tbuckley/cabot-search huggingface dataset:
First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian cancer
Authors: Nehal J Lakhani, Daphne Stewart, Debra L Richardson, Lauren E Dockery, Linda Van Le, Justin Call, Fatima Rangwala, Guanfang Wang, Bo Ma, Simon Metenou, Jade Huguet, Elliot Offman, Lini Pandite, Erika Hamilton
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG 4 -derived Fc domain. In preclinical studies, a murine equivalent SIRPα-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer. Methods SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity. Results 27 patients (median age 66 years (range, 33–85); median of 4 prior systemic therapies (range, 2–9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 C max and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4 + T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at &gt;3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients. Conclusions SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose. Trial registration number NCT04406623 .
Antibodies against the multifaceted cathepsin D protein open new avenues for TNBC immunotherapy
Authors: Pénélope Desroys du Roure, Timothée David, Aude Mallavialle, Valérie Laurent-Matha, Pascal Roger, Séverine Guiu, Thierry Chardès, Emmanuelle Liaudet-Coopman
Journal: Journal for ImmunoTherapy of Cancer (2025)

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype characterized by aggressive clinical behavior and poor prognosis. The immune landscape associated with TNBC often reveals high immunogenicity. Therefore, immunotherapy, which has demonstrated its efficacy in different cancer types, could be a promising strategy for TNBC, given the limited therapeutic options currently available besides conventional chemotherapy. The aspartic protease cathepsin D (cath-D) is a tumor cell-associated extracellular protein with protumor activity, a marker of poor prognosis, and a target for antibody-based therapy in TNBC. This commentary provides a synopsis/narrative summary of the development of anti-cath-D antibodies in different formats, their key roles in restoring the antitumor immunity, particularly via activation of tumor-infiltrating natural killer cells, and their dual antitumor effects on cancer cells and stromal cancer-associated fibroblasts, suggesting their interest for clinical use in the light of the current clinical knowledge on TNBC.
PD-1 suppresses human CD38<sup>+</sup>circulating Tfr cells and regulates humoral immunity
Authors: Heng Zhang, Hui Zheng, Yanchun Wang, Cuncun Chen, Ying Tong, Suhong Xie, Xiaolu Ma, Lin Guo, Renquan Lu
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Anti-programmed cell death protein 1 (anti-PD-1) antibodies have achieved revolutionary success in cancer therapy. However, the impact of anti-PD-1 therapy on host humoral immunity in humans during cancer immunotherapy requires further investigation. Methods We evaluated immunoglobulin titers by ELISA and screened the immune landscape of immune cells from 25 healthy donors and 50 cases including 25 new-onset hepatocellular carcinoma (HCC) patients prior to systemic treatment and 25 HCC patients undergoing anti-PD-1 therapy by multicolor flow cytometry. Flow or beads sorted cells were cultured ex vivo for proliferation and functional analysis. Results Anti-PD-1 therapy significantly increased the levels of IgG and IgA in the periphery of HCC patients. Anti-PD-1 treatment led to an increase in plasmablasts and a notable rise in circulating T follicular regulatory (cTfr) cells, while changes in circulating B cells, T follicular helper cells, or regulatory T cells were not significant. Anti-PD-1 therapy also influenced the proliferation and function of cTfr cells, promoting the differentiation of CD38 + cTfr cells. We observed that the CD38 + Tfr cell subset in the peripheral blood can promote plasmablast differentiation, associated with altered antibody production. Conclusions Together, these data demonstrate the immunomodulatory role of PD-1 in restricting the differentiation and function of human cTfr cells and in regulating humoral immunity.
Prevalence of Chronic Hand Eczema in adults: A cross-sectional survey of over 60,000 respondents in the general population in Canada, France, Germany, Italy, Spain, and the United Kingdom
Authors: Christian Apfelbacher, Anthony Bewley, Sonja Molin, Maria Concetta Fargnoli, Ana Maria Giménez-Arnau, Lysel Brignoli, Bleuenn Rault, Jenny M Norlin, Tea Skaaby, Marie-Noëlle Crépy
Journal: British Journal of Dermatology (2025)

Abstract Background The lack of attention to Chronic Hand Eczema (CHE) and the lack of a specific International Classification of Diseases code for CHE may have limited the assessment of CHE prevalence. To date, prevalence estimates have primarily been derived from (partly small) single-country studies. Objectives To estimate the annual prevalence of self-reported physician-diagnosed CHE across socio-demographic characteristics among adults in Canada, France, Germany, Italy, Spain, and the United Kingdom (UK). Methods In this observational Chronic Hand Eczema epidemiology, Care, and Knowledge of real-life burden (CHECK) study, a questionnaire was administered to adults between 18 and 69 years old in the general population, recruited through online panels. Quotas and minor weighting adjustments were performed to ensure that the participants were representative of the general population regarding sex, age, region, employment status, urban/rural setting, and, in the UK only, ethnicity. Additional weights were applied to account for population size differences when aggregating country results. Information on self-reported physician-diagnosed CHE was collected. CHE was defined, in accordance with the European Society of Contact Dermatitis, as having hand eczema continuously for three months or more or at least two flares in the past 12 months. CHE annual prevalence with 95% confidence intervals (CIs) was determined for each country, and by subgroups of sex, age, employment, and urban/rural. Results Among 60,131 participants, 2,847 self-reported physician-diagnosed CHE, yielding an annual prevalence of 4.7% (CI: 4.6-4.9). Subgroup analyses revealed the CHE prevalence was significantly higher in females than males (5.6% [5.4-5.9] vs. 3.8% [3.6-4.1]; P&amp;lt;0.001), in employed versus unemployed participants (5.3% [5.1-5.6] vs. 3.3% [3.1-3.6]; P&amp;lt;0.001), and in urban versus rural residents (5.0% [4.8-5.2] vs. 3.7% [3.4-4.1]; P&amp;lt;0.001). The prevalence was highest among those aged 30-39 years (6.5% [6.0-7.0]) and lowest in those aged 60-69 years (2.6% [2.3-3.0]). Conclusions This large multi-national study is the first to assess CHE prevalence in Europe and Canada using a consistent definition across a broad geographical population. This study reveals that CHE is a common skin disease with annual prevalence of 4.7%, with higher prevalence among females, individuals aged 30-39, those employed, and those living in urban areas.
AXL: shapers of tumor progression and immunosuppressive microenvironments
Authors: Yihui Liu, Lei Xu, Yuanyao Dou, Yong He
Journal: Molecular Cancer (2025)

As research progresses, our understanding of the tumor microenvironment (TME) has undergone profound changes. The TME evolves with the developmental stages of cancer and the implementation of therapeutic interventions, transitioning from an immune-promoting to an immunosuppressive microenvironment. Consequently, we focus intently on the significant role of the TME in tumor proliferation, metastasis, and the development of drug resistance. AXL is highly associated with tumor progression; however, previous studies on AXL have been limited to its impact on the biological behavior of cancer cells. An increasing body of research now demonstrates that AXL can influence the function and differentiation of immune cells, mediating immune suppression and thereby fostering tumor growth. A comprehensive analysis to identify and overcome the causes of immunosuppressive microenvironments represents a novel approach to conquering cancer. In this review, we focus on elucidating the role of AXL within the immunosuppressive microenvironments, discussing and analyzing the effects of AXL on tumor cells, T cells, macrophages, natural killer (NK) cells, fibroblasts, and other immune-stromal cells. We aim to clarify the contributions of AXL to the progression and drug resistance of cancer from its functional role in the immune microenvironment.
Hyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL-15
Authors: Gengwen Tian, Amy N Courtney, Hangjin Yu, Saleh Bhar, Xin Xu, Gabriel A Barragán, Claudia Martinez Amador, Nisha Ghatwai, Michael S Wood, Deborah Schady, Antonino Montalbano, Shantan Reddy, Aoife M Roche, David de la Cerda, Donald Williams Parsons, Erica J Di Pierro, Frederic D Bushman, Andras Heczey, Leonid S Metelitsa
Journal: Journal for ImmunoTherapy of Cancer (2025)

The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial ( NCT03294954 ) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.
Temporal Trends of Subsequent CNS Malignancies Among Survivors of Childhood Cancer
Authors: Robert T Galvin, Yan Chen, Yan Yuan, Tabitha Cooney, Rebecca Howell, Susan Smith, Michael A Arnold, Miriam Conces, Wendy Leisenring, Gregory T Armstrong, Joseph P Neglia, Lucie M Turcotte
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract PURPOSE It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms (SMNs) of the central nervous system (CNS), a frequently fatal late effect of cancer therapy. METHODS Five-year survivors of primary childhood cancers diagnosed between 1970-1999 in the Childhood Cancer Survivor Study with a subsequent CNS SMN were identified. Cumulative incidence rates and standardized incidence ratios (SIR) were compared among survivors diagnosed between 1970-1979 (N = 6223), 1980-1989 (N = 9680), and 1990–1999 (N = 8999). Multivariable models assessed risk factors for CNS SMN. RESULTS 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy (CRT) exposure was reduced over time (1970s 77.0%, 1980s 54.3%, 1990s 33.9%), while the proportion receiving &amp;gt;35Gy CRT showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence (95% CI) and SIR (95% CI) for CNS SMN by treatment decade were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for CRT dose levels &amp;gt;10Gy and for primary diagnoses of medulloblastoma/PNET (HR 18.7, 9.2-37.9) and astrocytoma (HR 10.1, 5.3-19.5). Three-year cumulative incidence of death after CNS SMN, by treatment decade, were 76%, 74%, and 73%, respectively. CONCLUSION CNS SMN incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS SMNs remain a substantial source of mortality for affected patients.
Tissue‐resident memory T cells in diseases and therapeutic strategies
Authors: Daoyuan Xie, Guanting Lu, Gang Mai, Qiuyan Guo, Guofeng Xu
Journal: MedComm (2025)

Abstract Tissue‐resident memory T (T RM ) cells are crucial components of the immune system that provide rapid, localized responses to recurrent pathogens at mucosal and epithelial barriers. Unlike circulating memory T cells, T RM cells are located within peripheral tissues, and they play vital roles in antiviral, antibacterial, and antitumor immunity. Their unique retention and activation mechanisms, including interactions with local epithelial cells and the expression of adhesion molecules, enable their persistence and immediate functionality in diverse tissues. Recent advances have revealed their important roles in chronic inflammation, autoimmunity, and cancer, illuminating both their protective and their pathogenic potential. This review synthesizes current knowledge on T RM cells’ molecular signatures, maintenance pathways, and functional dynamics across different tissues. We also explore the interactions of T RM cells with other immune cells, such as B cells, macrophages, and dendritic cells, highlighting the complex network that underpins the efficacy of T RM cells in immune surveillance and response. Understanding the nuanced regulation of T RM cells is essential for developing targeted therapeutic strategies, including vaccines and immunotherapies, to enhance their protective roles while mitigating adverse effects. Insights into T RM cells’ biology hold promise for innovative treatments for infectious diseases, cancer, and autoimmune conditions.
<i>LungDiag</i>: Empowering artificial intelligence for respiratory diseases diagnosis based on electronic health records, a multicenter study
Authors: Hengrui Liang, Tao Yang, Zihao Liu, Wenhua Jian, Yilong Chen, Bingliang Li, Zeping Yan, Weiqiang Xu, Luming Chen, Yifan Qi, Zhiwei Wang, Yajing Liao, Peixuan Lin, Jiameng Li, Wei Wang, Li Li, Meijia Wang, YunHui Zhang, Lizong Deng, Taijiao Jiang, Jianxing He
Journal: MedComm (2025)

Abstract Respiratory diseases pose a significant global health burden, with challenges in early and accurate diagnosis due to overlapping clinical symptoms, which often leads to misdiagnosis or delayed treatment. To address this issue, we developed LungDiag , an artificial intelligence (AI)‐based diagnostic system that utilizes natural language processing (NLP) to extract key clinical features from electronic health records (EHRs) for the accurate classification of respiratory diseases. This study employed a large cohort of 31,267 EHRs from multiple centers for model training and internal testing. Additionally, prospective real‐world validation was conducted using 1142 EHRs from three external centers. LungDiag demonstrated superior diagnostic performance, achieving an F1 score of 0.711 for top 1 diagnosis and 0.927 for top 3 diagnoses. In real‐world testing, LungDiag outperformed both human experts and ChatGPT 4.0, achieving an F1 score of 0.651 for top 1 diagnosis. The study emphasizes the potential of LungDiag as an effective tool to support physicians in diagnosing respiratory diseases more accurately and efficiently. Despite the promising results, further large‐scale multicenter validation with larger sample sizes is still needed to confirm its clinical utility and generalizability.
Comparison of diet and exercise on cardiometabolic factors in young adults with overweight/obesity: multiomics analysis and gut microbiota prediction, a randomized controlled trial
Authors: Zongyu Lin, Tianze Li, Fenglian Huang, Miao Wu, Lewei Zhu, Yueqin Zhou, Ying‐An Ming, Zhijun Lu, Wei Peng, Fei Gao, Yanna Zhu
Journal: MedComm (2025)

Abstract The optimal strategy for improving cardiometabolic factors (CMFs) in young obese individuals through diet and exercise remains unclear, as do the potential mechanisms. We conducted an 8‐week randomized controlled trial to compare the effects of different interventions in youth with overweight/obesity. Gut microbes and serum metabolites were examined to identify regulating mechanisms. A total of 129 undergraduates were randomly assigned to fiber‐rich (FR) diet, rope‐skipping (RS), combined FR–RS and control groups. The results showed that single interventions were as effective as combined interventions in improving weight, waist circumference, body fat, and lipid profile compared with control group. Notably, the FR group further reduced low‐density lipoprotein (LDL‐C) and uric acid (UA) (all p &lt; 0.05). Mediation analysis revealed four gut microbiota–metabolite–host axes in improving CMFs. Additionally, we used machine learning algorithms to further predict individual responses based on baseline gut microbiota composition, with specific microbial genera guiding targeted intervention selection. In conclusion, FR diet and/or RS were effective in improving CMFs, with the FR diet particular effectiveness in reducing LDL‐C and UA levels. These benefits may drive by gut microbiome–metabolite–host interactions. Moreover, the predictability of gut microbiota composition supports making targeted decisions in selecting interventions. Trial Registration: NCT04834687.
Corrigendum to “Antioxidative and antibacterial gallium (III)-phenolic coating for enhanced osseointegration of titanium implants via pro-osteogenesis and inhibiting osteoclastogenesis” [Biomaterials 301 (2023) 122268]
Authors: Kui Xu, Caiyun Mu, Chi Zhang, Sijie Deng, Shan Lin, Linlin Zheng, Weizhen Chen, Qiqing Zhang
Journal: Biomaterials (2025)
Cancer vaccines compensate for the insufficient induction of protective tumor-specific immunity of CD3 bispecific antibody therapy
Authors: Jim Middelburg, Gaby Schaap, Marjolein Sluijter, Katy Lloyd, Vitalijs Ovcinnikovs, Janine Schuurman, Sjoerd H van der Burg, Kristel Kemper, Thorbald van Hall
Journal: Journal for ImmunoTherapy of Cancer (2025)

CD3 bispecific antibody (CD3 bsAb) therapy has become an established treatment modality for some cancer types and exploits endogenous T cells irrespective of their specificity. However, durable clinical responses are hampered by immune escape through loss of tumor target antigen expression. Induction of long-lasting tumor-specific immunity might therefore improve therapeutic efficacy, but has not been studied in detail yet for CD3 bsAbs. Here, we examined multiple combination strategies aiming to improve survival rates in solid tumors and, simultaneously, install endogenous immunity capable of protection to tumor rechallenge. Two syngeneic mouse tumor models were employed: The immunologically "cold" B16F10 melanoma and the immunologically "hot" MC38.TRP1 colon carcinoma model. Mice were treated with CD3xTRP1 bsAb (murine Fc-inert immunoglobulin G2a) as monotherapy, or in combination with agonistic costimulatory antibodies, Fc-active tumor-opsonizing antibodies, or tumor-(non)specific vaccines. Treatment efficacy of primary tumors and protection from rechallenge was monitored, as well as induction of tumor-specific T-cell responses. In the immunologically "cold" B16F10 model, all combination therapies improved antitumor activity compared with CD3 bsAb monotherapy and induced systemic tumor-specific T-cell responses. However, this endogenous T-cell immunity swiftly waned and failed to protect mice from subsequent tumor rechallenge, except for combination therapy with tumor-specific vaccination. These vaccines strongly improved the therapeutic efficacy of CD3 bsAb against primary tumors and led to long-term immunological protection. In the immunologically "hot" MC38.TRP1 model, CD3 bsAb combined with only the vaccine adjuvant was sufficient to generate protective T-cell immunity and, moreover, prevented tumor escape via antigen loss. These results demonstrate the impact of tumor antigenicity on the induction of protective endogenous antitumor immunity during CD3 bsAb treatment and, importantly, show that the combination with tumor-specific vaccines improves therapeutic efficacy and installs long-term immunological memory in both "hot" and "cold" tumors.