tbuckley/cabot-search huggingface dataset:
AXL Tyrosine Kinases: A Growing Isoform Family that Promotes Cancer Pathogenesis
Authors: May Eriksen Gjerstad, Pia Aehnlich, Pascal Gelebart, Emmet Mc Cormack
Journal: Cancer Research (2025)

Abstract The AXL receptor tyrosine kinase (RTK) is implicated in various cancers and its expression is linked with poor survival and resistance to therapy. In this review, we overview the complexity of AXL receptor signaling, emphasizing the distinctions between the AXL isoforms. Recent studies have identified a third AXL isoform, AXL3, which lacks the GAS6 binding domains found in AXL1 and AXL2. This unique structure of AXL3 suggests alternative activation and signaling mechanisms. Activation of AXL1/2 typically occurs through ligand binding, dimerization, and phosphorylation, leading to downstream signaling via pathways including PI3K/AKT, MAPK/ERK, JAK/STAT, and NF-κB. Unlike other oncogenic kinases, whose overexpression and overactivation can be attributed to genomic alterations, AXL upregulation is generally caused by non-genetic mechanisms. Analysis of the promoter region of AXL3 reveals potential binding sites for transcription factors such as KLF16 and MEIS3, which are linked to oncogenic pathways. AXL signaling in cancer promotes cell survival, proliferation, migration, and immune evasion. Therefore, inhibiting AXL by therapeutic approaches has been explored with varying results. Elucidating the functions and regulatory mechanisms of the different AXL isoforms is imperative for developing effective targeted therapies that improve outcomes in AXL-driven cancers.
Mannose Enhances Immunotherapy Efficacy in Ovarian Cancer by Modulating Gut Microbial Metabolites
Authors: Chen Zhang, Yiying Wang, Mengdi He, Chenyang Wang, Kankan Cao, Yujing Zhong, Xueling Wang, Moran Yang, Guodong Zhang, Jiaqi Lu, Huan Yi, Haiou Liu, Congjian Xu
Journal: Cancer Research (2025)

Abstract The gut microbiome significantly influences the effectiveness of immune checkpoint blockade (ICB) therapy. However, its clinical application is hindered by the absence of cost-effective production methods. In this study, we demonstrated that oral mannose supplementation inhibits ovarian tumor growth in immunocompetent mice through the enrichment of Faecalibaculum rodentium (F. rodentium). Administration of F. rodentium not only suppressed tumor progression but also enhanced anti-tumor immune responses. Mannose supplementation fostered an immune stimulatory tumor microenvironment, characterized by the expansion and differentiation of progenitor exhausted CD8+ T cells (Tpex). Metabolomics analysis identified propionate and butyrate as critical metabolites driving the mannose-mediated tumor-suppressive effects, which was validated in vivo. Mechanistically, propionate and butyrate enhanced histone acetylation to promote Tpex cell expansion. Moreover, a mannose-related gene signature was associated with favorable response to ICB therapy across multiple cancer types. Supplementation with mannose also improved the efficacy of anti-PD-1 therapy and PARP inhibitor (PARPi) treatment. These findings highlight the role of F. rodentium-derived metabolites propionate and butyrate as key stimulators of Tpex cell expansion, thereby activating anti-tumor immune responses. This underscores the therapeutic potential of mannose supplementation in enhancing cancer immunotherapy outcomes in high-grade serous ovarian cancer.
Antigen Cross-Presentation by Type-2 Innate Lymphoid Cells Facilitates the Activation of Anti-Tumor CD8+ T Cells
Authors: Jihyun Kim, Seung Geun Song, Suhyun Park, Young Gyun Ko, Jongho Ham, TaeSoo Kim, Sang-Jun Ha, Yong-Soo Bae, Doo Hyun Chung, Hye Young Kim
Journal: Cancer Research (2025)

Abstract Type-2 innate lymphoid cells (ILC2s) exhibit dual functions in cancer, both promoting and inhibiting tumor growth by regulating anti-tumor immune responses. Elucidation of the precise mechanisms by which ILCs regulate adaptive immune responses could support development of improved immunotherapeutic approaches. Here, we revealed that ILC2s possess the capacity to internalize, process, and present exogenous tumor antigen on major histocompatibility complex class I (MHC I) molecules, along with costimulatory molecules, to CD8+ T cells, thereby inducing their differentiation into cytotoxic T lymphocytes (CTLs). Transferring ILC2s into tumor-bearing mice resulted in CD8+ T cell-dependent inhibition of tumor growth. Moreover, co-culturing CD8+ T cells with ILC2s upregulated the expression of cytotoxic molecules, leading to efficient killing of cancer cells in vitro as well as in vivo upon transfer into tumor-bearing mice. Mechanistically, ILC2s employed clathrin-dependent endocytosis to internalize exogenous antigens and process/present them to CD8+ T cells as effectively as conventional antigen-presenting cells. Based on this study, ILC2s emerge as proficient antigen-presenting cells capable of stimulating the tumor-killing activity of CD8+ T cells, thus offering promising anti-tumor immunotherapeutic strategies.
Long-term outcomes and clinical phenotypes associated with best response to low dose alemtuzumab in cutaneous T-cell lymphoma
Authors: Cecilia Larocca, Ai-Tram N Bui, John T O'Malley, Anita Giobbie-Hurder, Marianne Tawa, Jessica E Teague, Rachael A Clark, Corey Cutler, Eric Jacobsen, David C Fisher, Thomas S Kupper, Nicole R LeBoeuf
Journal: Blood Cancer Journal (2025)

Cutaneous T-cell lymphomas (CTCL) have in common malignant T-lymphocyte infiltration in the skin. Low dose alemtuzumab (LDA) appears to be an effective treatment for leukemic disease, but in the absence of clinical trials, there is need for improved characterization of patients with CTCL most likely to benefit. A retrospective cohort study of 38 patients with CTCL treated with LDA with at least 5 years' follow-up data was conducted. As a surrogate for a central memory T-cell (TCM) clinical phenotype, we evaluated whether the absence of a history of papules, plaques, and tumors (PPT) predicts better global and skin response. Twenty-five (65.8%) patients responded to LDA (95% CI: 49-80%). Patients with a TCM phenotype were more than eight times as likely to achieve a CR [OR: 8.2, 95% CI: 1.2-57.6]. CR rate in the skin was 81.8% in TCM phenotype patients compared to 37.0% in patients with a history of PPT (resident memory T-cell phenotype, TRM) [OR: 7.7, 95% CI: 1.4-42.7]. Three patients experienced any infection requiring systemic intervention. LDA monotherapy can safely produce exceptional response rates in those presenting with diffuse erythema but without a history of PPT.
Targeting LTBP2 Derived from Cancer-Associated Fibroblasts Sensitizes Esophageal Squamous Cell Carcinoma to Chemotherapy
Authors: Jiarong Zhan, Mengqing Li, Lei Li, Ting-Ting Zeng, Jun Liu, Qingyun Chen, Chen Jiang, Xin Wang, Dan Xie, Xin-Yuan Guan, Ying-Hui Zhu
Journal: Cancer Research (2025)

Abstract Cancer-associated fibroblasts (CAFs) are pivotal constituents of the tumor microenvironment that significantly influence cancer aggressiveness through the secretion of various factors. A more detailed characterization of the specific secretions exclusive to CAFs that drive tumor progression could identify potential targets to perturb this intracellular crosstalk. Here, we identified latent transforming growth factor β binding protein 2 (LTBP2) as a unique protein secreted exclusively by esophageal squamous cell carcinoma (ESCC) CAFs that promotes metastasis and chemoresistance. LTBP2 exerted its oncogenic effects by interacting with integrin α6β4, which serves as a functional receptor, and thereby activating Src signaling in ESCC cells. Notably, targeting LTBP2 with specific antagonistic antibodies markedly increased the susceptibility of ESCC cells to chemotherapeutic agents. These findings highlight the pivotal role of LTBP2 as a crucial mediator of CAF-induced cancer cell aggression and introduce it as a promising target to enhance chemotherapeutic efficacy in ESCC.
An oncolytic adenovirus targeting SLAMF7 demonstrates anti-myeloma efficacy
Authors: Georgia Stewart, Simon Tazzyman, Yidan Sun, Rebecca E Andrews, Jack Harrison, Darren Lath, Jenny Down, Georgia Robinson, Xue Wang, Munitta Muthana, Andrew D Chantry, Michelle A Lawson
Journal: Leukemia (2025)

Abstract We investigated a novel SLAMF7 -promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma, an incurable hematological malignancy. Ad[CE1A] infection, replication, and oncolysis were assessed in a panel of myeloma cell lines (n = 8) and ex vivo samples from myeloma patients (n = 17) and healthy donors (HDs) (n = 14). Ad[CE1A] efficiently infected, replicated, and induced oncolysis in myeloma cells, but not in control cell lines or HDs, demonstrating selective cytotoxicity. Mechanistic studies revealed Ad[CE1A]-induced cell death is caspase-independent, with a potential involvement of necroptosis. Ad[CE1A] also altered immunogenic cell death markers (calreticulin, CD47, extracellular ATP), enhanced antigen presentation via increased MHC class I and II receptor expression (HLA-ABC and HLA-DR), and stimulated bystander cytokine killing, indicating potential for direct and immune-mediated anti-myeloma responses. In vivo experiments with 5TGM1 syngeneic and U266 xenograft models showed Ad[CE1A] significantly reduced myeloma tumor burden compared to vehicle control. Combination therapy with anti-myeloma drugs, bortezomib, melphalan, panobinostat and pomalidomide, enhanced Ad[CE1A] efficacy, with melphalan upregulating SLAMF7 , resulting in increased viral replication. In summary, these findings support Ad[CE1A] as a promising myeloma therapy.
Developing palliative care interventions in liver disease using formative and summative qualitative evaluation
Authors: Marie Bakitas, Nicholas Hoppmann, Macy Stockdill, Shena Gazaway, Margaret Armstrong, Sarah Khalidi, Ivan Herbey, Stephanie Ford, Tamara Nix Parker, Jennifer Frank, Victor Navarro, Manisha Verma
Journal: Hepatology (2025)

Evaluation of the effectiveness of nascent care delivery interventions to integrate palliative care into end-stage-liver disease (ESLD) is limited. Intervention development and evaluation is a systematic, complex, and time-consuming process. Qualitative research approaches, known as formative and summative evaluations, are recommended during intervention development to explore intervention mechanisms, to determine the need for refinement, and to provide a deeper understanding of intervention efficacy, effectiveness, and implementation barriers and facilitators. Although qualitative formative and summative evaluations are resource-intensive, they provide critical information about intervention feasibility, patient and clinician acceptability, and patient-centeredness. This review summarizes how qualitative formative and summative evaluation methods can inform the design, adaptation, and evaluation of interventions to integrate palliative care into ESLD. We describe the completed qualitative summative evaluation study, embedded within PAL-LIVER, an in progress 19-site cluster randomized trial of hepatologist- vs palliative specialist-led palliative care for patients with ESLD and their caregivers. We include patient, family, and clinician demographic data emphasizing how the sample is representative of the parent RCT and describe how the embedded qualitative study explored patient, family, and clinicians’ perspectives on the intervention. Specifically, we sought to understand how the intervention was enacted (fidelity) and to provide a roadmap for future palliative care practice integration in ESLD. In conclusion, formative and summative evaluations play a vital role in improving interventions so that valuable and scarce palliative care resources are applied equitably and effectively and so that patients and their caregivers experience the best possible care and quality of life as they live with ESLD.
Improved Survival and Prognostication in Melanoma Patients With Brain Metastases: An Update of the Melanoma Graded Prognostic Assessment
Authors: Paul W. Sperduto, Kathryn E. Marqueen, Enoch Chang, Jing Li, Michael A. Davies, Daniel K. Ebner, William G. Breen, Nayan Lamba, Helen A. Shih, Donna Edwards, Michelle M. Kim, Amandeep Mahal, Rifaquat Rahman, Nii Ankrah, Drexell H. Boggs, Calvin Lewis, Daniel Hyer, John M. Buatti, Fasila Johri, Hany Soliman, Laura Masucci, David Roberge, Sanjay Aneja, Veronica Chiang, Christina Phuong, Steve Braunstein, Salah Dajani, Sean Sachdev, Zihan Wan, Donna Niedzwiecki, Eugene Vaios, John P. Kirkpatrick, Jared Pasetsky, Tony J.C. Wang, Tugce Kutuk, Rupesh Kotecha, Richard B. Ross, Chad G. Rusthoven, Toshimichi Nakano, Hussein A. Tawbi, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2025)

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.
GVHD prophylaxis in matched related stem cell transplantation: Why post-transplant cyclophosphamide can be recommended a study by the EBMT transplant complications working party
Authors: Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Malek Benakli, Nicolaus Kröger, Igor Wolfgang Blau, Didier Blaise, Jaime Sanz, Matthias Eder, Hakan Ozdogu, Dominik Schneidawind, Annoek E C Broers, Gerald G Wulf, Alberto Mussetti, Ivan Moiseev, Charlotte Graham, Hélène Schoemans, Zinaida Peric
Journal: Leukemia (2025)

Abstract Rabbit anti-thymocyte globulin (rATG) reduced chronic GVHD after matched related donor (MRD) allogeneic stem cell transplantation (alloSCT) from 69% to 32% in a randomized trial and is the recommended standard in Europe. Post-transplantation Cyclophosphamide (PTCy) is an emerging alternative but lacks such solid data in MRD alloSCT. We therefore analyzed outcomes of rATG ( n = 4140) vs. PTCy ( n = 1069) in adult patients with hematologic malignancies undergoing MRD alloSCT between 2017 and 2021 in the EBMT database. The provided hazard ratios (HR) and P-values are adjusted for potential risk factors using multivariate analysis. Results are given at 2 years after alloSCT for all endpoints except for acute GVHD (100 days). The main difference was a lower relapse incidence after PTCy vs. rATG (26.2% vs. 32.8%; HR 0.78 [CI 95%: 0.66–0.92], p = 0.003). Interaction analyses confirmed the consistency of this result across different disease risk index and conditioning intensity subgroups. Other major transplant outcomes showed no significant differences: non-relapse mortality, overall survival, progression-free survival, GVHD-free relapse-free survival, incidence and severity of acute GVHD as well as chronic GVHD. In summary, PTCy results in comparable GVHD and survival outcomes but lower relapse rates compared to rATG. We conclude that PTCy can be recommended in MRD alloSCT.
Gentle and efficient engineering of primary human NK cells by photoporation with polydopamine nanosensitizers
Authors: C Hinnekens, J Ramon, M Birben, W T V Germeraad, A Harizaj, M De Velder, S C De Smedt, B Vandekerckhove, K Braeckmans, J C Fraire
Journal: Journal of Controlled Release (2025)
Optimal structural characteristics of osteoinductivity in bioceramics derived from a novel high-throughput screening plus machine learning approach
Authors: Yunyi Liu, Quanle Cao, Shengyi Yong, Jing Wang, Xuening Chen, Yumei Xiao, Jiangli Lin, Mingli Yang, Kefeng Wang, Xiangfeng Li, Xiangdong Zhu, Xingdong Zhang
Journal: Biomaterials (2025)
Improved Immunocompatibility of Active Targeting Liposomes by Attenuating Nucleophilic Attack of Cyclic RGD Peptides on Complement 3
Authors: Nana Meng, Jiasheng Lu, Jianfen Zhou, Shengmin Yang, Chen Zhang, Ruiyi Jia, Yuan Ding, Yanning Bao, Jun Wang, Xiaopei Ma, Ruohan Chen, Zhixuan Jiang, Cao Xie, Linwei Lu, Weiyue Lu
Journal: Biomaterials (2025)
Reversing hypoxia-induced immune evasion in tumors to enhance cancer immunotherapy
Authors: Qiuting Sun, Guisong Shan, Wanrong Wang, Xueqian Li, Laiqing Yan, Rui Peng, Mengyu Liu, Xulin Huang, Xiaohe Ren, Xiaoyan He, Lei Qiao
Journal: Journal of Controlled Release (2025)
Evidence-Based Consensus on the clinical application of Photobiomodulation
Authors: Jalal Maghfour, Jessica Mineroff, David M Ozog, Jared Jagdeo, Henry W Lim, Indermeet Kohli, Rox Anderson, Christen Kelly, Andrew Mamalis, Gilly Munavalli, Ferraresi Cleber, Daniel Siegel, Ivayla Geneva, Robert Weiss, Akimich Morita, Anders Juanita, Mitchel P Goldman, Paraveen R Arany, David Sliney, Omar A Ibrahimi, Michael Chopp, Samia Esmat, Jan Tuner
Journal: Journal of the American Academy of Dermatology (2025)
Stimuli-responsive hydrogel with spatiotemporal co-delivery of FGF21 and H₂S for synergistic diabetic wound repair
Authors: Liuxi Chu, Jia-Men Shen, Zeping Xu, Junqing Huang, Luying Ning, Zunyong Feng, Yi Jiang, Ping Wu, Chen Gao, Wenjia Wang, Ziyi Li, Shaoxia Ning, Xinwang Ying, Shiyao Chen, Piao Wang, Xujie Zhou, Qian Xu, Ao Fang, Quan Zhang, Yuetong Wang, Haoman Chen, Rui Zhou, Xiaokun Li, Yanming Zuo, Yalin Zhang, Zhou-Guang Wang
Journal: Journal of Controlled Release (2025)
T-bet overexpression enhances CAR T cell effector functions and antigen sensitivity
Authors: Jennifer M Cimons, Kole R DeGolier, Samuel D Burciaga, Michael C Yarnell, Amanda J Novak, Amalia M Rivera-Reyes, M Eric Kohler, Terry J Fry
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background T cells modified to express a chimeric antigen receptor (CAR) are successful against B-lineage malignancies but fail to induce durable remissions in up to half of patients and have shown limited efficacy against other types of cancer. Strategies to improve CAR T cell potency and responses to low antigen densities without inducing CAR T cell dysfunction or limiting persistence are necessary to expand durability of remissions. Methods We overexpressed T-bet in human and mouse CAR T cells to mimic exposure to signal 3 cytokines during T cell priming to promote T helper cell 1 (Th1) polarization of CD4+CAR T cells with the goal of enhancing antitumor activity. Using human CAR T cells and xenograft models we interrogated the impact of T-bet overexpression on CAR T cell antitumor activity in vitro and in vivo. We also used a syngeneic murine CAR T cell model to study the impact of T-bet overexpression on long-term persistence and secondary responses to tumor rechallenge. Results T-bet overexpression reduced expression of the Th2 cytokine interleukin 4 and promoted polyfunctional production of Th1-associated cytokines in response to CAR stimulation. T-bet overexpression enhanced some effector functions in vitro but did not improve CAR T cell-mediated control of leukemia expressing high levels of antigen in vivo. T-bet overexpression also improved effector function of murine CD19 CAR T cells with no impairment to the persistence or ability of persistent CAR T cells to re-expand and clear a secondary leukemia challenge. Finally, T-bet overexpression promoted enhanced in vitro function against leukemia expressing low levels of CD19, which translated to improved control of CD19lo leukemia in vivo by human C19 CAR T cells containing a 4-1BB costimulatory domain. Conclusions Together, our data demonstrate that T-bet overexpression induces a reduction in Th2 cytokine production, an increase in polyfunctional Th1 cytokine production and enhances 4-1BB CAR T cell activity against cancers expressing low levels of target antigen without promoting a loss in functional CAR T cell persistence.
CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy
Authors: Regina M Myers, Amanda M DiNofia, Yimei Li, Caroline Diorio, Hongyan Liu, Gerald Wertheim, Joseph A Fraietta, Vanessa Gonzalez, Gabriela Plesa, Donald L Siegel, Emma Iannone, Laura Shinehouse, Jennifer L Brogdon, Clare Taylor, Julie K Jadlowsky, Elizabeth O Hexner, Boris Engels, Diane Baniewicz, Colleen Callahan, Marco Ruella, Richard Aplenc, Allison Barz Leahy, Susan E McClory, Susan R Rheingold, Lisa Wray, Carl H June, Shannon L Maude, Noelle V Frey, Stephan A Grupp
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed. Methods We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS). Results Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1–2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone. Conclusions The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies. Trial registration numbers NCT02650414 and NCT03620058 .