CD40 Receptor Research Articles

Subduing the Inflammatory Cytokine Storm

The inflammatory cytokine response is essential for protective immunity, yet bacterial and viral pathogens often elicit an exaggerated response (“cytokine storm”) harmful to the host that can cause multi-organ damage and lethality. Much has been published recently on the cytokine storm within the context of the coronavirus pandemic, yet bacterial sepsis, severe wound infections and toxic shock provide other prominent examples. The problem of the cytokine storm is compounded by the increasing incidence of multidrug-resistant bacterial strains. We created an incisive molecular tool for analyzing the role of the B7/CD28 costimulatory axis in the human inflammatory response. To attenuate the cytokine storm underlying infection pathology, yet preserve host defenses, we uniquely targeted the engagement of CD28 with its B7 co-ligands by means of short peptide mimetics of the human CD28 and B7 receptor homodimer interfaces. These peptides are not only effective tools for dissecting mechanism but also serve to attenuate the inflammatory response as a broad host-oriented therapeutic strategy against the cytokine storm. Indeed, such peptides protect mice from lethal Gram-positive bacterial superantigen-induced toxic shock even when dosed in molar amounts well below that of the superantigen and show promise in protecting humans from the severe inflammatory disease necrotizing soft tissue infections (‘flesh-eating’ bacterial sepsis) following traumatic wound injuries.

B-343 Development of CD40 and HER2 Bispecific Antibodies for Enhanced Efficacy against HER2-Positive Tumors

Abstract Background CD40, a member of the tumor necrosis factor superfamily, is primarily expressed on antigen-presenting cells. This receptor plays a crucial role in facilitating the interaction between dendritic cells, activating antigen-specific T cells. Agonist antibodies targeting the CD40 receptor have the potential to mimic the natural CD40 ligand, fostering dendritic cell maturation and stimulating immunity against “cold” tumors. Although this approach has shown promise in preclinical studies, translating it to clinical success has been challenging. Only modest anti-tumor activity was observed in cancer patients, and none of the developed CD40 monoclonal antibodies (mAbs) progressed beyond early clinical trials, highlighting a need for improved anti-tumor efficacy. Methods In this study, we successfully developed an anti-human CD40 agonist rabbit monoclonal antibody using Yurogen's proprietary SMAB(TM) platform. The most potent CD40 mAb clone was combined with trastuzumab (an anti-HER2 mAb) to create a therapeutic bispecific antibody. Our goal is to leverage immune cell activation through HER2-targeted cancer therapy to achieve enhanced anti-tumor activity. Dozens of diverse CD40xHER2 bispecific antibody designs (both symmetry and asymmetry) were explored, with careful evaluation of expression yield, purity, and binding profiles for each target respectively. Results A few bispecific antibody designs demonstrated robust binding to both HER2 and CD40 antigen proteins, as well as receptor-expressing cell lines. Notably, two developed bispecific antibodies exhibited potent killing of HER2-positive cancer cells with the assistance of innate immune cells. Conclusions In sum, this study provides novel insights into designing bispecific antibodies against HER2 and CD40, offering a promising avenue for advancing cancer immunotherapy.

Solving technical issues in flow cytometry to characterize porcine CD8α/β expressing lymphocytes

The CD8 molecule is a cell surface receptor and well described as co-receptor on T cells, binding directly to the major histocompatibility complex class I on antigen presenting cells. CD8 antigens are comprised of two distinct polypeptide chains, the α and the β chain. In the pig, the CD8 receptor is expressed by several lymphocyte subsets, including Natural Killer cells, γδ T cells and antigen experienced CD4+ αβ T cells. On these cell populations CD8 is expressed as αα homodimers. Porcine cytolytic T cells on the other hand exclusively express CD8 αβ heterodimers. Several monoclonal antibodies (mAbs) for either of the two chains are available and are frequently used in flow cytometry. We observed that distinct combinations of mAb clones for CD8α and CD8β chains can cause troubles in multi-color staining panels. Therefore, we aimed for an in-depth study of the usage of different CD8-specific mAb clones and optimizing co-staining strategies for flow cytometry. We tested mAb clones 11/295/33 and 76-2-11 for the detection of CD8α and mAb clones PPT23 and PG164A for the detection of CD8β. The results indicate that the CD8α clone 11/295/33 should not be used together with either of the two CD8β clones in the same incubation step, as co-staining led to a highly reduced ability of CD8β mAb binding and loss in signal in flow cytometry. This can lead to potential false results in detecting CD8αβ cytolytic T cells. In case of the CD8α mAb clone 76-2-11, no inhibition in binding of either CD8β mAb clones was observed, making it the preferred choice in multi-color staining panels. The obtained data will help in future panel designs for flow cytometry in the pig and therefore improving studies of porcine immune cells.

Modular Semisynthetic Approach to Generate T Cell-Dependent Bispecific Constructs from Recombinant IgG1 Antibodies.

Redirecting T cells to tumor cells by bispecific antibodies is an effective approach to treat cancer, and T cell-dependent bispecific antibodies (TDBAs) are an emerging class of potent immunotherapeutic agents. By simultaneously targeting antigens on tumor cells and T cells, T cells are activated to kill tumor cells. Herein, we report a platform to generate a novel class of 2:1 structure of T cell-dependent bispecific antibody with bivalency for HER2 receptors on tumor cells and monovalency for CD3 receptors on T cells. For this, we use a biogenic inverse electron-demand Diels-Alder (IEDDA) click reaction on genetically encoded tyrosine residues to install one TCO handle on therapeutically approved antibody trastuzumab. Subsequent TCO-tetrazine click with a tetrazine-functionalized CD3-binding Fab yields a 2:1 HER2 × CD3 TDBA that exhibits a tumor-killing capability at picomolar concentrations. Monovalency toward the CD3 receptor on T cells can lower the chances of cytokine release syndrome, which is a common side effect of such agents. Our semisynthetic approach can generate highly potent TDBA constructs in a few chemoenzymatic and synthetic steps.

Enhancing Anti-Cancer Immune Response by Acidosis-Sensitive Nanobody Display.

One of the main challenges with many cancer immunotherapies is that biomarkers are needed for targeting. These biomarkers are often associated with tumors but are not specific to a particular tumor and can lead to damage in healthy tissues, resistance to treatment, or the need for customization for different types of cancer due to variations in targets. A promising alternative approach is to target the acidic microenvironment found in most solid tumor types. This can be achieved using the pH (Low) Insertion Peptide (pHLIP), which inserts selectively into cell membranes under acidic conditions, sparing healthy tissues. pHLIP has shown potential for imaging, drug delivery, and surface display. For instance, we previously used pHLIP to display epitopes on the surfaces of cancer cells, enabling antibody-mediated immune cell recruitment and selective killing of cancer cells. In this study, we further explored this concept by directly fusing an anti-CD16 nanobody, which activates natural killer (NK) cells, to pHLIP, eliminating the need for antibody recruitment. Our results demonstrated the insertion of pH-sensitive agents into cancer cells, activation of the CD16 receptor on effector cells, and successful targeting and destruction of cancer cells by high-affinity CD16+ NK cells in two cancer cell lines.

Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.

447.8: Molecular incompatibility between pig CD200 and human CD200 receptor in xenogeneic immune responses.

447.8: Molecular incompatibility between pig CD200 and human CD200 receptor in xenogeneic immune responses.

Endothelial Cell-Derived Soluble CD200 Determines the Ability of Immune Cells to Cross the Blood-Brain Barrier.

The infiltration of immune cells into the central nervous system mediates the development of autoimmune neuroinflammatory diseases. We previously showed that the loss of either Fabp5 or calnexin causes resistance to the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis (MS). Here we show that brain endothelial cells lacking either Fabp5 or calnexin have an increased abundance of cell surface CD200 and soluble CD200 (sCD200) as well as decreased T-cell adhesion. In a tissue culture model of the blood-brain barrier, antagonizing the interaction of CD200 and sCD200 with T-cell CD200 receptor (CD200R1) via anti-CD200 blocking antibodies or the RNAi-mediated inhibition of CD200 production by endothelial cells increased T-cell adhesion and transmigration across monolayers of endothelial cells. Our findings demonstrate that sCD200 produced by brain endothelial cells regulates immune cell trafficking through the blood-brain barrier and is primarily responsible for preventing activated T-cells from entering the brain.

A Heuristic Approach to Analysis of the Genetic Susceptibility Profile in Patients Affected by Airway Allergies.

Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.

In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells

Monogenic blood diseases are among the most common genetic disorders worldwide. These diseases result in significant pediatric and adult morbidity, and some can result in death prior to birth. Novel ex vivo hematopoietic stem cell (HSC) gene editing therapies hold tremendous promise to alter the therapeutic landscape but are not without potential limitations. In vivo gene editing therapies offer a potentially safer and more accessible treatment for these diseases but are hindered by a lack of delivery vectors targeting HSCs, which reside in the difficult-to-access bone marrow niche. Here, we propose that this biological barrier can be overcome by taking advantage of HSC residence in the easily accessible liver during fetal development. To facilitate the delivery of gene editing cargo to fetal HSCs, we developed an ionizable lipid nanoparticle (LNP) platform targeting the CD45 receptor on the surface of HSCs. After validating that targeted LNPs improved messenger ribonucleic acid (mRNA) delivery to hematopoietic lineage cells via a CD45-specific mechanism in vitro, we demonstrated that this platform mediated safe, potent, and long-term gene modulation of HSCs in vivo in multiple mouse models. We further optimized this LNP platform in vitro to encapsulate and deliver CRISPR-based nucleic acid cargos. Finally, we showed that optimized and targeted LNPs enhanced gene editing at a proof-of-concept locus in fetal HSCs after a single in utero intravenous injection. By targeting HSCs in vivo during fetal development, our Systematically optimized Targeted Editing Machinery (STEM) LNPs may provide a translatable strategy to treat monogenic blood diseases before birth.

Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell proliferation.

In response to infection or vaccination, a successful antibody response must enrich high-affinity antigen-reactive B-cells through positive selection, but eliminate auto-reactive B-cells through negative selection. B-cells receive signals from the B-cell receptor (BCR) which binds the antigen, and the CD40 receptor which is stimulated by neighboring T-cells that also recognize the antigen. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decision and proliferation remains unclear. To investigate this, we developed a differential-equations-based model of the BCR and CD40 signaling networks activating NFκB. Our model accurately recapitulates the NFκB dynamics of B-cells stimulated through their BCR and CD40 receptors, correctly predicting that costimulation induces more NFκB activity. However, when linking it to established cell fate decision models of cell survival and cell cycle control, it predicted potentiated population expansion that was not observed experimentally. We found that this discrepancy was due to a time-dependent functional antagonism exacerbated by BCR-induced caspase activity that can trigger apoptosis in founder cells, unless NFκB-induced survival gene expression protects B-cells in time. Guided by model predictions, sequential co-stimulation experiments revealed how the temporal dynamics of BCR and CD40 signaling control the fate decision between negative and positive selection of B-cell clonal expansion. Our quantitative findings highlight a complex non-monotonic integration of BCR and CD40 signals that is controlled by a balance between NFκB and cell-death pathways, and suggest a mechanism for regulating the stringency of B-cell selection during an antibody response.

Gut microbiome, and immune cells mediated effect on depression: A two-step, two-sample Mendelian randomization analysis

BackgroundThe gut microbiota (GM) plays an important role in the development of immune-related diseases, and the immune response is one of the pathomechanisms of depression (Dep); whether the effect of GM on Dep is mediated by immune cells (ImC) is unclear. ObjectiveImC may mediate the effect of GM on Dep. Our aim is to identify and quantify the role of immune characteristics as potential mediators. MethodsPooled statistics for GM (n = 7738) and ImC (n = 3757) were obtained from publicly available genome-wide association studies (GWAS), and for Dep (n = 47,696) from the Finnish database R10. We used a mediated Mendelian randomization (MR) study to investigate the causal relationship between GM and Dep and the mediating role of ImC between GM and Dep associations. ResultsThe results showed that the genetically predicted GM was significantly correlated with both ImC as well as Dep. MR analysis identified five microbiomes that had significant causal effects on Dep (Methionine biosynthesis III, PWY-6737-Starch degradation V, Parasutterella excrementihominis, Parasutterella, and Lysine biosynthesis I). In addition, five of the 26 ImC trait significantly associated with GM were most closely associated with Dep (T cell %lymphocyte、CD28-CD127-CD25++CD8br AC、CD28-CD8br AC、CD27 receptor on peripheral blood plasma cells (CD27 on PB/PC) and CD11b receptor on mononuclear myeloid-derived suppressor cells (CD11b on Mo MDSC)). This mediated MR illustrates the causal role of methionine biosynthesis III on Dep (IVW: OR = 1.08, 95%CI [1.04,1.14], P = 0.001). And there was no strong evidence for a causal effect of depression on methionine biosynthesis III. In the B cell group, the proportion of CD27 on PB/PC mediated was 7.88 %(95%CI [−0.04,0.03]) of the total effect. This study further suggests that Dep patients should actively seek immunologic intervention therapy. ConclusionThis MR study found that GM may play a causal role in Dep by mediating ImC. Our findings will help to understand the pathogenic mechanism of GM in Dep and the risk of immune mediation.

JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results

AbstractOur phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T-cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n = 28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of regulatory T cells to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.

Spleen Tyrosine Kinase (SYK) negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy.

NK cells express activating receptors that signal through ITAM-bearing adapter proteins. The phosphorylation of each ITAM creates binding sites for SYK and ZAP70 protein tyrosine kinases to propagate downstream signaling including the induction of Ca 2+ influx. While all immature and mature human NK cells co-express SYK and ZAP70, clonally driven memory or adaptive NK cells can methylate SYK genes and signaling is mediated exclusively using ZAP70. Here, we examined the role of SYK and ZAP70 in a clonal human NK cell line KHYG1 by CRISPR-based deletion using a combination of experiments and mechanistic computational modeling. Elimination of SYK resulted in more robust Ca ++ influx after cross-linking of the CD16 and NKp30 receptors and enhanced phosphorylation of downstream proteins, whereas ZAP70 deletion diminished these responses. By contrast, ZAP70 depletion increased proliferation of the NK cells. As immature T cells express both SYK and ZAP70 but mature T cells often express only ZAP70, we transduced the human Jurkat cell line with SYK and found that expression of SYK increased proliferation but diminished TCR-induced Ca 2+ flux and activation. We performed transcriptional analysis of the matched sets of variant Jurkat and KHYG1 cells and observed profound alterations caused by SYK expression. As depletion of SYK in NK cells increased their activation, primary human NK cells were transduced with a CD19-targeting CAR and were CRISPR edited to ablate SYK or ZAP70 . Deletion of SYK resulted in more robust cytotoxic activity and cytokine production, providing a new therapeutic strategy of NK cell engineering for cancer immunotherapy.

Epigenetic recording of stimulation history reveals BLIMP1-BACH2 balance in determining memory B cell fate upon recall challenge.

Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1-BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.

A “Prime and Expand” strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming (“Prime” step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 (“Expand” step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting “Prime and Expand” ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the “Prime and Expand” strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.

Besides suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knockout neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and is related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.

Talquetamab (Tal) therapy in relapsed/refractory (R/R) multiple myeloma (MM): Assessing weight loss and dysgeusia.

e19514 Background: Tal, a bispecific antibody targeting CD3 and GPRC5D receptors, has shown high response rates in heavily pretreated R/R MM patients. This study aimed to evaluate adverse events (AEs), specifically dysgeusia and weight loss in MM patients treated with tal. Methods: Patients treated at the University of Arkansas for Medical Sciences who received at least one dose of tal were included. Common Terminology Criteria for Adverse Events (CTCAE) was used to grade AEs. The body mass index (BMI)-adjusted weight loss grading system (WLGS) was used to capture weight loss trends over duration of treatment. Weight loss based on BMI was graded based on the BMI-WLGS. Results: 17 patients were included in our analysis. Nine patients (53%) were male. Ten patients (59%) were African American. Median age at diagnosis was 62 (range: 51-75years). Six patients (35%) had Eastern Cooperative Oncology Group (ECOG) performance status ≥2. The median number of prior lines of therapy was seven (range: 3-12). Fourteen patients (82%) received at least one prior autologous hematopoietic stem cell transplant. The median number of tal doses received was 14.8 (range: 2-29). Median time on treatment (ranging from 1.15 to 15.84) was 4.36 months (range: 1.2-15.8 months). Overall response rate (ORR) for was 76%. Cytokine release syndrome occurred in 12 patients (70.6%), with 5 patients (29.4%) in grade 2 or higher CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) in four patients (23.6%), and 2 patients (11.8%) had grade 2 ICANS. Fourteen patients (82%) developed significant weight loss during treatment with tal. The median weight loss was 11.6 lbs., and median decrease in BMI was 1.85. Median percentage of weight loss was 6.1% from weight prior to tal ranging from 0% to 14.3%. Two patients had grade I, five patients had grade II, six patients had grade III, and one patient had grade IV weight loss per the BMI-WLGS grading system. Fourteen patients (82%) reported dysgeusia during tal treatment. Eight of these patients had grade I dysgeusia, and six patients had grade II dysgeusia. Two patients had persistent dysgeusia even after discontinuation of tal treatment at time of last follow up. Eight patients had weight gain after tal discontinuation (n = 8/14, 57%), with 5 returning to their baseline weight or higher. Six of these patients had dysgeusia during tal, and all six had resolution of dysgeusia after tal discontinuation. Conclusions: In this study, tal resulted in weight loss and dysgeusia in the majority of patients with most cases of dysgeusia resolving after tal discontinuation. Patients, on average, lost 6% of their initial weight during tal treatment. More than two-thirds of patients treated with tal developed BMI-adjusted WLGS grade ≥II. Weight loss persisted in approximately half of the patients after discontinuation of tal. Such AEs need to be discussed with patients and monitored during treatment.

Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma.

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.

Unveiling the Nexus of CD38 Overactivation, NAD+ Depletion, and Mitochondrial Dysfunction in Immunological Failure Among Virologically Suppressed HIV Patients

Introduction With the advent of antiretroviral therapy (ART), HIV has become a manageable chronic disease. Despite effective virologic suppression, approximately 30% of people living with HIV (PLWH) experience immunological failure, characterized by inadequate CD4+ T cell recovery. This study explores the hypothesis that overactivation of the CD38 receptor leads to NAD+ depletion and subsequent mitochondrial dysfunction, contributing to immunological failure in virologically suppressed HIV patients. Methods A comprehensive review of existing literature was conducted to investigate the roles of CD38, NAD+, and mitochondrial function in HIV pathogenesis. Data were collected from studies on CD38 expression, NAD+ metabolism, and mitochondrial dysfunction in the context of HIV and aging. The integrative approach included examining immune cell activation, metabolic pathways, and potential therapeutic interventions. Results CD38, a type II transmembrane glycoprotein, is overexpressed in PLWH and serves as a predictor of HIV progression. Its enzymatic activities deplete NAD+, a crucial coenzyme involved in energy metabolism, DNA repair, and cell signaling. NAD+ depletion impairs mitochondrial oxidative phosphorylation (OXPHOS), leading to reduced ATP production and increased reliance on glycolysis, which promotes inflammation. Overactivation of CD38 also activates the kynurenine pathway through IDO-1, further depleting NAD+ and generating toxic metabolites that damage mitochondria. This cascade results in persistent immune activation, immune exhaustion, and CD4+ T cell apoptosis. Conclusion The overactivation of CD38 and subsequent NAD+ depletion are central to the pathogenesis of immunological failure in virologically suppressed HIV patients. This mechanism links chronic immune activation, metabolic dysfunction, and accelerated aging. Therapeutic interventions targeting CD38 inhibition, NAD+ supplementation, and mitochondrial function enhancement could potentially reverse immunological failure and improve health outcomes in PLWH. Further experimental validation and clinical trials are necessary to confirm these findings and develop effective treatments.