tbuckley/cabot-search huggingface dataset:
Uncommon biphasic CAR-T expansion induces hemophagocytic lymphohistiocytosis-like syndrome and fatal multiple infections following BCMA CAR-T cell therapy: a case report
Authors: Wenqiang Yan, Yu Xiong, Rui Lv, Chenxing Du, Tengteng Yu, Shuaishuai Zhang, Weiwei Sui, Shuhui Deng, Jigang Xiao, Yan Xu, Dehui Zou, Lugui Qiu, Gang An
Journal: Journal for ImmunoTherapy of Cancer (2024)

B-cell maturation antigen(BCMA)-directed chimeric antigen receptor (CAR)-T-cell therapy has significantly improved the treatment of relapsed or refractory multiple myeloma (MM). Nevertheless, the uncommon phenomenon of biphasic CAR-T cell expansion in vivo and its related severe toxicities have not been methodically described and studied. Herein, we report a case of patients with MM who experienced two CAR-T cell expansion peaks and subsequently developed multiple severe toxicities following BCMA CAR-T cell infusion. The first expansion peak occurred on Day 7, accompanied by grade 3 cytokine release syndrome. The second peak occurred on Day 28, associated with severe immune effector cell-associated hematotoxicity (ICAHT), immune effector-cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and polymicrobial infections. Both ICAHT and IEC-HS were refractory to our standard treatments; however, human umbilical cord mesenchymal stem cell infusion exhibited some efficacy in improving cytopenia. Despite the administration of a broad-spectrum anti-infective regimen, cytomegalovirus viremia remained uncontrollable, resulting in the development of central nervous system infection, neurological symptoms, and ultimately death. Additionally, we also employed high-dimensional 33-color spectral flow cytometry to describe the dynamic changes in immune cell components and functions between the two expansion peaks. Collectively, this case provides novel insights into the biphasic CAR-T expansion and related immune effector cell-associated toxicities.
Degradation of PARP1 by MARCHF3 in tumor cells triggers cCAS-STING activation in dendritic cells to regulate antitumor immunity in hepatocellular carcinoma
Authors: Jun Cao, Bingbing Su, Chi Zhang, Rui Peng, Daoyuan Tu, Qiangwei Deng, Guoqing Jiang, Shengjie Jin, Qian Wang, Dou-Sheng Bai
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Resistance to immune checkpoint inhibitors (ICIs) significantly limits the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC). However, the mechanisms underlying immunotherapy resistance remain poorly understood. Our aim was to clarify the role of membrane-associated ring-CH-type finger 3 (MARCHF3) in HCC within the framework of anti-programmed cell death protein-1 (PD-1) therapy. Methods MARCHF3 was identified in the transcriptomic profiles of HCC tumors exhibiting different responses to ICIs. In humans, the correlation between MARCHF3 expression and the tumor microenvironment (TME) was assessed via multiplex immunohistochemistry. In addition, MARCHF3 expression in tumor cells and immune cell infiltration were assessed by flow cytometry. Results MARCHF3 was significantly upregulated in tumors from patients who responded to ICIs. Increased MARCHF3 expression in HCC cells promoted dendritic cell (DC) maturation and stimulated CD8 + T-cell activation, thereby augmenting tumor control. Mechanistically, we identified MARCHF3 as a pivotal regulator of the DNA damage response. It directly interacted with Poly(ADP-Ribose) Polymerase 1 (PARP1) via K48-linked ubiquitination, leading to PARP1 degradation. This process promoted the release of double-strand DNA and activated cCAS-STING in DCs, thereby initiating DC-mediated antigen cross-presentation and CD8 + T-cell activation. Additionally, ATF4 transcriptionally regulated MARCHF3 expression. Notably, the PARP1 inhibitor olaparib augmented the efficacy of anti-PD-1 immunotherapy in both subcutaneous and orthotopic HCC mouse models. Conclusions MARCHF3 has emerged as a pivotal regulator of the immune landscape in the HCC TME and is a potent predictive biomarker for HCC. Combining interventions targeting the DNA damage response with ICIs is a promising treatment strategy for HCC.
Sintilimab plus HPV vaccine for recurrent or metastatic cervical cancer
Authors: Buhai Wang, Yichen Liang, Yuechao Wu, Qiuxian Li, Yichun Zeng, Liqin Liu, Wenmiao Cao, Xiaoru Geng, Yuxiang Huang, Yinxia Wu, Jiulin Pan, Xian Zhang, J Juan Gu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Purpose Recurrent or metastatic cervical cancer (r/m CC) presents limited treatment options for patients failed or progressed quickly following first-line therapy. This study investigated the potential of sintilimab with a prophylactic human papillomavirus (HPV) quadrivalent vaccine as a second-line treatment for r/m CC. Methods In this phase 2 clinical trial, patients with r/m CC previously unresponsive or intolerant to standard treatments for metastatic or recurrent lesions were enrolled. Participants received sintilimab (3 mg/kg for body weight &lt;60 kg; 200 mg for ≥60 kg) every 3 weeks until 24 months or 35 cycles and 3 doses of the HPV quadrivalent vaccine (initial dose prior to sintilimab initiation, with subsequent doses at 2 and 6 months). The primary endpoint was the objective response rate (ORR). A Simon two-stage optimal design was used. Results From October 2019 to October 2022, 13 patients with r/m CC were enrolled. ORR achieved 53.8% (95% CI 25.1% to 80.8%), and the disease control rate was 76.9% (95% CI 46.2% to 95.0%). Median follow-up duration was 16.07 months (range: 3.64–48.2 months), and median progressive free survival was 7.16 months (95% CI 1.91 –not applicable (NA)). The median overall survival (OS) was not reached (95% CI 9.89 –NA). Hypothyroidism (15.6%) was the most common treatment-related adverse event (AE). No grade 3 or above AEs were observed. Conclusions This study suggests the combination of sintilimab plus prophylactic HPV vaccine offers a potentially promising therapeutic strategy for patients with r/m CC unresponsive or intolerant to standard therapies. Trial registration number NCT04096911 .
Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study
Authors: Caicun Zhou, Gongyan Chen, Yunchao Huang, Jianying Zhou, LiZhu Lin, Jifeng Feng, Zhehai Wang, Yongqian Shu, Jianhua Shi, Yi Hu, QiMing Wang, Ying Cheng, Fengying Wu, Jianhua Chen, Xiaoyan Lin, Yongsheng Wang, Jianan Huang, Jiuwei Cui, Lejie Cao, Yunpeng Liu, Yiping Zhang, Yueyin Pan, Jun Zhao, LiPing Wang, Jianhua Chang, Qun Chen, Xiubao Ren, Wei Zhang, Yun Fan, Zhiyong He, Jian Fang, Kangsheng Gu, XiaoRong Dong, Faguang Jin, Hongjun Gao, Guangyu An, Cuimin Ding, Xiaodong Jiang, Jianping Xiong, Xiangdong Zhou, Sheng Hu, Ping Lu, Anwen Liu, Shuliang Guo, Jianjin Huang, Chengchu Zhu, Jian Zhao, Beili Gao, Yinglan Chen, Chengping Hu, Jian Zhang, Hongmei Zhang, Hui Zhao, Zhigao Wang, Xinjing Ma, Wei Shi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background CameL phase 3 study demonstrated the superiority of camrelizumab plus chemotherapy over chemotherapy alone for progression-free survival in patients with previously untreated advanced non-squamous non-small-cell lung cancer (NSCLC) without EGFR / ALK alterations. Here, we present the 5-year outcomes. Methods Patients were randomized (1:1) and received 4–6 cycles of camrelizumab plus carboplatin and pemetrexed (n=205) or carboplatin and pemetrexed (n=207) every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only. Crossover from chemotherapy group to camrelizumab monotherapy was permitted after disease progression. Results Median time from randomization to data cut-off was 65.2 months (range, 59.7–72.2). HR for overall survival (OS) was 0.74 (95% CI 0.58 to 0.93; one-sided p=0.0043), and was 0.62 (95% CI 0.49 to 0.79; one-sided p&lt;0.0001) after adjustment for crossover. Five-year OS rates were 31.2% (95% CI 24.7% to 37.9%) with camrelizumab plus chemotherapy versus 19.3% (95% CI 13.9% to 25.3%) with chemotherapy alone. Among the 33 patients who completed 2 years of camrelizumab, 5-year OS rate was 84.3% (95% CI 66.4% to 93.2%), and 5-year duration of response rate was 46.5% (95% CI 24.9% to 65.6%) in the 32 responders. No new safety signals were noted. Conclusions Camrelizumab plus carboplatin and pemetrexed as first-line therapy continued to demonstrate long-term OS benefit over carboplatin and pemetrexed, with manageable toxicity. Patients who completed 2 years of camrelizumab had enduring response and impressive OS. Current 5-year updated analysis further supports camrelizumab plus carboplatin and pemetrexed as a standard-of-care for previously untreated advanced non-squamous NSCLC without EGFR / ALK alterations. Trial registration number NCT03134872 .
<scp>STING</scp> deficiency ameliorates mouse models of lupus and atherosclerosis
Authors: Yudong Liu, Carmelo Carmona‐Rivera, Nickie L. Seto, Christopher B. Oliveira, Eduardo Patino‐Martinez, Yvonne Baumer, Tiffany M. Powell‐Wiley, Nehal Mehta, Sarfaraz Hasni, Xuan Zhang, Mariana J. Kaplan
Journal: Arthritis & Rheumatology (2024)

Objective Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome characterized by autoreactive responses to nucleic acids, dysregulation of the type I interferon (IFN‐I) pathway, and accelerated atherosclerosis. The stimulator of IFN genes (STING), a cytosolic DNA sensor, has pathogenic implications in various inflammatory diseases. However, its specific role in SLE pathogenesis, particularly in tissue damage, remains unclear. This study aimed to elucidate the role of STING in murine models of Toll‐like receptor 7 (TLR7)–driven lupus and atherosclerosis. Methods A TLR7‐driven lupus model was induced using imiquimod (IMQ) in wild‐type (WT) and STING knockout (Sting1 −/− ) mice on a B6 background. Mice were assessed for organ involvement, serum autoantibodies, and innate and adaptive immune responses. Additionally, Sting1 −/− mice were backcrossed to apolipoprotein E knockout (Apoe −/− ) mice, and both Apoe −/− and Apoe −/− Sting1 −/− mice were fed a high‐fat chow diet to induce atherosclerosis. Phenotypic assessments were conducted. Results Compared with IMQ‐treated WT mice, Sting1 −/− mice exhibited reduced disease severity in the lupus‐like phenotype, characterized by decreased splenomegaly, lower renal immune complex deposition and renal damage, diminished expansion of myeloid cells, and reduced activation of T and B lymphocytes. IMQ‐induced DNA release associated with IFN‐β production and subsequent IFN‐induced responses were attenuated in Sting1 −/− mice. DNase I treatment mitigated IMQ‐induced proinflammatory responses in WT mice but had no effect in Sting1 −/− mice. Furthermore, STING deficiency conferred protection against vascular damage and reduced atherosclerosis burden, accompanied by decreased IFN‐I production. Human monocyte–derived macrophages treated with IFN‐I significantly internalized more acetylated low‐density lipoprotein when compared with untreated cells, whereas an association between oxidized nucleic acids and disease activity and vascular damage was found in human SLE. Conclusion These findings highlight a pathogenic role of STING and downstream IFN responses in TLR7‐driven autoimmunity, vascular damage and atherosclerosis, supporting a therapeutic potential for STING inhibition in SLE treatment. Further research is warranted to elucidate the mechanisms underlying STING's involvement in these processes and to explore the feasibility of targeting STING as a therapeutic strategy in SLE and related autoimmune disorders. image
Methotrexate Versus Mycophenolate Mofetil Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Malignancies: A Retrospective Analysis on Behalf of the Chronic Malignancies Working Party of the <scp>EBMT</scp>
Authors: Thomas Luft, Luuk Gras, Linda Koster, Nicolaus Kröger, Thomas Schröder, Uwe Platzbecker, Katja Sockel, Régis Peffault de Latour, Matthias Stelljes, Henrik Sengeloev, Matthias Eder, Igor Wolfgang Blau, Peter Dreger, Ibrahim Yakoub‐Agha, Johan Maertens, Urpu Salmenniemi, Wolfgang Bethge, Stephan Mielke, Guido Kobbe, Anastasia Pouli, Liesbeth C. de Wreede, Kavita Raj, Joanna Drozd‐Sokolowska, Donal P. McLornan, Marie Robin
Journal: American Journal of Hematology (2024)

Prophylaxis strategies for Graft versus host disease (GVHD) in allogeneic hematopoietic cell transplantation (allo-HCT) frequently encompass a combination of a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). The aim of this retrospective, EBMT registry-based study was to determine outcome differences for chronic myeloid malignancies and secondary acute myeloid leukemia (sAML) between MTX- and MMF-based prophylaxis regimens while taking potential heterogeneity between subgroups into consideration. Eligible were patients transplanted between 2007 and 2017 who received either MTX- or MMF prophylaxis in combination with a CNI. Endpoints after allo-HCT were overall survival, relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and Grades 2-4 acute GVHD (aGvHD). Overall, 13 699 patients from 321 centers were included. Median follow-up was 42.8 months (IQR 19.8-74.5 months). MTX prophylaxis was associated with reduced overall mortality (HR 0.87, 95% CI 0.81-0.95, p = 0.001) and NRM (HR 0.86, 95% CI 0.78-0.96, p = 0.006) compared with MMF in multivariable Cox regression models in the whole cohort without significant interaction between prophylaxis and subgroups. In contrast, there was no significant association of prophylaxis with risk of relapse (HR 1.03 MTX vs. MMF, 95% CI 0.94-1.14, p = 0.53) or RFS (HR 0.95, 95% CI 0.88-1.01, p = 0.12). There was a reduced risk of Grades 2-4 acute GVHD and reduced mortality after acute GVHD with MTX prophylaxis but no association with outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. In conclusion, MTX-complemented CNI prophylaxis was associated with favorable survival, and with favorable survival after aGVHD compared with MMF.
Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies
Authors: Paul G. Richardson, Aurore Perrot, Joseph Mikhael, Thomas Martin, Meral Beksac, Ivan Spicka, Marcelo Capra, Mattia D’Agostino, Pieter Sonneveld, Kamlesh Bisht, Taro Fukao, Rick Zhang, Keisuke Tada, Christina Tekle, Sandrine Macé, Zandra Klippel, Helgi van de Velde, Philippe Moreau
Journal: Blood Cancer Journal (2024)

Abstract The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab–pomalidomide–dexamethasone vs. pomalidomide–dexamethasone) and IKEMA (isatuximab–carfilzomib–dexamethasone vs. carfilzomib–dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) “Not classified”. Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979–2.358), stage III (HR 2.59, 95% CI 1.709–3.923), and stage IV (HR 3.51, 95% CI 2.124–5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436–0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.
The efficacy and safety of first-line metastatic melanoma treatment with ipilimumab + nivolumab versus nivolumab in a real-world setting
Authors: Billard Karine, Laurent Mortier, Olivier Dereure, Sophie Dalac, Henri Montaudié, Delphine Legoupil, Caroline Dutriaux, Julie De Quatrebarbes, Eve Maubec, Marie-Thérèse Leccia, Florence Granel-Brocard, Florence Brunet-Possenti, Jean-Philippe Arnault, Caroline Gaudy-Marqueste, Cecile Pages, Philippe Saiag, Jean-Matthieu L’orphelin, Ouidad Zehou, Thierry Lesimple, Clara Allayous, Raphael Porcher, Bastien Oriano, Stephane Dalle, Céleste Lebbé
Journal: British Journal of Dermatology (2024)

Abstract Background The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival and numerically, although not statistically, superior overall survival for ipilimumab + nivolumab. The objective of this study was to compare the efficacy and safety of nivolumab to ipilimumab + nivolumab as first-line treatment for metastatic melanoma in a real-world setting. Methods Patients were prospectively included in the French Melbase cohort from 2013 to 2022. Eligible patients were those in first-line treatment for stage-IIIc or -IV melanoma, undergoing immunotherapy with nivolumab or ipilimumab + nivolumab. The primary endpoint was overall survival at 36 months. The secondary endpoints included progression-free survival at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the IPTW method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, LDH levels, and BRAF mutation status). Results A total of 406 patients were treated with nivolumab, and 416 with ipilimumab + nivolumab. Overall survival at 36 months was higher in the ipilimumab + nivolumab group (57.1%, ([95%CI 50.7-64.2]) than in the nivolumab group (46.6% [95%CI 41.6-52.1]), HR 1.4[1.1;1.8]. Progression-free survival at 36 months was significantly improved in the ipilimumab + nivolumab group (42.3%) compared to the nivolumab group (21.9%), with a HR 1.6[1.4;1.9]. The objective response rate was similar for the two groups (44%). The overall incidence of side effects was comparable (82 vs. 84%), and severe toxicity (grade ≥ 3) was more frequent, though not significantly so, in the ipilimumab + nivolumab arm (29% vs. 41%). Conclusions Our results are consistent with those from the Checkmate 067 study, except for the objective response rate and the incidence of toxicities, which proved to be lower in our analysis.
Elevated rates of molecular evolution genome-wide in mutualist legumes and rhizobia
Authors: T L Harrison, J R Stinchcombe, M E Frederickson
Journal: Molecular Biology and Evolution (2024)

Abstract Rates of molecular evolution vary greatly among even closely related species. Although theory predicts that antagonistic interactions between species increase rates of molecular evolution, predictions for how mutualism affects evolutionary rates are mixed. We compared rates of molecular evolution between 1) mutualistic and non-mutualistic legumes, 2) an independent set of symbiotic rhizobia and their non-symbiotic close relatives, and 3) symbiotic and non-symbiotic clades within Ensifer, a diverse genus of bacteria with various lifestyles. We assembled transcriptomes de novo for 12 legume species and calculated dN/dS ratios at orthologous genes in all species to determine if genes in mutualistic plants evolve faster or slower than in their non-mutualistic relatives. We also calculated dN/dS ratios in genes known to be important for symbiosis. We found that mutualists have higher rates of molecular evolution genome-wide compared to non-mutualist legumes, but this pattern did not hold in symbiosis genes. We next calculated dN/dS ratios in 14 bacteria species across the proteobacteria phylogeny that differ in whether they associate mutualistically with plants, using published data. In most pairs, symbiotic rhizobia show higher dN/dS values compared to their non-symbiotic relatives. Within a bacterial genus with many well-characterized mutualist species (Ensifer), we calculated dN/dS ratios in symbiotic and non-symbiotic clades and found that symbiotic lineages have higher rates of molecular evolution genome-wide, but not at genes on the symbiotic plasmid pSymB. Our results suggest that although mutualism between legumes and rhizobia is associated with elevated rates of molecular evolution genome-wide, symbiosis genes may be evolutionarily stagnant.
Infection-related pathway activation and vulnerability to arsenic trioxide in acute promyelocytic leukemia with TTMV::RARA
Authors: Jiacheng Lou, Yi Zhang, Jingfen Tao, Wen Jin, Yongmei Zhu, Zhuo Wang, Min Wu, Hongmei Yi, Xiaoxiao Chen, Shuhong Shen, Junmin Li, Zhu Chen, Saijuan Chen, Yangyang Xie, Li Chen, Kankan Wang
Journal: Leukemia (2024)
Thioether‐Functionalized Cellulose for the Fabrication of Oxidation‐Responsive Biomaterial Coatings and Films
Authors: Eric M. DuBois, Kate E. Herrema, Matthew G. Simkulet, Laboni F. Hassan, Payton R. O'Connor, Riya Sen, Timothy M. O'Shea
Journal: Advanced Healthcare Materials (2024)

Abstract Biomaterial coatings and films can prevent premature failure and enhance the performance of chronically implanted medical devices. However, current hydrophilic polymer coatings and films have significant drawbacks, including swelling and delamination. To address these issues, hydroxyethyl cellulose is modified with thioether groups to generate an oxidation‐responsive polymer, HEC MTP . HEC MTP readily dissolves in green solvents and can be fabricated as coatings or films with tunable thicknesses. HEC MTP coatings effectively scavenge hydrogen peroxide, resulting in the conversion of thioether groups to sulfoxide groups on the polymer chain. Oxidation‐driven, hydrophobic‐to‐hydrophilic transitions that are isolated to the surface of HEC MTP coatings under physiologically relevant conditions increase wettability, decrease stiffness, and reduce protein adsorption to generate a non‐fouling interface with minimal coating delamination or swelling. HEC MTP can be used in diverse optical applications and permits oxidation‐responsive, controlled drug release. HEC MTP films are non‐resorbable in vivo and evoke minimal foreign body responses. These results highlight the versatility of HEC MTP and support its incorporation into chronically implanted medical devices.
Liquid Biopsy in Hepatocellular Carcinoma: Challenges, Advances, and Clinical Implications
Authors: Jaeho Park, Yi-Te Lee, Vatche G Agopian, Jessica S Liu, Ekaterina K Koltsova, Sungyong You, Yazhen Zhu, Hsian-Rong Tseng, Ju Dong Yang
Journal: Clinical and Molecular Hepatology (2024)

Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more objective readouts, requiring less reliance on healthcare professional's skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.