tbuckley/cabot-search huggingface dataset:
B7-H3 CAR-T cell therapy combined with irradiation is effective in targeting bulk and radiation-resistant chordoma cancer cells
Authors: Kun Wang, David O Osei-Hwedieh, Tara A Walhart, Yin P Hung, Yufeng Wang, Giulia Cattaneo, Tao Ma, Gianpietro Dotti, Xinhui Wang, Soldano Ferrone, Joseph H Schwab
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Chordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment, but high local recurrence rates are reported even with negative margins. High-dose radiation therapy (RT), such as with proton or carbon ions, has been used as an alternative to surgery, but late local failure remains a problem. B7-H3 is an immune checkpoint, transmembrane protein that is dysregulated in many cancers, including chordoma. This study explores the efficacy of B7-H3 chimeric antigen receptor T (CAR-T) therapy in vitro and in vivo. Methods Chordoma cancer stem cells (CCSCs) were identified using flow cytometry, sphere formation, and western blot analysis. The expression of B7-H3 in paraffin-embedded chordoma tissue was determined by immunohistochemical staining, and the expression of B7-H3 in chordoma cells was measured by flow cytometry. Retroviral particles containing either B7-H3 or CD19 CAR-expressing virus were transduced into T cells derived from peripheral blood mononuclear cells isolated from healthy human donor blood to prepare CAR-T cells. Animal bioluminescent imaging was used to evaluate the killing effect of CAR-T cells on chordoma cells in vivo. An irradiator was used for all irradiation (IR) experiments. Results The combination of B7-H3 CAR-T cell therapy and IR has a greater killing effect on killing radiation-resistant CCSCs and bulk chordoma cells compared with CAR-T cell or IR monotherapy. Additionally, increased expression of B7-H3 antigens on CCSCs and bulk tumor cells is associated with enhanced CAR-T cell killing in vitro and in vivo xenograft mouse models. Upregulation of B7-H3 expression by IR increases CCSCs sensitivity to B7-H3 CAR-T cell-mediated killing. Conclusions Our preliminary data show that IR and B7-H3 CAR-T cell therapy is synergistically more effective than either IR or CAR-T cell monotherapy in killing chordoma cells in vitro and in a xenograft mouse model. These results provide preclinical evidence for further developing this combinatorial RT and B7-H3 CAR-T cell therapy model in chordoma
PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment
Authors: Céline Godfroid, Jackeline Romero, Sara Labiano, Chia-Hsien Chuang, Andrea Kelemen, Tania Wyss, Vincent Roh, Grégory Verdeil, Christian Klein, Laura Codarri Deak, Pablo Umaña, Genrich V Tolstonog, Christine Trumpfheller, Marie-Catherine Vozenin, Pedro J Romero
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody. Methods We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response. Results The combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8 + T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8 + T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8 + PD-1 + TOX + (exhausted) T cells, already at the ‘early’ timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy. Conclusions We demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model.
First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies
Authors: Ana Carneiro, Amanda Hahn, Peter Ellmark, Karin Enell Smith, Lena Schultz, Sumeet Ambarkhane, Jeffrey Yachnin, Gustav J Ullenhag
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death. Methods In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers. Results Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3–92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%). Conclusions Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.
Leveraging mRNA technology for antigen based immuno-oncology therapies
Authors: Charalampos S Floudas, Siranush Sarkizova, Michele Ceccarelli, Wei Zheng
Journal: Journal for ImmunoTherapy of Cancer (2025)

The application of messenger RNA (mRNA) technology in antigen-based immuno-oncology therapies represents a significant advancement in cancer treatment. Cancer vaccines are an effective combinatorial partner to sensitize the host immune system to the tumor and boost the efficacy of immune therapies. Selecting suitable tumor antigens is the key step to devising effective vaccinations and amplifying the immune response. Tumor neoantigens are de novo epitopes derived from somatic mutations, avoiding T-cell central tolerance of self-epitopes and inducing immune responses to tumors. The identification and prioritization of patient-specific tumor neoantigens are based on advanced computational algorithms taking advantage of the profiling with next-generation sequencing considering factors involved in human leukocyte antigen (HLA)-peptide-T-cell receptor (TCR) complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. This review discusses the development and clinical application of mRNA vaccines in oncology, with a particular focus on recent clinical trials and the computational workflows and methodologies for identifying both shared and individual antigens. While this review centers on therapeutic mRNA vaccines targeting existing tumors, it does not cover preventative vaccines. Preclinical experimental validations are crucial in cancer vaccine development, but we emphasize the computational approaches that facilitate neoantigen selection and design, highlighting their role in advancing mRNA vaccine development. The versatility and rapid development potential of mRNA make it an ideal platform for personalized neoantigen immunotherapy. We explore various strategies for antigen target identification, including tumor-associated and tumor-specific antigens and the computational tools used to predict epitopes capable of eliciting strong immune responses. We address key design considerations for enhancing the immunogenicity and stability of mRNA vaccines, as well as emerging trends and challenges in the field. This comprehensive overview highlights the therapeutic potential of mRNA-based cancer vaccines and underscores ongoing research efforts aimed at optimizing these therapies for improved clinical outcomes.
Combining SKY92 gene expression profiling and FISH (according to R2‐ISS) defines ultra‐high‐risk Multiple Myeloma
Authors: Xiang Zhou, Annika Hofmann, Benedict Engel, Cornelia Vogt, Silvia Nerreter, Yoko Tamamushi, Friederike Schmitt, Maria leberzammer, Emilia Stanojkovska, Marietta Truger, Xianghui Xiao, Christine Riedhammer, Maximilian J. Steinhardt, Mara John, Julia Mersi, Seungbin Han, Umair Munawar, Johannes M. Waldschmidt, Claudia Haferlach, Hermann Einsele, Leo Rasche, K. Martin Kortüm
Journal: HemaSphere (2025)

Abstract The definition of high‐risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: n = 109; relapsed/refractory [RR] MM: n = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compared with NDMM (17/95, 17.9%) ( p &lt; 0.0001). RRMM patients with HR SKY92 showed significantly shorter progression‐free survival (PFS) ( p &lt; 0.0001) and overall survival (OS) ( p &lt; 0.0001) than SKY92 standard‐risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS ( p &lt; 0.0001) in comparison with SR. We combined SKY92 with FISH (HR: t(4;14), del17p, +1q21 according to R2‐ISS) in 181 patients (NDMM: n = 79; RRMM: n = 102). We found a discrepancy between both risk stratification systems, with only 49 (27.1%) patients being defined as HR by both SKY92 and FISH (“double HR”). In terms of survival outcomes, “double HR” presented a negative prognostic factor for PFS in both NDMM ( p &lt; 0.0001) and RRMM ( p &lt; 0.0001). Furthermore, “double‐HR” patients showed the worst OS ( p = 0.000 13) in RRMM. Additionally, whole genome sequencing (WGS) revealed CRBN mutation ( n = 3) and bi‐allelic events (mutation and/or deletion) in TP53 ( n = 7) and TNFRSF17 ( n = 1). Altogether, we provide the first prospective real‐world evidence that the combination SKY92 and FISH (according to R2‐ISS) identifies a subset of patients with ultra‐HR MM, and WGS complements SKY92 and FISH in MM risk stratification.
Stratification system with dual human endogenous retroviruses for predicting immunotherapy efficacy in metastatic clear-cell renal cell carcinoma
Authors: Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Virginie Verkarre, Cheng-Ming Sun, Wenxuan Cheng, Li Xu, Fangrong Yan, Salma Kotti, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored. Methods This study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (−009 to –010 and −025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm from RNA sequencing data. Our primary objective was to correlate ERV expression with progression-free survival, with overall survival and time-to-second-treatment survival as secondary endpoints. We used bootstrap methods with univariate Cox regression on 666 substantially expressed ERVs to evaluate their prognostic significance and stability. Results Our analysis centered on two ERVs, E4421_chr17 and E1659_chr4, which consistently exhibited opposing prognostic impacts across both cohorts. We developed a stratification system based on their median expression levels, categorizing patients into four ERV subgroups. These subgroups were further consolidated into a three-tier risk model that significantly correlated with ICI treatment outcomes. The most responsive ERV risk category showed enhanced endothelial cell infiltration, whereas the resistant category was characterized by higher levels of myeloid dendritic cells, regulatory T cells, myeloid-derived suppressor cells, and markers of T-cell exhaustion. Notably, this ERV-based classification outperformed traditional transcriptomic signatures in predicting ICI efficacy and showed further improvement when combined with epigenetic DNA methylation markers. Conclusions Our findings introduce a dual ERV-based stratification system that effectively categorizes patient risk and predicts clinical outcomes for ccRCC patients undergoing ICI therapy. Beyond enhancing the predictive precision of existing transcriptomic models, this system paves the way for more targeted and individualized approaches in the realm of precision oncology.
Prevalence of type I Gaucher disease in patients with smoldering or multiple myeloma: Results from the prospective, observational CHAGAL study
Authors: Sonia Morè, Irene Federici, Alessandra Bossi, Serena Rupoli, Erika Morsia, Valentina M. Manieri, Attilio Olivieri, Maria T. Petrucci, Francesca Fazio, Chiara Lisi, Silvia Sorella, Adele D. Paoli, Francesca Farina, Anna Mele, Rossella De Francesco, Antonino Greco, Francesca Fioritoni, Carmine Liberatore, Tommaso C. De Toritto, Attilio Tordi, Agostina Siniscalchi, Marino Brunori, Nicola Sgherza, Pellegrino Musto, Angela Amendola, Angelo Vacca, Antonio G. Solimando, Assunta Melaccio, Antonio Palma, Lorella M. A. Melillo, Lucia Ciuffreda, Silvia Gentili, Gabriele Buda, Maria L. Del Giudice, Antonietta P. Falcone, Patrizia Tosi, Simona Tomassetti, Francesco Rotondo, Alessandro Gozzetti, Piero Galieni, Miriana Ruggieri, Ferdinando Frigeri, Rosario Bianco, Alessandra Lombardo, Fabio Trastulli, Laura Corvatta, Carmela Zizzo, Giovanni Duro, Massimo Offidani
Journal: HemaSphere (2025)
Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes
Authors: David Rombaut, Sarah Sandmann, Tobias Tekath, Simon Crouch, Aniek O. de Graaf, Alexandra Smith, Daniel Painter, Olivier Kosmider, Magnus Tobiasson, Andreas Lennartsson, Bert A. van der Reijden, Sophie Park, Maud D'Aveni, Borhane Slama, Emmanuelle Clappier, Pierre Fenaux, Lionel Adès, Arjan van de Loosdrecht, Saskia Langemeijer, Argiris Symeonidis, Jaroslav Čermák, Claude Preudhomme, Aleksandar Savic, Ulrich Germing, Reinhard Stauder, David Bowen, Corine van Marrewijk, Elsa Bernard, Theo de Witte, Julian Varghese, Eva Hellström‐Lindberg, Martin Dugas, Joost Martens, Luca Malcovati, Joop H. Jansen, Michaela Fontenay
Journal: HemaSphere (2025)

Abstract Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR‐MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well‐annotated cohort of treatment‐naive patients with LR‐MDS at diagnosis from the EUMDS registry ( ClinicalTrials.gov.NCT00600860 ). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome‐wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP‐1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower‐risk IPSS‐M, this cluster displayed a significantly inferior overall survival ( p &lt; 0.0001). Our study showed that genetic and DNA methylation features of LR‐MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.
Efficacy and Safety Results With Rilzabrutinib, an Oral Bruton Tyrosine Kinase Inhibitor, in Patients With Immune Thrombocytopenia: Phase 2 Part B Study
Authors: Nichola Cooper, A. J. Gerard Jansen, Robert Bird, Jiří Mayer, Michelle Sholzberg, Michael D. Tarantino, Mamta Garg, Paula F. Ypma, Vickie McDonald, Charles Percy, Milan Košťál, Isaac Goncalves, Lachezar H. Bogdanov, Terry B. Gernsheimer, Remco Diab, Mengjie Yao, Ahmed Daak, David J. Kuter
Journal: American Journal of Hematology (2025)

Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 109/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 109/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 109/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 109/L or ≥ 30 × 109/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 109/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.
Associations of objectively measured physical activity and sedentary time with all-cause mortality in Japanese older adults: a 10-year prospective study
Authors: Tao Chen, Sanmei Chen, Takanori Honda, Hiro Kishimoto, Yu Nofuji, Kenji Narazaki
Journal: British Journal of Sports Medicine (2025)

To examine the associations of accelerometer-measured physical activity and sedentary time with all-cause mortality in older Japanese adults. A total of 1723 independent Japanese adults aged ≥65 years were followed from 2011 to 2021. Moderate-to-vigorous physical activity (MVPA), light physical activity (LPA) and sedentary time were measured using a triaxial accelerometer secured to participants' waists. Over a median follow-up of 9.9 years, 336 deaths were recorded. When examined as tertiles, higher MVPA (both ≥10 and <10 min bouts) and LPA were associated with a lower mortality risk. Additional adjustment for MVPA attenuated the associations of LPA, but the HRs in the highest tertile remained significant. Longer sedentary time was significantly associated with an increased mortality risk, but not after adjusting for MVPA. In spline analyses, a linear dose-response association with all-cause mortality was observed for LPA, while the HRs declined progressively with higher levels of MVPA until approximately 80 min/day, beyond which they levelled out. Replacing 10 min/day of sedentary time with MVPA but not LPA was associated with a 12% lower risk of morality (HR 0.88; 95% CI 0.83 to 0.93); the HR for replacing 10 min/day LPA with MVPA was 0.89 (95% CI 0.84 to 0.95). These results were materially unchanged when excluding deaths within the first 5 years of follow-up. Physical activity, regardless of intensity, was associated with a lower all-cause mortality risk among older Japanese adults. Replacing sedentary time or LPA with MVPA was associated with a lower mortality risk. The mortality benefit started from a low MVPA dose and additional benefits were associated with higher doses.
Physical activity, cathepsin B, and cognitive health
Authors: Qian Yu, Zhihao Zhang, Fabian Herold, Sebastian Ludyga, Jin Kuang, Yanxia Chen, Zijun Liu, Kirk I Erickson, Bret H Goodpaster, Boris Cheval, Dominika M Pindus, Arthur F Kramer, Charles H Hillman, Teresa Liu-Ambrose, Keith W Kelley, Hyo Youl Moon, Aiguo Chen, Liye Zou
Journal: Trends in Molecular Medicine (2025)
Deep Learning Enabled Scoring of Pancreatic Neuroendocrine Tumors Based on Cancer Infiltration Patterns
Authors: Soner Koc, Ozgur Can Eren, Rohat Esmer, Fatma Ulkem Kasapoglu, Burcu Saka, Orhun Cig Taskin, Pelin Bagci, Nazmi Volkan Adsay, Cigdem Gunduz-Demir
Journal: Endocrine Pathology (2025)