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SummaryADG106,a ligand-blocking agonistic antibody targeting CD137 (4-1BB),exhibits promising results in preclinical studies,demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies,revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg,resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%),neutropenia (22.6%),elevated alanine aminotransferase (22.6%),rash (21.0%),itching (17.7%),and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin’s lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T,B,and natural killer cells and cytokines interferon γ and interleukin-6,which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955). Graphical abstract Highlights•ADG106 is a ligand-blocking agonistic antibody targeting CD137•ADG106 enhances cytotoxic T cell activity within the tumor environment•ADG106 shows manageable safety and preliminary anti-tumor efficacy in this phase 1 study Ma et al. demonstrate the safety,efficacy,and survival benefits of ADG106,a fully human agonistic monoclonal IgG4 antibody targeting a unique and crossreactive epitope of CD137,in patients with advanced solid tumors and non-Hodgkin’s lymphoma. They show that ADG106 exhibits a favorable safety profile and encourages anti-tumor activity. View Publication

The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of serum amyloid A (SAA) > 20.0 mg/L has the highest accuracy in predicting anti-PD-1 resistance in HCC. Further experiments show a correlation between peritumoral SAA expression and circulating SAA levels in patients with progressive disease after PD-1 inhibition. In vitro experiments demonstrate that SAA induces neutrophils to express PD-L1 through glycolytic activation via an LDHA/STAT3 pathway and to release oncostatin M,thereby attenuating cytotoxic T cell function. In vivo,genetic or pharmacological inhibition of STAT3 or SAA eliminates neutrophil-mediated immunosuppression and enhances antitumor efficacy of anti-PD-1 treatment. This study indicates that SAA may be a critical inflammatory cytokine implicated in anti-PD-1 resistance in HCC. Targeting SAA-induced PD-L1+ neutrophils through STAT3 or SAA inhibition may present a potential approach for overcoming anti-PD1 resistance. The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC. View Publication

The study introduces a new immunotherapy for treating melanoma and other cancers by developing a PROTAC that degrades NR4A1,an intracellular nuclear factor that plays a crucial role in immune suppression. An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME,we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here,we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC,named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level,NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC),all of which are known to be clinically relevant immune cell populations in human melanomas. Overall,NR-V04–mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma. Graphical Abstract View Publication

Peripheral nerve injury (PNI) remains a significant clinical challenge,often leading to long-term functional impairment. Despite advances in therapies,current repair strategies offer unsatisfactory clinical outcomes. Exosomes derived from induced pluripotent stem cells (iPSC-Exos) have emerged as a promising therapeutic approach in regenerative medicine. This study assesses the efficacy and safety of iPSC-Exos in a rat model of sciatic nerve crush injury. Briefly,iPSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors using Sendai virus vectors and validated for pluripotency. iPSC-Exos were characterized and injected at the injury site. Functional recovery was assessed through gait analysis,grip strength,and pain response. Histological and molecular analyses were used to examine axonal regeneration,myelination,Schwann cell (SC) activation,angiogenesis,and changes in gene expression. iPSC-Exos were efficiently internalized by SC,promoting their proliferation. No adverse effects were observed between groups on body weight,organ histology,or hematological parameters. iPSC-Exos injection significantly enhanced nerve regeneration,muscle preservation,and vascularization,with RNA sequencing revealing activation of PI3K-AKT and focal adhesion pathways. These findings support iPSC-Exos as a safe and effective non-cell-based therapy for PNIs,highlighting their potential for clinical applications in regenerative medicine. View Publication

BackgroundSchizophrenia (SCZ) is a severe psychiatric disorder associated with alterations in early brain development. Details of underlying pathomechanisms remain unclear,despite genome and transcriptome studies providing evidence for aberrant cellular phenotypes and pathway deregulation in developing neuronal cells. However,mechanistic insight at the protein level is limited.MethodsHere,we investigate SCZ-specific protein expression signatures of neuronal progenitor cells (NPC) derived from patient iPSC in comparison to healthy controls using high-throughput Western Blotting (DigiWest) in a targeted proteomics approach.ResultsSCZ neural progenitors displayed altered expression and phosphorylation patterns related to Wnt and MAPK signaling,protein synthesis,cell cycle regulation and DNA damage response. Consistent with impaired cell cycle control,SCZ NPCs also showed accumulation in the G2/M cell phase and reduced differentiation capacity. Furthermore,we correlated these findings with elevated p53 expression and phosphorylation levels in SCZ patient-derived cells,indicating a potential implication of p53 in hampering cell cycle progression and efficient neurodevelopment in SCZ.ConclusionsThrough targeted proteomics we demonstrate that SCZ NPC display coherent mechanistic alterations in regulation of DNA damage response,cell cycle control and p53 expression. These findings highlight the suitability of iPSC-based approaches for modeling psychiatric disorders and contribute to a better understanding of the disease mechanisms underlying SCZ,particularly during early development.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12888-024-06127-x. View Publication

The intricate interplay between biochemical and physical cues dictates pluripotent stem cell (PSC) differentiation to form various tissues. While biochemical modulation has been extensively studied,the role of biophysical microenvironments in early lineage commitment remains elusive. Here,we introduce a novel 3D cell culture system combining electrospun nanofibers with microfabricated polydimethylsiloxane (PDMS) patterns. This system enables the controlled formation of semispherical human induced pluripotent stem cell (hiPSC) colonies,facilitating the investigation of local mechanical stem cell niches on mechano-responsive signaling and lineage specification. Our system unveiled spatially organized RhoA activity coupled with actin-myosin cable formation,suggesting mechano-dependent hiPSC behaviors. Nodal network analysis of RNA-seq data revealed RhoA downstream regulation of YAP signaling,DNA histone modifications,and patterned germ layer specification. Notably,altering colony morphology through controlled PDMS microwell shaping effectively modulated the spatial distribution of mechano-sensitive mediators and subsequent differentiation. This study provides a cell culture platform to decipher the role of biophysical cues in early embryogenesis,offering valuable insights for material design in tissue engineering and regenerative medicine applications. Graphical abstractImage 1 View Publication