tbuckley/cabot-search huggingface dataset:
Targeting MARCO in combination with anti-CTLA-4 leads to enhanced melanoma regression and immune cell infiltration via macrophage reprogramming
Authors: Hidenori Takahashi, Patricio Perez-Villarroel, Rana Falahat, James J Mulé
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the tumor microenvironment (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood. Methods The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay. Results ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy. Conclusions Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.
Novel anti-CD73-IL-2v bispecific fusion protein augments antitumor immunity by alleviating immunosuppressive adenosine pathways in CD8<sup>+</sup>T cells
Authors: Kayoung Shin, Min Park, Seoho Kim, Haejong Lee, Yuseong Lee, Jongil Kim, Suyoun Park, Jisoo Kim, Kyungwha Lee, Chong Woo Park, Ji-Hyun Kim, Eun-Jin Lee, Hyuckjun Mok, Sung-Man Oh, Sanghee Lee, Young Min Oh, Wonjae Lee, Yaein Amy Shim, Young-Gyu Cho, Junsik Park, Jung-Yun Lee, Young Jun Koh, Kook Hwan Kim, Myoung Ho Jang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Adenosine accumulated in the tumor microenvironment functions as an immune-modulating factor, exerting immunosuppressive actions via adenosine A2A/A2B receptor (A2AR/A2BR) in various immune cell types. CD73, a key enzymatic regulator responsible for adenosine production, is frequently overexpressed in diverse cancers, and its overexpression is associated with reduced responsiveness to conventional anti-cancer drug treatments such as chemotherapy, radiation therapy, targeted therapy, or immunotherapy. Despite numerous therapeutic applications of IL-2 in cancer immunotherapy, the relationship between the CD73-adenosine axis and IL-2-based immunotherapy remains largely unexplored. Methods To evaluate the effect of CD73 blockade on IL-2 signaling of CD8 + T cells, we screened novel CD73 antibodies using human single-chain variable fragment phage library and immunized Alpaca phage library. To optimize targeting to CD73-expressing cells and reinvigorate the antitumor effect of IL-2 in adenosine-rich microenvironment, we engineered a novel bifunctional GI-αCD73/IL-2v fusion protein. Functionality of GI-αCD73/IL-2v fusion protein was assessed in the in vitro cell-based assays and the in vivo tumor-bearing mouse model or cynomolgus monkey. Results IL-2-induced increase in proliferation of CD8 + T cells was not observed under adenosine-rich microenvironment. We demonstrated that the functional impairment of IL-2 signaling in CD8 + T cells in these conditions can be reversed by our anti-CD73 antibody (GI-αCD73). Furthermore, GI-αCD73/IL-2v fusion protein significantly restored the impaired proliferation of CD8 + T cells and consequently enhanced tumor cell killing under adenosine-mediated immunosuppression, surpassing the combined treatment of GI-αCD73 and Fc-IL-2v. These synergistic effects were attributed to the enhanced delivery of the IL-2v component of GI-αCD73/IL-2v to IL-2Rβγ on CD73-expressing CD8 + T cells through a cis-binding mechanism. GI-αCD73/IL-2v elicited a potent antitumor effect in both the human CD73 knock-in (hCD73 KI) mouse model and the humanized mouse model. In non-human primates, GI-αCD73/IL-2v exhibited excellent tolerability while inducing robust and durable expansions of cytotoxic lymphocytes. Conclusions GI-αCD73/IL-2v bispecific protein is a novel and potent immunocytokine with significant antitumor immunity through cis-binding on CD8 + T cells.
RANKL blockade inhibits cancer growth through reversing the tolerogenic profile of tumor-infiltrating (plasmacytoid) dendritic cells
Authors: Charlotte Pilard, Patrick Roncarati, Marie Ancion, Margaux Luyckx, Michael Renard, Celia Reynders, Thomas Lerho, Florian Poulain, Diane Bruyere, Alizee Lebeau, Elodie Hendrick, Rebekah Crake, Raphael Peiffer, Marie-Julie Nokin, Olivier Peulen, Philippe Delvenne, Pascale Hubert, Michael Herfs
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Originally identified for its involvement in bone remodeling, accumulating data emerged in the past years indicating that receptor activator of nuclear factor κB ligand (RANKL) actually acts as a multifunctional soluble molecule that influences various physiological and pathological processes. Regarding its role in carcinogenesis, while direct effects on tumor cell behavior have been precisely characterized, the impact of the RANKL/RANK system (and its inhibition) on the intratumoral immune landscape remains unclear. Methods After various in silico/in situ/in vitro analyses, the immunotherapeutic efficacy of RANKL blockade (alone and in combination with immune checkpoint inhibitors (anti-programmed cell death protein-1 (PD-1)) or doxorubicin/paclitaxel-based chemotherapy) was investigated using different syngeneic mouse models of triple-negative breast cancer (4T1, 67NR and E0771). Isolated from retrieved tumors, 14 immune cell (sub)populations, along with the activation status of antigen-presenting cells, were thoroughly analyzed in each condition. Finally, the impact of RANKL on the functionality of both dendritic cells (DC) and plasmacytoid dendritic cells (pDC) was determined. Results A drastic tumor growth inhibition was reproductively observed following RANKL inhibition. Strikingly, this antitumor activity was not detected in immunocompromised mice, demonstrating its dependence on the adaptive immune responses and justifying the diverse enriched signatures linked to immune cell regulation/differentiation detected in RANKL high -expressing human neoplasms. Interestingly, neoadjuvant chemotherapy (but not PD-1 checkpoint inhibition) potentiated the anticancer effects of RANKL blockade by priming effector T cells and increasing their infiltration within the tumor microenvironment. Mechanistically, we highlighted that RANKL indirectly promotes regulatory T cell differentiation and suppressive function by inhibiting the mTOR signaling pathway on antigen-presenting cells. Conclusions Taken together, this study provides insight into the role of RANKL/RANK axis in immune tolerance, demonstrates the significant impact of RANKL-dependent impairment of T cell–DC/pDC crosstalk on tumor development and, ultimately, supports that this ligand could be an interesting actionable target for cancer immunotherapy.
Phase 2 study of neoadjuvant durvalumab plus docetaxel, oxaliplatin, and S-1 with surgery and adjuvant durvalumab plus S-1 for resectable locally advanced gastric cancer
Authors: Yoon-Koo Kang, Hyung-Don Kim, Hyungwoo Cho, Young Soo Park, Jong Seok Lee, Min-Hee Ryu
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Based on the phase 3 PRODIGY study, neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) have emerged as a viable treatment option for Asian patients with resectable locally advanced gastric cancer (LAGC). This phase 2 study evaluated the efficacy and safety of combining neoadjuvant durvalumab with DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, for resectable LAGC. Methods Patients with LAGC with cT2/3N+or cT4Nany tumors were enrolled in this study. Patients with proficient mismatch repair protein (pMMR) tumors received three cycles of neoadjuvant durvalumab plus DOS, administered every 3 weeks, followed by surgery and adjuvant S-1 plus durvalumab (main study arm). The primary endpoints were the rate of pathologic complete regression (pCR) and safety. An exploratory arm evaluated patients with deficient mismatch repair protein (dMMR) tumors, who received three cycles of neoadjuvant durvalumab and tremelimumab, followed by surgery and adjuvant durvalumab. Results In the main study arm, 50 pMMR patients were enrolled, and received at least one dose of neoadjuvant treatment. The median age was 63 years, with 72.0% being men. 18 and 32 patients presented with clinical stage II and III tumors, respectively. 49 (98.0%) underwent surgery, with 45 achieving R0 resection. A pCR rate of 30.0% was observed, meeting the prespecified primary efficacy endpoint. With a median follow-up of 21.8 months, the 3-year progression-free survival and overall survival rates were 69.9% and 88.1%, respectively. 10% of patients experienced predefined unacceptable severe toxicities, including febrile neutropenia (n=3) and persistent G4 neutropenia (n=2) lasting more than 7 days, thereby meeting the primary safety endpoint. Nine patients with dMMR tumors were enrolled in the exploratory arm. All nine underwent surgery, with a pCR rate of 22.2%. Conclusions This study met its primary efficacy and safety endpoints. The combination of neoadjuvant durvalumab plus DOS, followed by surgery and adjuvant durvalumab plus S-1 chemotherapy, warrants further investigation in a phase 3 trial for Asian patients with LAGC. Clinical trial information: 04221555.
<i>BTLA</i>promoter hypomethylation correlates with enhanced immune cell infiltration, favorable prognosis, and immunotherapy response in melanoma
Authors: Minglei Yang, Chenxi Zheng, Yu Miao, Cuicui Yin, Longfei Tang, Chongli Zhang, Pu Yu, Qingfang Han, Yihui Ma, Shenglei Li, Guozhong Jiang, Wencai Li, Peiyi Xia
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint blockade (ICB)-based immunotherapy has significantly improved survival in advanced melanoma. However, many patients exhibit resistance to these therapies. This study examines the impact of BTLA promoter methylation on its expression, immune cell infiltration, and clinical outcomes, evaluating its potential as a prognostic and predictive biomarker for immunotherapy response. Methods We analyzed methylation and gene expression data from public datasets (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO)) and an in-house cohort of melanoma patients treated with ICB therapy at the First Affiliated Hospital of Zhengzhou University. We developed a quantitative methylation-specific PCR (qMSP) assay to measure methylation levels of the cg24157392 and cg03995631 CpG sites, and a targeted bisulfite sequencing assay was used to validate the accuracy of qMSP. We measured BTLA protein expression using multiplex immunofluorescence and immunohistochemical staining methods. Pearson correlation, survival analysis, and immune cell infiltration estimation were conducted to explore the associations between BTLA promoter methylation, mRNA and protein expression, clinical outcomes, and immune characteristics. Results Hypomethylation at CpG sites cg24157392 and cg03995631 in the BTLA promoter were significantly associated with higher BTLA mRNA and protein expression. In the TCGA dataset, low methylation at these sites predicted longer overall survival and was validated in an independent cohort of 50 stage III/IV melanoma patients, with an area under the curve of 0.94 for predicting 5-year survival. Furthermore, BTLA promoter hypomethylation correlated with higher infiltration of immune cells, such as CD8+T cells, CD4+T cells, B cells, and macrophages. Additionally, low methylation at cg24157392 and cg03995631, as quantified by the qMSP assay, was significantly associated with better progression-free survival in patients treated with immune checkpoint inhibitors. These findings were further validated using GEO datasets. Conclusions BTLA promoter hypomethylation serves as a significant biomarker for favorable prognosis and enhanced response to ICB therapy in melanoma. The developed qMSP assays for cg24157392 and cg03995631 accurately quantified methylation levels and demonstrated their potential for clinical application in patient stratification and personalized immunotherapy.
Enhancing diagnostic capability with multi-agents conversational large language models
Authors: Xi Chen, Huahui Yi, Mingke You, WeiZhi Liu, Li Wang, Hairui Li, Xue Zhang, Yingman Guo, Lei Fan, Gang Chen, Qicheng Lao, Weili Fu, Kang Li, Jian Li
Journal: npj Digital Medicine (2025)

Large Language Models (LLMs) show promise in healthcare tasks but face challenges in complex medical scenarios. We developed a Multi-Agent Conversation (MAC) framework for disease diagnosis, inspired by clinical Multi-Disciplinary Team discussions. Using 302 rare disease cases, we evaluated GPT-3.5, GPT-4, and MAC on medical knowledge and clinical reasoning. MAC outperformed single models in both primary and follow-up consultations, achieving higher accuracy in diagnoses and suggested tests. Optimal performance was achieved with four doctor agents and a supervisor agent, using GPT-4 as the base model. MAC demonstrated high consistency across repeated runs. Further comparative analysis showed MAC also outperformed other methods including Chain of Thoughts (CoT), Self-Refine, and Self-Consistency with higher performance and more output tokens. This framework significantly enhanced LLMs' diagnostic capabilities, effectively bridging theoretical knowledge and practical clinical application. Our findings highlight the potential of multi-agent LLMs in healthcare and suggest further research into their clinical implementation.
Human Cases of Highly Pathogenic Avian Influenza A<b>(</b>H5N1<b>)</b> — California, September–December 2024
Authors: Sophie Zhu, Kathleen Harriman, Caterina Liu, Vit Kraushaar, Cora Hoover, Kyoo Shim, Sharon I. Brummitt, Jocelyn Limas, Kathleen Garvey, Jennifer McNary, Nina J. Gao, Rahil Ryder, Brandon Stavig, Jeffrey Schapiro, Christina Morales, Debra A. Wadford, Holly Howard, James Heffelfinger, Rebecca Campagna, Esmeralda Iniguez-Stevens, Hamed Gharibi, Denise Lopez, Laura Esbenshade, Paula Ptomey, Kavita K. Trivedi, Jade A. Herrera, Joanna Locke, Nicholas Moss, Paul Rzucidlo, Kimberly Hernandez, Minhphuong Nguyen, Simon Paul, Justin Mateo, Carlos Del Carmen Luna, Yer Chang, Maria Rangel, Keiryl DeLeon, Aisha Masood, Thea Papasozomenos, Payeng Moua, Katie Reinhart, Krista Kniss, C. Todd Davis, Marie K. Kirby, Erica Pan, Erin L. Murray, Annabelle de St. Maurice, Eric El-Tobgy, Nicole Green, Allison Joyce, Cristin Mondy, Taylor Mundt, Heidi Ransohoff, Shayra Sanchez, Elizabeth Traub, Matthew Bacinskas, John Bell, Cynthia Bernas, Brandon Brown, Jahara Cayabyab, Alice Chen, Jesse Elder, Shiffen Getabecha, Carol Glaser, Olena Gomez, Bianca Gonzaga, Ydelita Gonzales, Hugo Guevara, April Hatada, Katya Ledin, Deidra Lemoine, Adrienne Macias, Sergio Martinez-Paredes, Blanca Molinar, Tasha Padilla, Chao-Yang Pan, Kiana Pattni, Rolando Ramirez, Kao Saechao, Estela Saguar, Maria Salas, Ioana Seritan, Anthony Tran, Cindy Wong, Chelsea Wright
Journal: MMWR Morbidity and Mortality Weekly Report (2025)

Persons who work closely with dairy cows, poultry, or other animals with suspected or confirmed infection with highly pathogenic avian influenza (HPAI) A(H5N1) viruses are at increased risk for infection. In September 2024, the California Department of Public Health was notified of the first human case of HPAI A(H5N1) in California through monitoring of workers on farms with infected cows. During September 30-December 24, 2024, a total of 38 persons received positive test results for HPAI A(H5N1) viruses in California; 37 were dairy farm workers with occupational exposure to sick cows, and one was a child aged <18 years with an undetermined exposure, the first pediatric HPAI A(H5N1) case reported in the United States. All patients had mild illness. The identification of cases associated with occupational exposure to HPAI A(H5N1) viruses on dairy farms highlights the continued risk for persons who work with infected animals. The pediatric case was identified through routine surveillance. Given recent increases in the prevalence of HPAI A(H5N1) viruses among some animal populations, public health agencies should continue to investigate cases of HPAI A(H5N1) in humans as part of control measures, pandemic preparedness, to identify concerning genetic changes, and to prevent and detect potential human-to-human transmission of the virus. To date, no human-to-human transmission of HPAI A(H5N1) virus has been identified in the United States.
Selecting patients with sickle cell disease for gene addition or gene editing‐based therapeutic approaches: Report on behalf of a joint EHA Specialized Working Group and EBMT Hemoglobinopathies Working Party consensus conference
Authors: Lucia de Franceschi, Franco Locatelli, David Rees, Christian Chabannon, Jean‐Hugues Dalle, Stefano Rivella, Achille Iolascon, Stephan Lobitz, Miguel R. Abboud, Josu de la Fuente, Pagona Flevari, Emanuele Angelucci, Mariane de Montalembert
Journal: HemaSphere (2025)

ABSTRACT Sickle cell disease (SCD) remains associated with reduced life expectancy and poor quality of life despite improvements observed in the last decades mostly related to comprehensive care, use of hydroxycarbamide, screening to identify patients at risk of strokes, and implementation of safe transfusion protocols. The course of the disease is highly variable, making it difficult to predict severity and response to therapy. Allogeneic hematopoietic stem cell transplantation potentially provides a cure with a relatively low rate of complications, but few patients have an HLA‐identical sibling. The hopes of patients and healthcare providers have been raised after the initial excellent results of gene therapy studies. However, there is a strong contrast between the high expectations of families and patients and the limited availability of the product, which is technically complex and very expensive. In light of this consideration and of the limited data available on the long‐term efficacy and toxicity of different gene therapy approaches, the European Hematology Association Red Cell &amp; Iron Specialized Working Group (EHA SWG) and the hemoglobinopathy working part of the European Blood &amp; Marrow Transplant (EBMT) Group have prioritized the development of recommendations for selection of patients with SCD who are good candidates for gene therapy. The decision‐making algorithm was developed by a panel of experts in hemoglobinopathies and/or transplantation chosen by EHA SWG and EBMT, to discuss the selection of SCD patients for gene therapy and draw notes on the related clinical problems.
Immune history shapes human antibody responses to H5N1 influenza viruses
Authors: Tyler A. Garretson, Jiaojiao Liu, Shuk Hang Li, Gabrielle Scher, Jefferson J. S. Santos, Glenn Hogan, Marcos Costa Vieira, Colleen Furey, Reilly K. Atkinson, Naiqing Ye, Jordan T. Ort, Kangchon Kim, Kevin A. Hernandez, Theresa Eilola, David C. Schultz, Sara Cherry, Sarah Cobey, Scott E. Hensley
Journal: Nature Medicine (2025)
A B7H3-targeting antibody–drug conjugate in advanced solid tumors: a phase 1/1b trial
Authors: Yuxiang Ma, Yunpeng Yang, Yan Huang, Wenfeng Fang, Jinhui Xue, Xiangjiao Meng, Yun Fan, Siqing Fu, Lin Wu, Yulong Zheng, Jian Liu, Zhihua Liu, Wu Zhuang, Seth Rosen, Song Qu, Bihui Li, Mingjun Li, Yanqiu Zhao, Shujun Yang, Yinghua Ji, David Sommerhalder, Suxia Luo, Kunyu Yang, Jingao Li, Dongqing Lv, Peng Zhang, Yuanyuan Zhao, Shaodong Hong, Yang Zhang, Shen Zhao, Steve Chin, Xian Zhang, Wei Lian, Jiaqiang Cai, Tongtong Xue, Li Zhang, Hongyun Zhao
Journal: Nature Medicine (2025)

Antibody–drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg−1, and the recommended expansion dose was selected as 2.0 mg kg−1 and 2.4 mg kg−1 every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 . In a large-scale, international, multicenter, phase 1/1b trial, treatment of patients with advanced solid tumors with the B7H3-targeting antibody–drug conjugate YL201 was safe and showed preliminary clinical efficacy.