study was to assess the effect of dietary supplementation of chicken intestinal-derived antimicrobial peptide as an alternative to antibiotic growth promoters on the immune response of birds. Methods: Immune organs of randomly selected birds were collected for immune organ index. Blood samples were collected for serum to measure the antibody titre against infectious bursal disease and Newcastle disease virus using ELISA. Whole blood was collected to study the cytokine gene expression (IL-17A, IFN-α, IFN-γ, TGF-β, IL-10) using Real-time PCR. Result: Antimicrobial peptide supplementation had no significant effect (P greater than 0.05) on the immune organ index and serum antibody Titre against infectious bursal disease and Newcastle disease virus on the 21st and 35th days of the study. However, it significantly (P less than 0.01) downregulated the gene expression of pro-inflammatory cytokines viz., IL-17A, IFN-α, IFN-γ and upregulated IL-10 expression in peripheral blood mononuclear cells. The results suggest that supplementation of antimicrobial peptide at a level of 100 mg/kg diet improved the cell-mediated immune response in broiler chicks but would not have been sufficient to enhance the humoral immune response and immune organ index in chicks.

Waning of antibody levels induced by a 13-valent pneumococcal conjugate vaccine, using a 3 + 0 schedule, within the first year of life among children younger than 5 years in Blantyre, Malawi: an observational, population-level, serosurveillance study

Pneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibodies, effectively reducing vaccine-serotype carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty surrrounding correlate of protection (CoP) estimates and with persistent vaccine-serotype carriage and vaccine-serotype IPD after PCV13 introduction, we aimed to profile population-level immunogenicity among children younger than 5 years in Blantyre, Malawi. For this serosurveillance study, we used a random subset of samples from a prospective population-based serosurvey in Blantyre, Malawi, done between Dec 16, 2016, and June 27, 2018. Sample selection was based on age category optimisation among children younger than 5 years, adequate sample volume, and available budget. We measured serotype-specific IgGs against the 13 vaccine serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and two non-vaccine serotypes (12F and 33F), as well as IgGs against three pneumococcal proteins (PsaA, NanA, and Ply), using ELISA and a direct-binding electrochemiluminescence-based multiplex assay. We estimated population-level, serotype-specific immunogenicity profiles using a linear spline regression model. Analyses included samples stratified to 20 3-month age strata (eg, age <3 months to 57-59 months). We evaluated 638 plasma samples: 556 primary samples and 82 unique secondary samples (each linked to one primary sample). Immunogenicity profiles revealed a consistent pattern among vaccine serotypes except serotype 3: a vaccine-induced IgG peak followed by waning to a nadir and subsequent increase in titre. For serotype 3, we observed no apparent vaccine-induced increase. Heterogeneity in parameters included age range at post-vaccination nadir (from 11·2 months [19A] to 27·3 months [7F]). The age at peak IgG titre ranged from 2·69 months (5) to 6·64 months (14). Titres dropped below CoPs against IPD among nine vaccine serotypes (1, 3, 4, 5, 6B, 7F, 9V, 18C, and 23F) and below CoPs against carriage for ten vaccine serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F). Increasing antibody concentrations among older children and seroincident events were consistent with ongoing vaccine-serotype exposure. A 3 + 0 PCV13 schedule with high uptake has not led to sustained population-level antibody immunity beyond the first year of life. Indeed, post-vaccine antibody concentrations dropped below putative CoPs for several vaccine serotypes, potentially contributing to persistent vaccine-serotype carriage and residual vaccine-serotype IPD in Malawi and other similar settings. Policy decisions should consider alternative vaccine strategies, including a booster dose, to achieve sustained vaccine-induced antibody titres, and thus control. Bill & Melinda Gates Foundation, Wellcome UK, and National Institute for Health and Care Research.

Neutralizing antibody responses in healthcare personnel after three doses of mRNA BNT162b2 vaccine and association with baseline characteristics and past SARS-CoV-2 infection

AimTo estimate neutralizing antibody (NAb) immunity against SARS-CoV-2 in 739 healthcare personnel (HCP) vaccinated with three doses of BNT162b2 mRNA vaccine. MethodsSerum samples were collected at 3, 6, and 9 months after the second vaccine dose and at 7–55 days after the third dose. Samples were tested for NAbs against SARS-CoV-2 receptor binding domain. ResultsThe mean inhibition rates at 3, 6, and 9 months after the second dose were 86.33%, 73.38%, and 61.18%, and increased to 95.57% after the booster dose. Younger HCP and HCP with past SARS-CoV-2 infection had higher inhibition rates while there was an inverse correlation between NAb levels and comorbidities or tobacco use (p-values < 0.001). Increased NAb titers were also noticed in women (p-value = 0.033), especially at the end of the 9-month study period. ConclusionNAb levels increased considerably after a booster mRNA vaccine dose. Host factors and past SARS-CoV-2 infection influence NAb titers.

Extracellular vesicle-mediated immunoregulation in cancer.

Extracellular vesicles (EVs) have emerged as immunomodulatory regulators during tumor progression. These small vesicles encapsulate a variety of molecules, including DNA, RNA, and proteins. When EVs come in contact with recipient cells, the EVs transmit various physiological characteristics; for example, proteins on the surface of EVs act as ligands. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown promise in a subset of cancer patients. PD-L1 on EVs acts as a key immunomodulator. Suppression of EV secretion enhances the efficacy of immunotherapy using immune checkpoint blockade antibodies. In addition to immune checkpoint blockade therapy, chimeric antigen receptor T (CAR-T) cell therapy has also been used to successfully eliminate cancer cells. Interestingly, CAR-T-cell-derived EVs express CAR on their surface. Compared with CAR-T cells, CAR-expressing EVs do not express PD1, so their antitumor effect cannot be weakened. In this review, we describe the current understanding of EVs in cancer immunity and summarize their crucial roles in immunomodulation.

An intranasal ASO therapeutic targeting SARS-CoV-2

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify an LNA ASO binding to the 5′ leader sequence of SARS-CoV-2 that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the COVID-19 mouse model potently suppresses viral replication (>80-fold) in the lungs of infected mice. We find that the LNA ASO is efficacious in countering all SARS-CoV-2 “variants of concern” tested both in vitro and in vivo. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce or prevent transmission and decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences and could be stockpiled for future coronavirus pandemics.