Activation Of Adaptive Immune Cells Research Articles

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.

Gut bacteria, host immunity, and colorectal cancer: From pathogenesis to therapy.

The emergence of 16S rRNA and metagenomic sequencing has gradually revealed the close relationship between dysbiosis and colorectal cancer (CRC). Recent studies have confirmed that intestinal dysbiosis plays various roles in the occurrence, development, and therapeutic response of CRC. Perturbation of host immunity is one of the key mechanisms involved. The intestinal microbiota, or specific bacteria and their metabolites, can modulate the progression of CRC through pathogen recognition receptor signaling or via the recruitment, polarization, and activation of both innate and adaptive immune cells to reshape the protumor/antitumor microenvironment. Therefore, the administration of gut bacteria to enhance immune homeostasis represents a new strategy for the treatment of CRC. In this review, we cover recent studies that illuminate the role of gut bacteria in the progression and treatment of CRC through orchestrating the immune response, which potentially offers insights for subsequent transformative research.

Natural killer-like B cells are a distinct but infrequent innate immune cell subset modulated by SIV infection of rhesus macaques.

Natural killer-like B (NKB) cells are unique innate immune cells expressing both natural killer (NK) and B cell receptors. As first responders to infection, they secrete IL-18 to induce a critical cascade of innate and adaptive immune cell infiltration and activation. However, limited research exists on the role of NKB cells in homeostasis and infection, largely due to incomplete and erroneous evaluations. To fill this knowledge gap, we investigated the expression of signaling and trafficking proteins, and the in situ localization and transcriptome of naïve NKB cells compared to conventionally-defined NK and B cells, as well as modulations of these cells in SIV infection. Intracellular signaling proteins and trafficking markers were expressed differentially on naïve NKB cells, with high expression of CD62L and Syk, and low expression of CD69, α4β7, FcRg, Zap70, and CD3z, findings which were more similar to B cells than NK cells. CD20+NKG2a/c+ NKB cells were identified in spleen, mesenteric lymph nodes (MLN), colon, jejunum, and liver of naïve rhesus macaques (RM) via tissue imaging, with NKB cell counts concentrated in spleen and MLN. For the first time, single cell RNA sequencing (scRNAseq), including B cell receptor (BCR) sequencing, of sorted NKB cells confirmed that NKB cells are unique. Transcriptomic analysis of naïve splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. While only 15% of sorted NKB cells showed transcript expression of both KLRC1 (NKG2A) and MS4A1 (CD20) genes, only 5% of cells expressed KLRC1, MS4A1, and IgH/IgL transcripts. We observed expanded NKB frequencies in RM gut and buccal mucosa as early as 14 and 35 days post-SIV infection, respectively. Further, mucosal and peripheral NKB cells were associated with colorectal cytokine milieu and oral microbiome changes, respectively. Our studies indicate that NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings that could only be resolved using genomic techniques. Although NKB cells were clearly elevated during SIV infection and associated with inflammatory changes during infection, further interrogation is necessary to acurately identify the true phenotype and significance of NKB cells in infection and inflammation.

Abstract CT078: Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001)

Abstract Background: Epidermal growth factor receptor (EGFR) is a cell surface receptor expressed in a variety of solid tumors. Gamma delta (γδ)-T cells represent a conserved T cell subset that can induce cell death in a wide range of malignancies. The presence of γ9δ2-T cells in solid tumors strongly correlates with better patient survival (Gentles 2015; Tosolini 2017). In addition to direct, potent killing by release of cytotoxic molecules, activated γ9δ2-T cells process and present antigen and contribute to a cascade response resulting in downstream activation of innate and adaptive immune cells to mediate further tumor cell killing (Brandes 2005; Devilder 2006; Vantourout 2013). Novel approaches that improve targeting and activation of γ9δ2-T cells may lead to the development of effective and safe cancer treatments. SGN-EGFRd2 is an investigational, bispecific humanized heavy chain-only antibody (HcAb). Advantages of HcAbs include their small size, high solubility, high stability, and excellent tissue penetration in vivo (Bannas 2017). SGN-EGFRd2 simultaneously binds EGFR and the γ9δ2-T cell receptor, resulting in the conditional activation of γ9δ2-T cells. Importantly, full activation of γ9δ2-T cells requires a secondary phosphoantigen stress signal present only in malignant and certain infected cells (Deseke 2020; Herrmann 2020; Rigau 2020; Vantourout 2013), but not normal healthy cells, conferring preferential tumor-directed cytotoxicity. The proposed cytotoxic mechanism of action is independent of KRAS and BRAF mutations (King 2023) known to confer resistance to approved anti-EGFR therapies in colorectal cancer (CRC). This first-in-human study is evaluating the safety, tolerability, and antitumor activity of SGN-EGFRd2 in patients with advanced solid tumors. Methods: SGNEGFRd2-001 (NCT05983133) is an open-label, multicenter, phase 1, dose escalation and expansion study evaluating SGN-EGFRd2 monotherapy in patients with relapsed/refractory (R/R) CRC, head and neck squamous cell cancer, non-small cell lung cancer, and pancreatic ductal adenocarcinoma in 3 parts: dose escalation (Part A; n ~ 75), dose optimization (Part B; optional; up to n = 40), and dose expansion (Part C; up to n = 160). Patients must have R/R disease, or be intolerant to standard of care therapies, with no appropriate standard therapy available. Patients must have measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function. Patients are eligible regardless of tumor EGFR expression or EGFR/KRAS/BRAF mutation status. Patients will receive SGN-EGFRd2 as an intravenous infusion. Primary study objectives are safety and tolerability, maximum tolerated dose, and recommended dose and schedule. Secondary objectives include pharmacokinetics, immunogenicity, and antitumor activity. Tumor samples will be analyzed for exploratory biomarkers. Accrual is ongoing in the US. Additional sites in Europe and Canada are planned. Citation Format: Hirva Mamdani, Joel Randolph Hecht, Rachel E. Sanborn, Maria Corinna Palanca-Wessels, Mingjin Yan, Martin Gutierrez, David L. Bajor. Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001) [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 CT078.

Abstract 1183: A first-in-class and SHP1 allosteric inhibitor, SB8091, shows a good efficacy and safety profile in preclinical models

Abstract Introduction: Src homology 2 domain-containing phosphatase 1 (SHP1) is a cytoplasmic protein tyrosine phosphatase (PTP) that is primarily expressed in hematopoietic cells and is commonly recognized as a negative regulator of multiple signaling pathways1. Previously, we showed that inhibition of the phosphatase activity of SHP1 by a novel SHP1 allosteric inhibitor, SB6299, results in the activation of innate and adaptive immune cells and enhanced anti-tumor immune responses2. Here, we report SB8091, an advanced SHP1 allosteric inhibitor with a promising initial safety profile and improved pharmacokinetic properties. Methods: SHP1 inhibitors were developed through a structure-based drug design approach, and optimized for cellular activity on target, in vitro ADME, and in vivo pharmacokinetic properties. Pharmacokinetic (PK) and preliminary toxicity studies were performed with mice. The lead series was assessed in in-vitro studies with mouse or human primary immune cells. In-vivo efficacy and pharmacodynamic data were generated using mouse syngeneic tumor models. Results: Structurally, SB8091 seemed to stabilize the autoinhibitory form of SHP1 as an allosteric inhibitor, in a nanomolar range and which can explain the outstanding selectivity compared to other PTP enzymes, including SHP2. In several human primary immune cell types, SB8091 significantly increased cytokine responses and demonstrated significantly enhanced activity in NK cells and macrophages against various cancer target cells. As a single agent, this compound exhibited inhibitory effects on tumor growth when administered orally, and the efficacy was further enhanced when co-administered with anti-PD1 antibodies in various syngeneic tumor models. Notably, this effect was associated with a pharmacodynamic response marked by increased levels of phosphorylated substrates regulated by SHP1. SB8091 exhibited favorable pharmacokinetic properties for oral administration, and SafetyScreen data showed a very low potential for off-target activity and drug-drug interactions. Additionally, during a 2-week repeat pilot toxicity study in mice, SB8091 demonstrated excellent tolerability even at high doses, indicating a high therapeutic index (TI > 100). Conclusion: Our advanced compound, SB8091, is a potent, highly selective, and orally bioavailable allosteric inhibitor of SHP1. It has demonstrated excellent efficacy as a monotherapy or in combination with immune checkpoint blockers, with favorable drug properties and safety profiles. Research to advance to the clinical stage is being conducted.

Gene-edited pigs: a translational model for human food allergy against alpha-Gal and anaphylaxis.

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha-1,3-galactosyltransferase (GGTA1) gene in humans, the disaccharide galactose-α-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1-deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Gal-sensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions.

Lipid peroxidation of immune cells in cancer.

Growing evidence indicates that cellular metabolism is a critical determinant of immune cell viability and function in antitumor immunity and lipid metabolism is important for immune cell activation and adaptation to the tumor microenvironment (TME). Lipid peroxidation is a process in which oxidants attack lipid-containing carbon-carbon double bonds and is an important part of lipid metabolism. In the past decades, studies have shown that lipid peroxidation participates in signal transduction to control cell proliferation, differentiation, and cell death, which is essential for cell function execution and human health. More importantly, recent studies have shown that lipid peroxidation affects immune cell function to modulate tumor immunity and antitumor ability. In this review, we briefly overview the effect of lipid peroxidation on the adaptive and innate immune cell activation and function in TME and discuss the effectiveness and sensitivity of the antitumor ability of immune cells by regulating lipid peroxidation.

A Bidirectional Immunological Relationship between Diabetes Mellitus and Tuberculosis: A Narrative Review

Tuberculosis (TB) is one of the most common contagious diseases worldwide. Over the past few decades, researchers have made significant efforts to prevent TB. Recent predictions indicate that the prevalence of Diabetes Mellitus (DM) will reach 552 million by 2023 due to ongoing epidemiological changes in several countries across the globe. India is expected to have 62-80 million people with diabetes by 2030, making it the "Diabetes Capital" of the world. Present review discusses the urgent need to understand the mechanisms and implications of DM on the immune systems of TB patients. The correlation between TB and DM has been shown to be bidirectional. Numerous studies have revealed a higher prevalence of diabetes in TB patients, as their immune systems are compromised. TB patients with DM experience progressive deficits in both innate and adaptive immune cell activity, reducing their ability to suppress Mycobacterium tuberculosis (M. tuberculosis) and increasing their risk of developing TB. Increased inflammation and elevated levels of inflammatory cytokines in circulation are characteristics of TB with DM co-morbidity, which indicate the active involvement of the angiogenesis-inflammation nexus. Therefore, to alleviate the burden of both disorders, it would be beneficial to make informed therapy choices by gaining a better understanding of TB immunology in the context of DM.

Based on Weighted Gene Co-Expression Network Analysis Reveals the Hub Immune Infiltration-Related Genes Associated with Ulcerative Colitis.

Immune infiltration plays a pivotal role in the pathogenesis of mucosal damage in ulcerative colitis (UC). The objective of this study was to systematically analyze and identify genetic characteristics associated with immune infiltration in UC. Gene expression data from three independent datasets obtained from the Gene Expression Omnibus (GEO) were utilized. By employing the ssGSEA and CIBERSORT algorithms, we estimated the extent of immune cell infiltration in UC samples. Subsequently, Weighted Correlation Network Analysis (WGCNA) was performed to identify gene modules exhibiting significant associations with immune infiltration, and further identification of hub genes associated with immune infiltration was accomplished using least absolute shrinkage and selection operator (LASSO) regression analysis. The relationship between the identified hub genes and clinical information was subsequently investigated. Our findings revealed significant activation of both innate and adaptive immune cells in UC. Notably, the expression levels of CD44, IL1B, LYN, and ITGA5 displayed strong correlations with immune cell infiltration within the mucosa of UC patients. Immunohistochemical analysis confirmed the significant upregulation of CD44, LYN, and ITGA5 in UC samples, and their expression levels were found to be significantly associated with common inflammatory markers, including the systemic immune inflammation indices, C-reactive protein, and erythrocyte sedimentation rate. CD44, LYN, and ITGA5 are involved in the immune infiltration pathogenesis of UC and may be potential therapeutic targets for UC.

Tumor-derived extracellular vesicles in the immune microenvironment of head and neck squamous cell carcinoma: Foe or future?

Head and neck squamous cell carcinoma (HNSCC) is considered a “cold tumor” due to its suppressive immune microenvironment, and is associated with a poor prognosis. Tumor-derived extracellular vesicles (EVs) play an essential role in the tumor microenvironment and mediate intercellular communications. EVs have been proven to be key immune regulators involved in antitumor immune responses and escape from immune surveillance. Tumor-derived EVs favor the formation of an immunosuppressive tumor microenvironment by regulating the differentiation, proliferation and activation of innate and adaptive immune effector cells, as well as myeloid cells, acting as a “foe” in the microenvironment. However, EVs are also valuable for predicting and improving the prognosis of HNSCC, and represent hope for future treatments. In this review, we summarize the impact of HNSCC-derived EVs on the immune microenvironment, describe their roles as biomarkers and for drug delivery in disease monitoring and treatment. We provide insights into important areas for future research and identify potential therapeutic targets for HNSCC treatment.

TMIC-59. IL-2 SECRETING ENGINEERED MYELOID CELLS POTENTIATE CYTOTOXIC EFFECTOR CELL ACTIVATION TO DELAY MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA

Abstract INTRODUCTION Gliomas are the most prevalent brain tumor in the adolescent and young adult population (AYA) and one of the leading causes of cancer-related death. In fact, two-thirds of glioma AYA patients are affected by low-grade gliomas (LGGs). Moreover, there are no therapies to prevent glioma LGG malignant progression. Malignant progression is associated with a significant reduction of tumor infiltrating cytotoxic effector immune cells, primarily due to the immunosuppressive tumor microenvironment (TME) mediated by regulatory T lymphocytes, tumor associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). To that end, immunotherapies have had limited efficacy in improving outcomes for primary and secondary HGGs. HYPOTHESIS We hypothesize that engineered myeloid cells that release IL-2 will enhance the trafficking of activated effector T cells and potentiate a pro-inflammatory cascade in the low-grade glioma TME, delaying malignant progression. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were retro-orbitally treated at day 21 with a single dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The inflammatory status of the TME along with the composition and functional status of tumor infiltrating immune cells were investigated in vivo by cytokine array, mass cytometry, and bulk RNA sequencing. RESULTS Our complementary dataset demonstrated that GEMys-IL2 infiltrated the glioma microenvironment and triggered a pro-inflammatory cascade involving the upregulation and release of IL2, IFNy, CXCL9, Tim1, CD26 and other pro-inflammatory cytokines associated with the activation and recruitment of innate and adaptive immune cells within the TME. In addition, we observed a downregulation of immunosuppressive signaling pathways such as IL10, PPAR, LXR/RXR, CTLA4 and PD-1. Also, a single dose of GEMys-IL2 systemically injected in RCAS/t-va immunocompetent LGG bearing mice potentiated pro-inflammatory remodeling of the TME and significantly improved overall survival. CONCLUSIONS These preclinical studies highlight a novel approach in developing next-generation innate immunotherapies.

Modakafusp Alfa Demonstrates Type I Interferon-Mediated Innate and Adaptive Immune Enhancement in a Phase 1/2 Study in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Modakafusp alfa (moda), a novel immunocytokine, is an innate immunity enhancer comprising two attenuated interferon (IFN) α2b molecules fused to an anti-CD38 IgG4 monoclonal antibody backbone, driving preferential IFNα signalling in CD38-expressing innate and adaptive immune cells as well as myeloma cells. Here, we present pharmacodynamic (PD) data from the first-in-human Phase 1/2 study of moda as a monotherapy in patients with RRMM (iinnovate-1; NCT03215030). A total of 37 patients treated with moda at 1.5 or 3 mg/kg every 4 weeks were included in the analysis. Peripheral blood (PB) and bone marrow (BM) samples were collected during screening or pre-dose on cycle 1 day 1 (C1D1) and at multiple timepoints after treatment. BM and PB samples were evaluated by cytometry time of flight (CyTOF) and bulk RNA sequencing (RNAseq) to assess pharmacodynamic changes in immune cell populations, cell activation, and gene expression. Administration of moda led to enhanced innate immune cell activation and cytotoxic function as demonstrated by increased proportions of CD69+ and granzyme B+ in peripheral NK cells analyzed by CyTOF. This was accompanied by a decrease in the proportion of TIGIT+ NK cells, indicating reduced inhibitory signaling. Furthermore, enhanced proliferation (%Ki67+) of NK cells was observed in both BM and PB. Moda also impacted myeloid cell populations in BM and PB. Dendritic cells (DCs) and monocytes in PB showed increased surface expression of the co-stimulatory molecule CD86, suggesting a potential for enhanced antigen presentation and co-stimulation ability. Increased proliferation (%Ki67) of DCs and monocytes was detected in both PB and BM, accompanied by a decrease in numbers of peripheral DCs which may indicate recruitment or homing to secondary lymphoid organs. Additionally, RNAseq analysis revealed that treatment with moda led to upregulation of CD68 expression in both PB and BM, indicating a proinflammatory M1 macrophage type response. Finally, CyTOF analysis also indicated that moda significantly impacted adaptive immunity. We observed enhanced activation (%CD69, %PD1 and %CD40L) and cytotoxic function (%granzyme B) of peripheral CD8 T cells, and increased CD8 T cell proliferation (%Ki67 CD8) in both PB and BM samples. Enhanced activation of peripheral CD4 T cells (%CD69, %CD40L) was also detected. Consistent with activation of the adaptive immune system, there was a reduction in naïve CD8 T cells accompanied by an increase in CD8 T effector memory cells in PB. Analysis of exhaustion markers (TIGIT, PD-1) in cycle 1 (C1D8, C1D15, and C2D1 predose) showed that moda did not induce CD8 T cell exhaustion in either PB or BM, and there was no change in FoxP3+ Treg cells. Moda-induced innate and adaptive immune cell phenotypic changes were evaluated for correlation with clinical response at timepoints with sufficient number of evaluable samples. While none of the associations were statistically significant after correcting for multiplicity testing (using the false discovery rate method), we observed trends warranting further investigation. There was a greater increase of CD40L+ NK cells and PD1+ CD8 cells in responders vs. non-responders at C1D2. Additionally, at C1D15 responders showed a lower increase in proliferation (%Ki67+) of classical monocytes, NK cells, and myeloid DCs in PBas compared to non-responders. A similar trend was also observed in the BM classical monocytes. Even though the peak of Ki67 expression was observed at C1D8, diminished increases of proliferating cells at C1D15 in responders was a surprising observation that needs further consideration. The PD biomarker data from this first-in-human clinical trial demonstrated that treatment with moda enhances both innate and adaptive immune cell activation in PB and BM. Importantly, moda-mediated immune activation did not result in T cell exhaustion during cycle 1, as evaluated in both PB and BM. We have observed interesting trends of immune phenotypic changes that may correlate with response. Follow-up analyses of the correlation of biomarkers with clinical response are in progress and will be presented. Further clinical trials are underway (iinnovate-2, NCT05556616; iinnovate-3, NCT05590377) to evaluate moda's novel immune activating mechanism in combination with standard of care anti-myeloma therapies.

Ferroptosis in the post-transplantation inflammatory response

Transplantation is a life-saving therapy for patients with end-stage organ disease. Successful outcomes after transplantation require mitigation of the post-transplant inflammatory response, limiting alloreactivity, and prevention of organ rejection. Traditional immunosuppressive regimens aim to dampen the adaptive immune response; however, recent studies have shown the feasibility and efficacy of targeting the innate immune response. Necroinflammation initiated by donor organ cell death is implicated as a critical mediator of primary graft dysfunction, acute rejection, and chronic rejection. Ferroptosis is a form of regulated cell death that triggers post-transplantation inflammation and drives the activation of both innate and adaptive immune cells. There is a growing acceptance of the clinical relevance of ferroptosis to solid organ transplantation. Modulating ferroptosis may be a potentially promising strategy to reduce complications after organ transplantation.

Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells.

Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it is well established that aberrant activity of adaptive and innate immune cells plays a crucial role in its pathogenesis. Several immune cell abnormalities have been described in MS and its animal models, including T lymphocytes, B lymphocytes, dendritic cells, neutrophils, microglia/macrophages, and astrocytes, among others. Physical exercise offers a valuable alternative or adjunctive disease-modifying therapy for MS. A growing body of evidence indicates that exercise may reduce the autoimmune responses triggered by immune cells in MS. This is partially accomplished by restricting the infiltration of peripheral immune cells into the central nervous system (CNS) parenchyma, curbing hyperactivation of immune cells, and facilitating a transition in the balance of immune cells from a pro-inflammatory to an anti-inflammatory state. This review provides a succinct overview of the correlation between physical exercise, immune cells, and MS pathology, and highlights the potential benefits of exercise as a strategy for the prevention and treatment of MS.

Counteracting Immunosenescence-Which Therapeutic Strategies Are Promising?

Aging attenuates the overall responsiveness of the immune system to eradicate pathogens. The increased production of pro-inflammatory cytokines by innate immune cells under basal conditions, termed inflammaging, contributes to impaired innate immune responsiveness towards pathogen-mediated stimulation and limits antigen-presenting activity. Adaptive immune responses are attenuated as well due to lowered numbers of naïve lymphocytes and their impaired responsiveness towards antigen-specific stimulation. Additionally, the numbers of immunoregulatory cell types, comprising regulatory T cells and myeloid-derived suppressor cells, that inhibit the activity of innate and adaptive immune cells are elevated. This review aims to summarize our knowledge on the cellular and molecular causes of immunosenescence while also taking into account senescence effects that constitute immune evasion mechanisms in the case of chronic viral infections and cancer. For tumor therapy numerous nanoformulated drugs have been developed to overcome poor solubility of compounds and to enable cell-directed delivery in order to restore immune functions, e.g., by addressing dysregulated signaling pathways. Further, nanovaccines which efficiently address antigen-presenting cells to mount sustained anti-tumor immune responses have been clinically evaluated. Further, senolytics that selectively deplete senescent cells are being tested in a number of clinical trials. Here we discuss the potential use of such drugs to improve anti-aging therapy.

Mixtures of per- and poly-fluoroalkyl substances (PFAS) reduce the in vitro activation of human T cells and basophils

In the last decades, per- and poly-fluoroalkyl substances (PFAS), widely used industrial chemicals, have been in the center of attention because of their omnipotent presence in water and soils worldwide. Although efforts have been made to substitute long-chain PFAS towards safer alternatives, their persistence in humans still leads to exposure to these compounds. PFAS immunotoxicity is poorly understood as no comprehensive analyses on certain immune cell subtypes exist. Furthermore, mainly single entities and not PFAS mixtures have been assessed. In the present study we aimed to investigate the effect of PFAS (short-chain, long-chain and a mixture of both) on the in vitro activation of primary human immune cells.Our results show the ability of PFAS to reduce T cells activation. In particular, exposure to PFAS affected T helper cells, cytotoxic T cells, Natural Killer T cells, and Mucosal associated invariant T (MAIT) cells, as assessed by multi-parameter flow cytometry. Furthermore, the exposure to PFAS reduced the expression of several genes involved in MAIT cells activation, including chemokine receptors, and typical proteins of MAIT cells, such as GZMB, IFNG and TNFSF15 and transcription factors. These changes were mainly induced by the mixture of both short- and long-chain PFAS. In addition, PFAS were able to reduce basophil activation induced by anti-FcεR1α, as assessed by the decreased expression of CD63.Our data clearly show that the exposure of immune cells to a mixture of PFAS at concentrations mimicking real-life human exposure resulted in reduced cell activation and functional changes of primary innate and adaptive human immune cells.

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas

BackgroundSEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater...

Multiplexed trackable intratumor microdosing of the investigational STING agonist TAK-676 alone and in combination in the native tumor microenvironment of patients with head and neck cancer: A phase 0 trial.

2579 Background: TAK-676 is a novel synthetic STING agonist developed to induce an inflammatory state through release of interferon (IFN), production of proinflammatory chemokines and cytokines, and activation of innate and adaptive immune cells in the tumor microenvironment (TME). To gain early mechanistic insights on the effects of TAK-676 in the native TME alone and in combination with standard-of-care chemotherapies, we completed a Phase 0 intratumoral microdosing trial in head and neck squamous cell carcinoma patients using the Comparative In Vivo Oncology (CIVO) platform. CIVO enables direct evaluation of biomarker response in trackable, distinct regions of drug exposure upon resection. These studies were designed to identify rational combinations that could be evaluated in future clinical trials with therapeutic intent. Methods: This IRB-approved study was conducted at four centers within the United States. Fifteen subjects provided Informed Consent and enrolled in the trial. Microdoses (≤1/100th systemic dose) of TAK-676, carboplatin, 5-FU, paclitaxel, and combinations thereof, were simultaneously injected via CIVO to eligible patients presenting with a surface-accessible primary or metastatic lesion ≥ 2 cm and planned surgical resection of the target lesion at 24 (n=8) or 72–96 (n=7) hours. Injection sites were identified via co-injection of fluorescent tracking markers (CIVO GLO). Multiplexed ISH, IHC, and spatial molecular profiling via GeoMx and CosMx were used to resolve molecular responses at each injection site. Patients were monitored for adverse events (AEs) for 28 days following injection. Results: TAK-676 exposure was associated with increased IFN signaling in all samples analyzed at the 24-hour cohort. This was accompanied by increased expression of pro-inflammatory cytokines and chemokines, “M1-like” macrophages, NK cells, and CD8+ T cells. Spatial profiling with GeoMx and CosMx revealed an IFN signature and elevated pro-inflammatory markers across multiple cell types throughout the TME. In addition, exposure to TAK-676 plus chemotherapy resulted in localized enhancement of apoptosis vs. chemotherapy alone across multiple tumors. The responses observed at 24 hours were transient and not detected in the 72–96-hour cohort. No AEs related to injection procedure or contents were reported. Conclusions: Intratumor microdosing via CIVO of TAK-676 alone and in combination with chemotherapy was shown to promote an early pro-inflammatory response, providing evidence of an on-target mechanism of action. The absence of effect at the late timepoints could be due to pharmacokinetics of drug exposure or compensatory signaling within the TME. In this Phase 0 clinical trial we safely demonstrated precise, mechanistic effects of TAK-676 on the native TME of intact human tumors. Clinical trial information: NCT04541108 .

A phase 1 study of AGEN2373, a novel CD137 agonist antibody designed to avoid hepatoxicity, in patients with advanced solid tumors.

2524 Background: We present results from the completely enrolled monotherapy arm of the first-in-human dose escalation study of AGEN2373, a novel CD137 agonist antibody engineered to maximize efficacy by circumventing the dose-limiting hepatotoxicity reported for prior CD137 agonists (NCT04121676). AGEN2373 binds to a unique epitope of CD137 on effector T and NK cells in the tumor and tumor-draining lymph nodes, promoting co-engagement of activating Fcγ receptors. CD137 (4-1BB) is a tumor necrosis factor receptor superfamily protein and co-stimulatory receptor that promotes anti-tumor activity of adaptive and innate immune cells, making it an attractive target for immunotherapy. Methods: 46 patients (pts) received AGEN2373 IV every 2 weeks (Q2W), Q3W, or Q4W at doses between 0.03 and 10 mg/kg in a 3+3 design. Key endpoints included safety, tolerability, PK, preliminary efficacy, and PD markers. Imaging was Q8W. Results: Pts were enrolled between Oct 2019 and May 2022 with a median follow-up of 7.2 months. The median age was 64 (range 33-82). The most common tumor types were colorectal cancer, 13 pts (28%) and sarcoma, 8 (17%). Median prior therapies were 4 (range 1-14) including 48% with prior immunotherapy. There were no dose-limiting toxicities (DLTs) and no treatment-related hepatitis. 37% of pts had treatment-related AEs (TRAEs). TRAEs >10% were limited to fatigue (17%) and nausea (15%). There were no G3, 4 or 5 TRAEs. Pharmacokinetic parameters including half-life, clearance, and volume of distribution were consistent with a human IgG1 Fc backbone. Induction of soluble CD137 was dose dependent with 2 mg/kg as the lowest saturating dose and minimum predicted efficacious dose. In 19 pts treated at 2 mg/kg or higher who had at least one post-baseline scan, the overall response rate (ORR) was 11% (n=2); 37% had SD (n=7) resulting in a disease control rate (DCR) (CR, PR or SD) of 47%. Notable responses include: a pt with vulvar SCC who had progressed rapidly on pembrolizumab and had a confirmed partial response (cPR) while remaining on AGEN2373 x 2 mg/kg q2w for ~40 wks, and a pt with ampullary carcinoma with 4 prior regimens had a cPR on AGEN2373 x 6 mg/kg q3w with complete resolution of the pancreatic lesion. A pt with CRPC had a 38% tumor reduction in liver target lesions (confirmed) on AGEN2373 x 10mg/kg q3w but was non-evaluable due to palliative radiation to bone metastases. Conclusions: AGEN2373 showed objective responses as monotherapy in heavily pretreated pts with solid tumors and was well-tolerated with no evidence of hepatotoxicity. This distinguishes AGEN2373 from previous CD137-targeted agents that reported dose-limiting hepatotoxicity. Combination therapy with botensilimab, a novel Fc-enhanced CTLA-4 antagonist, is being studied in pts with PD(L)-1 pretreated melanoma. Clinical trial information: NCT04121676 .

Immunometabolomics provides a new perspective for studying systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by clinical heterogeneity, unpredictable progression, and flare ups. Due to the heterogeneous nature of lupus, it has been challenging to identify sensitive and specific biomarkers for its diagnosis and monitoring. Despite the fact that the mechanism of SLE remains unknown, impressive progress has been made over the last decade towards understanding how different immune cells contribute to its pathogenesis. Research suggests that cellular metabolic programs could affect the immune response by regulating the activation, proliferation, and differentiation of innate and adaptive immune cells. Many studies have shown that the dysregulation of the immune system is associated with changes to metabolite profiles. The study of metabolite profiling may provide a means for mechanism exploration and novel biomarker discovery for disease diagnostic, classification, and monitoring. Here we review the latest advancements in understanding the role of immunometabolism in SLE, as well as the systemic metabolite profiling of this disease along with possible clinical application.