Immune Effector Research Articles

The diversity of natural killer cell functional and phenotypic states in cancer.

The role of natural killer (NK) cells as immune effectors is well established, as is their utility as immunotherapeutic agents against various cancers. However, NK cells' anti-cancer roles are suppressed in cancer patients by various immunomodulatory mechanisms which alter these cells' identity, function, and potential for immunosurveillance. This manifests in abnormal NK cell responses accompanied by changes in phenotypic or genotypic identity, giving rise to specific NK cell subsets that are either hypofunctional or, more broadly, defective in their responses. Anergy, senescence, and exhaustion are some of the terms that have been used to define and characterize these NK cell functional states. These responses vary not only with cancer type but also NK cell location within tissues. Collectively, these phenomena suggest a highly plastic nature of NK cell biology in tumors. In this review, we present and discuss a summary of these functionally distinct states and provide an overview of how NK cells behave at different locations within the context of cancer.

October 2024 ACIP Meeting Update: Influenza, COVID-19, RSV and Other Vaccines.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The ACIP met October 23-24, 2024, to discuss influenza vaccines, chikungunya vaccines, coronavirus disease (COVID-19) vaccines, RSV immunizations, meningococcal vaccines, human papillomavirus (HPV) vaccines, pneumococcal vaccines, and adult and child/adolescent immunization schedule revisions. This update summarizes the proceedings of these meetings, with an emphasis on topics that are most relevant to the pediatric population. Major updates for pediatric clinicians include information regarding COVID-19 and influenza vaccine recommendations, meningococcal vaccination considerations, and updates regarding implementation and effectiveness of RSV immunization in pregnant people and infants.

The roles of STAT1, CASP8, and MYD88 in the care of ischemic stroke.

Ischemic stroke is caused by blockage of blood vessels in brain, affecting normal function. The roles of Signal Transformer and Activator of Transcription 1 (STAT1), CASP8, and MYD88 in ischemic stroke and its care are unclear. The ischemic stroke datasets GSE16561 and GSE180470 were found from the Gene Expression Omnibus database. Batch effect removal, finding differentially expressed genes (DEGs), weighted gene co-expression network analysis, protein-protein interaction analysis, functional enrichment analysis, immune infiltration analysis, comparative toxicogenomics database analysis were carried out. Gene expression heat maps were drawn, and miRNAs were found that regulate core DEGs. A total of 1183 DEGs were obtained, which were mainly concentrated in immune effector processes, cell activation, and protein serine/threonine kinase activity, the NOD-like receptor signaling pathway, NF-kappa B signaling pathway, C-type lectin receptor signaling pathway, and P53 signaling pathway. Four core genes were identified. Heatmap revealed high expression of (CASP8, MYD88, and STAT1) in whole blood samples of ischemic stroke. Comparative toxicogenomics database analysis demonstrated (CASP8, MYD88, and STAT1) are related to cerebral hemorrhage, reperfusion injury, hypertension, and inflammation. In ischemic stroke, expression of STAT1, CASP8, and MYD88 is higher and leads to poorer prognosis.

Fluorouracil enhances the anti-pancreatic cancer effect of anti-PD-L1 antibodies via up-regulating the expression of PD-L1 in cancer cells.

Pancreatic cancer is characterized by occult onset, low early diagnosis rate, rapid progress, and poor prognosis. Due to the low response rate and low programmed cell death ligand 1 (PD-L1) expression in pancreatic cancer, the therapeutic application of PL-L1 inhibitors in pancreatic cancer is greatly limited. In vitro studies showed that the expression of PD-L1 increased in pancreatic cancer cells stimulated by fluorouracil (5-FU). We aim to explore the combined effect of 5-FU and anti-PD-L1 antibodies and to provide a reference for the clinical application of PD-L1 antibodies in pancreatic cancer. In the current study, male BALB/c mice were adopted to construct a tumor-bearing model of pancreatic cancer cells. 5-FU and anti-mouse PD-L1 antibodies were combined and administered to evaluate their synergistic effects. The enhancing immune cytotoxicity effect of 5-FU sensitizing the anti-PD-L1 antibody in vivo and in vitro was analyzed by immunohistochemistry and western blot assays. Results showed that 5-FU and anti-PD-L1 antibody combination increased the expression of PD-L1 and IFN-γ, and infiltration of CD8+ T lymphocytes in pancreatic xenograft tumor tissues, which was proven by immunohistochemistry and western analysis. Moreover, the combination with the 5-FU remarkably enhanced the immune cytotoxicity of anti-PD-L1 antibodies in mice. In vitro analysis demonstrates that 5-FU increases the expression of PD-L1 on the surface of pancreatic cancer cell lines via up-regulating nuclear factor kappa B (NF-κB) and Protein kinase B (AKT) pathways. This synergistic effect could be abolished by NF-κB and AKT inhibitors.

Intratumoral or Subcutaneous MK-2118, a Non-Cyclic Dinucleotide STING Agonist, With or Without Pembrolizumab for Advanced or Metastatic Solid Tumors or Lymphomas.

We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas. This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints. 140 patients were enrolled (arm 1, n=27; arm 2, n=57; arm 4, n=56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses. IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.

Engineered allogeneic stem cells orchestrate T lymphocyte driven immunotherapy in immunosuppressive leptomeningeal brain metastasis.

Immune-checkpoint inhibitors have shown clinical benefit in non-small cell lung cancer (NSCLC) derived brain metastasis (BM), however, their efficacy in lung to leptomeningeal brain metastasis (LLBM) remains poor. A paired matched RNA expression dataset of patients with NSCLCs and BMs was analyzed to idenfiy BM specific suppressive tumor microenvironment (TME) features. Next, we created immune-competent LLBM mouse models that mimic clinical LLBM. We evaluated the efficacy of intrathecal (IT) delivery of allogeneic stem cells (SCs) engineered to release single-chain variable fragment anti-PD-1 (scFvPD-1). To enhance tumor cell killing and subsequent modulation of the immune TME, we explored the therapeutic activity of dual SCs releasing oncolytic herpes simplex virus (oHSV) and scFvPD-1 and profiled immune and metabolic consequences. RNA sequencing analysis of primary NSCLCs and BMs revealed an immune-suppressive TME with reduced immune cells and increased PD-1+ T cells in BMs. We showed significantly decreased immune cells and increased PD-1+ T cells in the TME of LLBM compared to primary NSCLC tumors in LLBM mouse tumor models. Next, we showed that locoregional IT treatment with SC releasing scFvPD-1, but not conventional systemic injection of anti-PD-1 antibody, suppressed tumor growth and improved survival in our immune-competent LLBM models. Furthermore, dual SCs releasing oHSV and scFvPD-1 (SC-oHSV/scFvPD-1) enhanced therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, activating anti-tumor T cell signaling, and disrupting oxidative phosphorylation, which sensitized tumors to cisplatin. Locoregional delivery of SC-oHSV/scFvPD-1 effectively targets the immune-suppressive TME in LLBM, providing a promising strategy for treating LLBM.

Bivalent OX40 Aptamer and CpG as Dual Agonists for Cancer Immunotherapy.

Cancer immunotherapy has revolutionized cancer treatment by harnessing the body's immune system to recognize and attack tumors. Over the past 25 years, the use of blocking antibodies has fundamentally transformed the landscape of cancer therapy. However, despite extensive research, agonist antibodies targeting costimulatory receptors such as ICOS, GITR, OX40, CD27, and 4-1BB have consistently underperformed in clinical trials over the past 15 years, failing to meet the anticipated success. One reason the agonist antibodies failed is that researchers escalated the dose to the highest tolerable level, which can lead to cell exhaustion, especially when used as a single agent. In this study, we introduced novel in situ therapeutic agents by combining a bivalent RNA aptamer of OX40, biROX40, which binds to two copies of the OX40 receptor as an agonist, with CpG, a toll-like receptor 9 (TLR9) immune stimulator. These agents were specifically designed for lymphoma treatment, with the dose reduced to the lowest bioactive amount to maximize efficacy while minimizing potential side effects. BiROX40 and CpG exhibited a dual immune activation effect and demonstrated a synergistic response even at extremely low dose of 0.32 mg/kg (5.75 μg per mouse) for biROX40 and moderate dose of 1.39 mg/kg (25 μg per mouse) for CpG, resulting in remarkable antitumor efficacy. This effect was achieved through the promotion of intratumoral CD8+ T cell proliferation and cytokine secretion, inhibition of regulatory T cell (Treg) proliferation, and enhanced generation and proliferation of memory T cells in immune organs. The agonistic effects of these reagents led to tumor regression not only at the treated sites but also at distant, nontreated locations in the animal models. This outcome highlighted the induction of a robust systemic antitumor immune response, which effectively suppressed tumor recurrence. This in situ combination therapy, utilizing low-dose biROX40 alongside CpG, offers a straightforward and widely applicable strategy to enhance immune responses in cancer immunotherapy. This approach overcomes the limitations of high-dose single-agent anti-OX40 therapies (whether antibodies or aptamers), including immune cell exhaustion and diminished efficacy.

Population-based age-period-cohort analysis of declining Human Papillomavirus prevalence.

Most countries in the world have launched human papillomavirus (HPV) vaccination programmes and declining prevalences of HPV are reported. We aimed to disentangle the influences of calendar time, birth cohort and age by analysing HPV prevalences in the population-based cervical screening programme using age-period-cohort modelling. All 836,314 primary HPV-based cervical screening tests from women aged 23-64 between 2014-2023 in the capital region of Sweden were identified in the Swedish National Cervical Screening Registry. The odds ratio of HPV16/18 infection was estimated comparing each birth cohort to the unvaccinated 1984-born using an age-period-cohort model. The impact of changing HPV prevalences on the numbers needed to screen (NNS) to detect and prevent 1 cervical cancer case were calculated. HPV vaccination coverage was 82-83% among women born in 1999-2000. Before 2019 the HPV16/18 prevalence was highest among the youngest women in the screening program. During 2020-2023 the prevalence consistently decreased among the birth cohorts offered organised school-based vaccination. There was a 98% decline in HPV16 prevalence (odds ratio=0.02 [95% CI 0.01-0.04]) and a 99% decline in HPV18 prevalence (odds ratio=0.01 [0.00-0.04]) among the 2000-born compared to the HPV unvaccinated 1984-born. The declining HPV16/18 prevalences resulted in major increases in the NNS to detect and to prevent 1 case of cervical cancer. The declines of HPV16/18 were considerably larger than the vaccination coverage, suggesting herd immunity effects. The changing epidemiology of HPV types impacts screening needs, necessitating updated screening programs.

The Role of Innate Immunity in Healthy Aging Through Antimicrobial Peptides.

In a super-aging society, the increase in the elderly population is closely tied to a rise in infectious diseases due to factors such as weakened immune systems and decreased vaccine efficacy in older adults. Various opportunistic pathogens commonly encountered in everyday life can cause infections and diseases when an individual's immune defence is weakened due to aging. These factors underscore the importance of preventive measures against pathogenic infections and the aging of immune systems in the elderly. The immune response acts as the defence mechanism against foreign substances, including pathogens and abnormal cells. Specifically, the innate immune response is the body's first line of defence, offering a rapid and nonspecific response to pathogens. Advances in the study of innate immunity's regulatory functions in both immune and non-immune cells have broadened our understanding of innate immune responses' impact on health. This includes a focus on immune effectors like antimicrobial peptides (AMPs) and their potential implications for health and longevity. This review summarises the common principles and evolutionary adaptations of innate immunity via AMPs, in mammals and invertebrates. Especially, this review discusses the conserved mechanisms regulating AMP production and the role of AMPs in modulating aging and diseases from invertebrate to human. Therefore, it highlights the potential role of innate immunity in addressing aging through AMPs.

Microneedle patch-involved local therapy synergized with immune checkpoint inhibitor for pre- and post-operative cancer treatment.

The metastasis and recurrence of cancer post-surgery remain the major reasons for treatment failures. Herein, a photo-immune nanoparticle decorating with M1 macrophage membrane (BD@LM) is designed based on the inflammatory environment after surgical resection. By loading photosensitizer black phosphorus quantum dots (BPQDs) and chemotherapeutics doxorubicin (DOX) in BD@LM nanoparticles, an effective chemophototherapy-mediated immunogenic cell death of tumor cells is triggered, subsequently leading to the maturation of dendritic cells for further immune cascade. Moreover, by accommodating BD@LM in a dissolvable microneedle patch, the skin barrier is directly broken for efficacious delivery of BD@LM into solid tumors, which boosts the effectiveness of aPD-L1-based checkpoint blockade therapy. Consequently, the growth of both orthotopic and post-surgical breast tumor and melanoma is significantly inhibited. Specifically, an effective T cell activation accompanied with dramatic inhibition of immunosuppressive cells is observed. Meanwhile, the proportion of memory T cells remarkably grows after proposed treatment, indicating the establishment of a long-term immune memory effect for prevention of second tumor attack. Altogether, this work offers a meaningful strategy by combining photo-immune-inspired nanoparticles with microneedle patches for boosting aPD-L1-based tumor immunotherapy.

Prolonged neurologic symptoms following immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphoma treated with chimeric antigen receptor-modified T cell therapy.

While immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-defined adverse effect associated with chimeric antigen receptor-modified T cell (CAR-T) therapy, some patients develop prolonged neurologic symptoms. Few studies have examined characteristics and outcomes of patients who develop such symptoms. To provide an analysis of patients who developed ICANS in a single-center cohort of patients with large B-cell lymphoma (LBCL) who received commercial CAR-T and compare characteristics and outcomes between patients with vs. without subsequent prolonged neurologic symptoms. We examined a retrospective cohort of patients with LBCL treated with CAR-T at our institution who developed ICANS. Prolonged neurologic symptoms were defined as those lasting longer than four weeks. Thirty three of 278 (12%) LBCL patients treated with commercial CAR-T experienced ICANS. Nine patients (27%) experienced prolonged neurologic symptoms following ICANS, eight with ICANS grade ≥3 (high-grade) and one with ICANS grade <3 (low-grade). There were a range of symptoms experienced by these patients including difficulties with short-term memory, difficulties with long-term memory, aphasia, and tremors. The incidence of prolonged neurologic symptoms was greater in patients experiencing high-grade as compared to low-grade ICANS (42.1% vs. 7.1%, p = 0.049). However, no other pre-treatment characteristics or post-treatment outcomes were associated with development of prolonged neurologic symptoms following ICANS. Nearly half of all patients with LBCL treated with CAR-T at our institution who developed high-grade ICANS experienced prolonged neurologic symptoms; however, pre-treatment characteristics and post-treatment outcomes were not predictive of this clinical condition. Further work is needed to identify patients treated with CAR-T at risk for experiencing prolonged neurologic symptoms and developing strategies for evaluation and treatment of this toxicity.

Cardiovascular Complications of Immune Effector Cell Therapies in Pediatric Hematological and Solid Tumors.

Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR)-modified T-cell therapy, have shown efficacy in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and are being investigated for other malignancies. A common toxicity associated with IEC therapy is cytokine release syndrome (CRS), which can lead to cardiovascular decompensation due to systemic inflammation. Data are limited regarding cardiovascular adverse effects in children. This study aims to describe the cardiovascular adverse effect profile of IEC therapies in pediatric patients with hematologic and solid tumor malignancies. We retrospectively reviewed patients who received IECs directed towards various targets in patients with hematologic, solid, and brain tumor malignancies from January 2014 to June 2023 at Texas Children's Hospital. The primary end point was hypotension requiring vasoactive support and/or heart failure within 30 days of infusion. A total of 203 patients met inclusion criteria. Pretreatment echocardiogram was available for 142 (70%) pediatric patients, of whom 140 (96%) had normal baseline systolic function. Hypotension requiring vasoactive support occurred in 26 (13%) patients. Hematologic malignancy indications (p = 0.002), total body irradiation (TBI) (p = 0.002), and allogenic hematopoietic stem cell transplants (HCT) (p = 0.035) were associated with increased risk of hypotension requiring vasoactive support. Follow-up echocardiograms were available for 14 patients who met the primary end point, and all showed return to baseline within 6 months. Significant hemodynamic compromise occurred in a minority of patients treated with IEC therapies. All experiencing cardiac dysfunction had recovery of function, and there was no cardiovascular-related mortality.

Immune Modulation Effect of Administration of Rice Bran Extract with Increased Solubility Fermented by Lentinus edodes UBC-V88 in Cyclophosphamide-Treated Mice Model

Immune Modulation Effect of Administration of Rice Bran Extract with Increased Solubility Fermented by Lentinus edodes UBC-V88 in Cyclophosphamide-Treated Mice Model

Comprehensive Review of Early and Late Toxicities in CAR T-Cell Therapy and Bispecific Antibody Treatments for Hematologic Malignancies.

Chimeric antigen receptor T-cell (or CAR-T) therapy and bispecific antibodies (BsAbs) have revolutionized the treatment of hematologic malignancies, offering new options for relapsed or refractory cases. However, these therapies carry risks of early complications, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and delayed issues like graft-versus-host disease (GVHD), infections, and secondary cancers. Effective management requires early diagnosis using advanced biomarkers and imaging, along with prompt interventions involving immunosuppressants, corticosteroids, and cytokine inhibitors. A multidisciplinary approach is essential, integrating hematologists, oncologists, and infectious disease specialists, with emerging strategies like targeted biologics and personalized medicine showing promise in balancing efficacy with toxicity management. Ongoing research is critical to refine diagnostics and treatments, ensuring that these therapies not only extend survival but also improve patients' quality of life. This review provides critical insights for healthcare professionals to quickly recognize and treat complications of CAR-T and BsAbs therapies. By focusing on early detection through biomarkers and imaging and outlining timely therapeutic interventions, it aims to equip the multidisciplinary care team with the knowledge necessary to manage the challenges of these advanced treatments effectively, ultimately optimizing patient outcomes.

Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models.

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited potent and specific cytotoxicity against uPAR-expressing PDAC cell lines, stromal and immune cells, and bystander killing of uPAR-negative cells. In vivo, the ADC induced remission or sustained tumor regression and extended survival in xenograft models. In syngeneic orthotopic models, the antitumor effect promoted immunomodulation by enhancing infiltrating immune effectors and decreasing immunosuppressive cells. This study lays grounds for further exploring FL1-PNU as a putative clinical ADC candidate, potentially providing a promising therapeutic avenue for PDAC as a monotherapy or in combinatorial regimens.

Role of procalcitonin, C reactive protein and ferritin in cytokine release syndrome after CAR T-cell therapy in children and young adults

ABSTRACT Purpose Chimeric antigen receptor (CAR) T-cell CD19 therapy has changed the treatment paradigm for patients with relapsed/refractory B-cell acute lymphoblastic leukemia. It is frequently associated with potentially severe toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and admission to PICU is often required. Some biomarkers seem to correlate with CRS severity. Our goal is to elucidate the role of procalcitonin (PCT), C-reactive protein (CRP) and ferritin in the context of CRS following CAR T-cell infusion to predict its severity and PICU admission. Methods Prospective observational study (2016-2022) in children and young adult who received CAR T-cell therapy (Tisagenlecleucel/ARI-0001). We collected epidemiologic data, specific CAR T-cell toxicities, PICU admission, biomarker results (procalcitonin, CRP and ferritin), length of stay and mortality. Biomarkers were analyzed considering two values: the highest value during ward admission, and the highest overall value including PICU admission. Results Seventy-seven patients were included. Median age at infusion was 9.1 years (IQR 6-13), 49.4% were females. Before CAR T-cell infusion, the median bone marrow blast was 9% (IQR 0-59). The most frequent toxicity was CRS in 62 patients (80.5%), it was severe in 18 cases (23.4%). Fourteen patients (18.1%) had ICANS. Thirty-one patients (40.3%) required admission to the PICU. PCT and ferritin were higher in patients admitted to PICU (PCT 0.8 ng/ml vs 0.15 ng/ml, p < 0.001, ferritin 5490 vs. 2900 ug/l, p < 0.019). The proposed cut-off for PCT to predict admission to PICU is 0.55 ng/mL, presenting a sensitivity of 67.7% and a specificity of 86.7%. The maximum value of the three biomarkers was higher in those who presented any primary outcome: development of a severe CRS, the need for admission to PICU, and in-hospital mortality. Biomarkers were higher in those who needed inotropic or respiratory support. Conclusions PCT levels increase after CAR-T cell therapy in the setting of systemic inflammation and could be a predictor of PICU admission and evolution to death. Further research studying its role in the context of CRS and the differential diagnosis between infection and CRS is needed to better understand the biology of this biomarker and to define its value in clinical practice.

Construction and analysis of the immune effect of subunit vaccines based on the flagellin FlaB and FlaC of Vibrioharveyi.

Vibrio harveyi is a common sort of pathogenic bacterium in marine, which annually gives rise to huge financial losses in aquaculture industry. Flagellin is one of the important virulence factors for bacteria, but meanwhile it is also a preferable vaccine candidate. In this study, we have identified and analyzed two flagellin antigens of V. harveyi, FlaB and FlaC; and moreover, on this basis, two subunit vaccines (rFlaB and rFlaC) were constructed, and the potential as vaccines against V. harveyi infection were determined and compared. Sequence analysis indicated that the coding region of FlaB was 1131 bp, sharing the highest sequence identity (97.07%) with the counterparts of V. campbellii, and that FlaC (1155 bp) shared the highest sequence identity (98.18%) with the counterparts of V. campbellii. The vaccine potential of subunit vaccines, rFlaB and rFlaC, were analyzed in the Epinephelus coioides model. The results showed that fish vaccinated with rFlaB or rFlaC at 4-week post-vaccination (p.v.), exhibiting a relative percent survival (RPS) of 81.8% and 59.1%, respectively; when fish were vaccinated with rFlaB or rFlaC at 8-week p.v., the RPS of rFlaB and rFlaC were 76.2% and 42.9%, respectively. Compared to control group, immunological analysis showed that both rFlaB and rFlaC could elicited specific antibody expression and innate immune responses. Of note, rFlaB could induce higher levels of IgM, AKP, LZM, ACP and SOD activity in fish in comparison with rFlaC. Additionally, qPCR results manifested that the expressions of IL-1β, CD4, CD8α, IgM, IFNγ, MHCⅠα, MHCⅡα, TLR5M and TLR5S were significantly up-regulated in the fish immunized with rFlaB and rFlaC, indicating their ability to activate innate immunity and trigger the inflammatory and cell immune responses. Overall, FlaB is superior to FlaC as regards potential as vaccines. This research has developed two promising subunit vaccines against diseases caused by V. harveyi that are well-suited for application in aquaculture.

Spatial Kinetic Modeling of Crowd Evacuation: Coupling Social Behavior and Infectious Disease Contagion

This paper introduces a kinetic model of crowd evacuation from a bounded domain, integrating social behavior and contagion dynamics. The model describes the spatial movement of individuals in a crowd, taking into account interactions with other people and the geometry of the environment. Interactions between healthy and infectious individuals can lead to disease transmission and are considered. The approach is grounded in the kinetic theory of active particles, where the activity variable represents both the infectious disease status of individuals (e.g., susceptible, infected) and the psychological state of pedestrians, including contagion awareness. Varying awareness levels influence individual behavior, leading to more cautious movement patterns, potentially reducing the overall infection rate. The performance of the model is evaluated through a series of numerical simulations. Different scenarios are examined to investigate the impact of awareness levels on pedestrian behavior, infectious disease spread, and evacuation times. Additionally, the effects of population immunization and individual contagion awareness are assessed to determine the most effective strategy for reducing infections. The results provide valuable insights into targeted strategies to mitigate contagion.

Multiple Myeloma Cells Shift the Fate of Cytolytic ILC2s Towards TIGIT-Mediated Cell Death.

Growing evidence attests to the multifaceted roles of group 2 innate lymphoid cells (ILC2s) in cancer immunity. They exhibit either pro- or anticancer activity depending on tumor type but their function in Multiple Myeloma (MM) is still not elucidated. The bone marrow (BM) and peripheral blood (PB) of patients (pts) with MM or precancerous conditions were collected, and specific properties of ILC2 subsets were assessed by flow cytometry. By dissecting ILC2s according to c-Kit marker, we observed that NKp30 and NKG2D were mainly confined to c-Kithi ILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kitlo cells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kitlo subset, but the expression of DNAM-1 in these cells was significantly reduced, especially in BM. Interestingly, MM-ILC2s from PB expressed granzyme B (GZMB), but its expression was impaired in BM-ILC2s. Accordingly, MM cells were susceptible to killing by MM-ILC2s derived from PB while eluding ILC2 surveillance in BM. Indeed, in MM-ILC2s derived from BM, the downregulation of DNAM-1 is accompanied by the upregulation of TIGIT, which mediate cell death in ILC2s upon recognition of the cognate ligands expressed by MM cells. These ILC2 changes appeared in clinical precursor conditions and eventually accumulated with disease progression. MM-ILC2s can act as cytolytic immune effectors that are fully competent in PB. However, MM cells shift ILC2 fate towards cell death in BM via the upregulation of TIGIT, thereby representing a potential therapeutic target to restore ILC2 antitumor activity.

A phase 1 trial of prizloncabtagene autoleucel, a CD19/CD20 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma.

Prizloncabtagene autoleucel (prizlon-cel), a novel bispecific chimeric antigen receptor (CAR) T-cell, targets and eliminates CD19/CD20 positive tumor cells. This phase 1, open-label study investigated the safety and efficacy of prizlon-cel in patients with relapsed/refractory B-cell non-Hodgkin Lymphoma (r/r B-NHL). Patients with CD19 and/or CD20-positive r/r B-NHL received a 3-day lymphodepletion (cyclophosphamide: 300 mg/m2/d; fludarabine: 30 mg/m2/d) followed by an intravenous dose of prizlon-cel. The primary endpoints were dose-limiting toxicity (DLT) and incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of the 48 patients infused prizlon-cel, 44 had large B-cell lymphoma (LBCL). No patient experienced DLT. Cytokine release syndrome occurred in 93.8% of patients, with only one case of grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in 6.3% of patients, with no grade 3 or higher events. The most common grade 3 or higher TEAEs were neutropenia (83.3%) and leukopenia (50%). The ORR and complete response (CR) rates in all patients were 91.5% and 85.1%, respectively, and in LBCL patients, ORR was 90.7% with 86.0% CR. With median follow up of 30.0 months, median DOR, PFS, and OS were all not reached. The Kaplan-Meier estimate of 2-year DOR, PFS and OS rates were 66.0%, 62.6%, and 76.5%, respectively. Prizlon-cel showed a favorable safety profile and a high and durable response in patients with r/r B-NHL, suggesting a promising treatment option for patients with r/r B-NHL. (ClinicalTrials.gov number: NCT04317885, NCT04655677, NCT04696432, NCT04693676).