tbuckley/cabot-search huggingface dataset:
Potency-optimized CD28-activating bispecific antibody for the targeted treatment of Nectin-4 positive cancers
Authors: Manpreet Kaur, Katja Rüger, Elaine C Chen, Udaya S Rangaswamy, Laura M Davison, Sebastian Moreno Arteaga, Imani Smith, Ruth Chu, Soumili Chattopadhyay, Mathias Rickert, Shelley Force Aldred, Katherine E Harris, Nathan D Trinklein, Starlynn C Clarke
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background T-cell costimulation is crucial for an effective and sustained antitumor immune response, and inadequate expression of costimulatory ligands within tumors can impair T-cell function. Bispecific antibodies (bsAbs) targeting a tumor-associated antigen and the T-cell costimulatory receptor CD28 represent a novel class of immune-stimulatory therapeutics designed to enhance antitumor immune responses by selectively delivering T-cell costimulation directly to the tumor microenvironment. This approach holds the potential to improve the survival, proliferation, and cytotoxic function of antitumor T cells while minimizing the risk of systemic immune activation. Urothelial cancer (UC) is associated with significant morbidity and mortality worldwide, particularly in advanced disease settings. Nectin-4, a membrane protein highly expressed in UC with limited expression in healthy tissues, presents a compelling target for therapeutic intervention. Methods Using our proprietary high-throughput antibody discovery pipeline, we identified a panel of novel antibodies with a range of affinities for CD28 and Nectin-4 and successfully engineered them as bsAbs. We tested the T-cell costimulatory function of these molecules in vitro using primary human T cells and human cancer cell lines. Based on these results, we selected a clinical candidate which we assessed in a syngeneic mouse tumor model system and investigated tolerability and pharmacokinetics (PK) in non-human primates (NHP). Results Our in vitro studies demonstrated that these bsAbs effectively enhance T-cell activation and cytotoxicity against Nectin-4 positive tumor cells in the presence of T-cell receptor engagement. The bsAb panel exhibited a range of potencies, enabling the selection of a clinical candidate, termed RNDO-564, that maximized antitumor efficacy as well as the likelihood of a broad therapeutic window. Tumor-bearing syngeneic mouse models confirmed the in vivo efficacy of RNDO-564, demonstrating significant tumor regression both as a single agent and in combination with an immune checkpoint inhibitor. We observed favorable PK and tolerability profiles in NHP assessments. Conclusions Our study reports the first CD28 bsAb targeting Nectin-4 and highlights the potential of CD28 × Nectin-4 bsAbs as a new immunotherapeutic modality. The findings support the clinical development of RNDO-564 in patients with locally advanced and metastatic UC and other Nectin-4 positive malignancies.
Topical TLR7 agonist and radiotherapy in patients with metastatic breast cancer
Authors: Sylvia Adams, Sandra Demaria, Darawan Rinchai, Ena Wang, Yelena Novik, Ruth Oratz, Maria Fenton-Kerimian, Pascale G Levine, Xiaochun Li, Francesco Marincola, Ping Jin, David Stroncek, Judith Goldberg, Davide Bedognetti, Silvia Chiara Formenti
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Toll-like receptor (TLR) agonists and radiation therapy hold promise for cancer immunotherapy. We conducted a phase I/II trial combining topical imiquimod (IMQ, a TLR-7 agonist) and local radiotherapy (RT) in patients with metastatic breast cancer accompanied by longitudinal transcriptional analysis of tumor biopsies. Methods The primary objective of the trial ( NCT01421017 ) was to assess systemic responses by immune-related response criteria (irRC) after an 8-week cycle of topical IMQ and concurrent local RT (cohort 1). An amendment to the trial added two cohorts, both received one dose of cyclophosphamide (CTX) administered 1 week before study treatment initiation, IMQ/RT/CTX (cohort 2) and RT/CTX control (cohort 3). Cutaneous metastases were prospectively assigned to treatment with IMQ and RT (area A) or IMQ alone (area B). Secondary objectives were safety (Common Terminology Criteria for Adverse Events criteria) and local response in skin metastases. In all IMQ cohorts, tumors were biopsied before treatment and at 2 and 3 weeks. Results 31 patients were enrolled (n=12, n=12, and n=7, in cohort 1, 2, and 3, respectively), with 4 out of 24 patients in the IMQ cohorts showing systemic tumor responses (two complete responses (CR) and two partial responses (PR)). No objective responses were observed in the seven patients enrolled in the control arm (RT alone). The treatment was well-tolerated, no grade 4–5 treatment-related adverse events occurred and grade 3 AEs were manageable (anemia, local pain, and local ulceration, n=1 each). Local objective responses were observed in 19/24 (9 CR and 10 PR) and 5/24 (5 PR) in areas treated with combined IMQ-RT and IMQ alone, respectively (p&lt;0.001). All 24 patients treated with IMQ underwent serial biopsies, and 84 samples yielded sufficient material for transcriptional analyses. These revealed that the presence of a T-helper 1 functional orientation of the tumor microenvironment paralleled by the downregulation of DNA-repair genes was associated with CR after IMQ+RT, but not after IMQ alone. No post-treatment activation of immune-effector functions was observed in stable and progressing lesions. Conclusions Our findings support the safety and clinical efficacy of combining topical IMQ with local RT for recurrent breast cancer, with evidence of local and occasional systemic antitumor activity. Trial registration number NCT01421017 .
PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy
Authors: Shiyu Chen, Zheyi Chen, Bingqian Zhou, Yongyu Chen, Yiren Huang, Jian Cao, Lisong Shen, Yingxia Zheng
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) plays a significant role in immune regulation, particularly within the tumor microenvironment (TME). Macrophages are crucial modulators of both innate and adaptive immune responses, and their differentiation into tumor-associated macrophages is critical in shaping the TME. Despite ongoing clinical trials of small molecule inhibitors of PRMT5 for cancer therapy, their effects on macrophages, a key component of the immune system, remain poorly understood. Methods A pan-cancer single-cell transcriptional analysis was initially conducted to investigate the expression of PRMT5 in tumor-infiltrating myeloid cells. Myeloid-specific deletion of Prmt5 in mice, as well as the use of a PRMT5-specific inhibitor, was performed to evaluate the impact of PRMT5 on macrophage polarization and tumor progression. Bulk and single-cell transcriptomics were employed to explore the mechanistic roles of PRMT5 in regulating lipid metabolism and macrophage polarization. Additionally, the therapeutic potential of combining Prmt5 deletion with anti-programmed death-ligand 1 (PD-L1) therapy was assessed to study its effects on antitumor immunity in vivo. Results The pan-cancer single-cell transcriptional analysis revealed that PRMT5 is highly expressed in the PPARG-macrophage subset, which correlates with poor patient survival. Myeloid-specific deletion of Prmt5 reprogrammed macrophages towards an antitumor phenotype, effectively inhibiting tumor progression. Mechanistically, PRMT5 was found to regulate lipid metabolism and drive macrophage polarization toward an anti-inflammatory state via the STAT6-PPARγ pathway, fostering an immunosuppressive TME conducive to tumor growth. Notably, Prmt5 deletion induced PD-L1 expression on myeloid cells. Combining Prmt5 deletion with anti-PD-L1 therapy significantly enhanced antitumor efficacy, demonstrating a synergistic therapeutic effect. Conclusions These findings uncover a crucial role for PRMT5 in macrophage biology and suggest that targeting PRMT5 in myeloid cells offers a promising new approach for cancer immunotherapy. The combination of PRMT5 inhibition with anti-PD-L1 therapy may provide a potent strategy to reprogram the TME and enhance antitumor immune responses.
Conformation-sensitive targeting of CD18 depletes M2-like tumor-associated macrophages resulting in inhibition of solid tumor progression
Authors: Ik-Hwan Han, Ilseob Choi, Hongseo Choi, Soyoung Kim, Chanmi Jeong, Juwon Yang, Yingying Cao, Jeongyoon Choi, Heekyung Lee, Jin Sun Shin, Hye Duck Yeom, Eun-Ji Lee, Nari Cha, Hyemin Go, Se Eun Lim, Songah Chae, Won-Jun Lee, Minjin Kwon, Hongsung Kim, Hyojung Choi, Sehyun Pak, Namgyeong Park, Eunbin Ko, Deok-Sang Hwang, Junho H Lee, Hwan-Suck Chung, Seong Ho Kang, Hyunsu Bae
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Tumor-associated macrophages (TAMs) primarily exist in the M2-like phenotype in the tumor microenvironment (TME). M2-TAMs contribute to tumor progression by establishing an immunosuppressive environment. However, TAM targeting is hindered, mainly owing to a lack of specific biomarkers for M2-TAMs. Previously, we demonstrated that a novel peptide drug conjugate (TB511) consisting of a TAM-binding peptide and the apoptosis-promoting peptide targets M2-TAMs. This was achieved through M2-TAM targeting, although the target mechanism of action remained elusive. Herein, we elucidate the anticancer efficacy of TB511 by identifying new target proteins that preferentially bind to M2-TAMs and clarifying the apoptosis-inducing mechanism in these cells. Methods We investigated the target proteins and binding site of TB511 using LC-MS/MS analyses, surface plasmon resonance and peptide–protein interaction 3D modeling. Activated CD18 expression in M2 TAMs was assessed using Quantibrite PE beads in PBMCs. The anticancer efficacy of TB511 was tested using colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) mouse model. The immunotherapeutic effect of TB511 was investigated through spatial transcriptomics in human pancreatic ductal adenocarcinoma (PDAC) model. Results Activated CD18 was highly expressed in human tumor tissues and was significantly higher in M2 TAMs than in other immune cells. TB511 showed high binding affinity to CD18 among the cell membrane proteins of M2 macrophages and appeared to bind to the cysteine-rich domain in the activated form. Moreover, TB511 specifically induced apoptosis in M2 TAMs, but its targeting ability to M2 macrophages was inhibited in CD18 blockade or knockout model. In mouse or humanized mouse models of solid tumors such as CRC, NSCLC, and PDAC, TB511 suppressed tumor growth by targeting M2-TAMs via CD18 and enhancing the presence of CD8 + T cells in the TME. Conclusions Collectively, our findings suggest that activated CD18 holds promise as a novel target protein for cancer therapy, and TB511 shows potential as a therapeutic agent for tumor treatment.
Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors
Authors: Xiangyun Niu, Pengchao Zhang, Liujiang Dai, Xixia Peng, Zhongming Liu, Yexiao Tang, Guizhong Zhang, Xiaochun Wan
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Adoptive cell therapy using genetically engineered chimeric antigen receptor (CAR)-T cells is a new type of immunotherapy that directs T cells to target cancer specifically. Although CAR-T therapy has achieved significant clinical efficacy in treating hematologic malignancies, its therapeutic benefit in solid tumors is impeded by the immunosuppressive tumor microenvironment (TME). Therefore, we sought to remodel the TME by activating tumor-infiltrating immune cells to enhance the antitumor function of CAR-T cells. Methods We engineered CAR-T cells expressing Salmonella flagellin (Fla), a ligand for toll-like receptor 5, to activate immune cells and reshape the TME in solid tumors. Functional validation of the novel Fla-engineered CAR-T cells was performed in co-cultures and mouse tumor models. Results Fla could activate tumor-associated macrophages and dendritic cells, reshaping the TME to establish an “immune-hot” milieu. Notably, this “cold” to “hot” evolution not only improved CAR-T cell function for better control of target-positive tumors, but also encouraged the production of endogenous cytotoxic CD8 + T cells, which targeted more tumor-associated antigens and were thus more effective against tumors with antigenic heterogeneity. Conclusion Our study reveals the potential and cellular mechanisms for Fla to rewire antitumor immunity. It also implies that modifying CAR-T cells to express Fla is a viable strategy to improve the efficacy of CAR-T cell treatment against solid tumors.
β-blocker suppresses both tumoral sympathetic neurons and perivascular macrophages during oncolytic herpes virotherapy
Authors: Konstantina Kyritsi, Rafal Pacholczyk, Eugene Douglass, Miao Yu, Hui Fang, Gang Zhou, Balveen Kaur, Qin Wang, David H Munn, Bangxing Hong
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The autonomic nervous system (ANS) plays a key role in regulating tumor development and therapy resistance in various solid tumors. Within the ANS, the sympathetic nervous system (SNS) is typically associated with protumor effects. However, whether the SNS influences the antitumor efficacy of intratumoral injections of oncolytic herpes simplex virus (oHSV) in solid tumors remains unknown. Methods In this study, we examined SNS innervation and its interaction with immune cell infiltration in both human and murine triple-negative breast cancer models during intratumoral oHSV injections and SNS blockade on oHSV’s antitumor activity. Results Intratumor oHSV injection promotes SNS innervation accompanied by CD45+cell infiltration in both the human MDA-MB-468 orthotopic model and the murine 4T1 mammary tumor model. Mechanistically, tumor-secreted factors vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-β) and transcription factors (CREB, AP-1, MeCP2, and REST), which promote SNS innervation, were found to be upregulated in oHSV-treated tumors. Combining the SNS antagonist, a β-blocker, with oHSV significantly increased immune cell infiltration, particularly CD8+T cells in oHSV-treated 4T1 tumors. Single-cell messenger RNA sequencing revealed that oHSV injection upregulated a specific population of perivascular macrophages (pvMacs) expressing high levels of VEGFA, CD206, CCL3, and CCL4, which suppress T-cell activation. The use of a β-blocker reduced the infiltration of oHSV-induced pvMacs, transition to inflammatory macrophages expressing Hexb, enhancing the diversity of T-cell receptor clonotypes. Further analysis suggested that TGF-β signaling within the tumor partially mediates SNS activation in the 4T1 model. Conclusion Our findings demonstrate that combining a β-blocker with oHSV significantly enhances the antitumor efficacy of oHSV in breast cancer by targeting TGF-β-mediated SNS innervation and immunosuppression.
[11C]ER176 images brain inflammation across TSPO genotypes and colocalizes with tau
Authors: Aisling M Chaney, Brian A Gordon
Journal: Trends in Neurosciences (2025)

Accurately measuring brain inflammation in Alzheimer's disease (AD) is crucial due to the role of inflammatory processes in neurodegeneration. In a recent study, Appleton, Finn, et al. used [11C]ER176, a novel translocator protein 18 kDa (TSPO)-positron emission tomography (PET) tracer overcoming genotype-related binding issues, to show increased inflammation in early-onset AD, with patterns aligning more closely with tau pathology than amyloid deposition or atrophy.
Amplification-free ECL biosensor for the detection of Fn using tetrahedral DNA based CRISPR/Cas12a
Authors: Xindan Zhang, Minkang Wu, Haoran Shi, Soochan Kim, Shixiang Lu, Ping Wang, Jieling Qin
Journal: Cyborg and Bionic Systems (2025)

Fusobacterium nucleatum, a bacterium linked to colorectal cancer, possesses a specific gene called fadA that serves as an early diagnostic biomarker. The CRISPR/Cas12a system has demonstrated marked potential for nucleic acid detection due to its satisfactory selectivity and trans-cleavage ability. However, most CRISPR/Cas-based sensors suffer from problems such as probe entanglement or local aggregation, reducing the Cas enzyme efficiency. In this study, an amplification-free biosensing platform for ultrasensitive detection of F. nucleatum was developed by integrating the highly specific CRISPR/AsCas12a with an improved electrochemiluminescence (ECL) biosensor. Different from the conventional 1- or 2-dimensional probes, the platform was constructed by tetrahedral DNA nanostructure (TDN) probes conjugated with quenchers and coralliform gold (CFAu) functionalized with luminescent agents. The TDN serves as an exceptional scaffold to modulate the recognition unit, substantially enhancing the recognition and cleavage efficiency of AsCas12a toward the probes. Furthermore, the high surface area of CFAu provides extensive landing sites for the luminescent agents, thereby improving the detection sensitivity. The prepared ECL biosensor exhibited a wider linear range (10 fM to 100 nM) and was capable of detecting F. nucleatum down to 1 colony-forming unit/ml. Additionally, the high mismatch sensitivity of AsCas12a to protospacer adjacent motifs and nearby areas provides a strategy for distinguishing mutant from wild-type sequences. Finally, by designing CRISPR RNA (crRNA), this diagnostic method can also be easily modified to detect other bacteria or biomarkers for the early diagnosis of various diseases.
The cGAS‒STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications
Authors: Mengzhou Shen, Xianjie Jiang, Qiu Peng, Linda Oyang, Zongyao Ren, Jiewen Wang, Mingjing Peng, Yujuan Zhou, Xiyun Deng, Qianjin Liao
Journal: Journal of Hematology & Oncology (2025)

Innate immunity represents the body's first line of defense, effectively countering the invasion of external pathogens. Recent studies have highlighted the crucial role of innate immunity in antitumor defense, beyond its established function in protecting against external pathogen invasion. Enhancing innate immune signaling has emerged as a pivotal strategy in cancer therapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key innate immune signal that activates the immune response and exerts antitumor effects; this is primarily attributed to the DNA receptor function of cGAS, which recognizes exogenous DNA to activate downstream STING signaling. This, in turn, promotes the activation of downstream targets such as IRF-3(Interferon Regulatory Factor 3) and NF-κB, leading to the secretion of type I interferons and proinflammatory cytokines, thereby increasing cellular immune activity. The activation of the cGAS-STING pathway may thus play a crucial role in enhancing anticancer immunity. In this paper, we reviewed the role of cGAS-STING signaling in anticancer immunity and its molecular mechanisms. Additionally, we briefly discuss the current applications of the cGAS-STING pathway in cancer immunity, summarize recent developments in STING agonists, and address the challenges facing the use of the cGAS-STING pathway in cancer therapy. Finally, we provide insights into the role of the cGAS‒STING pathway in cancer and propose new directions for cancer immunotherapy.
Semi-synthetic fibrous fibrin composites promote 3D microvascular assembly, survival, and host integration of endothelial cells without mesenchymal cell support
Authors: Firaol S Midekssa, Christopher D Davidson, Megan E Wieger, Jordan L Kamen, Kaylin M Hanna, Danica Kristen P Jayco, Michael M Hu, Nicole E Friend, Andrew J Putnam, Adam S Helms, Ariella Shikanov, Brendon M Baker
Journal: Bioactive Materials (2025)
Suprachoroidal space-inducing hydrogel-forming microneedles (SI-HFMN): An innovative platform for drug delivery to the posterior segment of the eye
Authors: Jaibyung Choi, Suhyeon Shim, Jiwoo Shin, Ahhyun Lee, Jaan Strang, Tobias Braun, Reto Naef, Hyungil Jung
Journal: Bioactive Materials (2025)
Acid-responsive contractile hyaluronic acid-based hydrogel loaded with ginsenoside Rg1 for hemostasis and promotion of gastric wound healing
Authors: Yixing Li, Tongyang Li, Jinteng Feng, Bohao Liu, Zhiyu Wang, Jiahui He, Zhe Chen, Runyi Tao, Hongyi Wang, Kun Fan, Ye Sun, Jizhao Wang, Baolin Guo, Guangjian Zhang
Journal: Biomaterials (2025)
Colorectal cancer incidence after the first surveillance colonoscopy and the need for ongoing surveillance: a retrospective, cohort analysis
Authors: Emma C Robbins, Kate Wooldrage, Matthew D Rutter, Andrew M Veitch, Amanda J Cross
Journal: Gut (2025)

Background Recommendations for the first postpolypectomy surveillance colonoscopy (SC1), based on stratifying postpolypectomy colorectal cancer (CRC) risk, are well established. Limited data inform recommendations for surveillance beyond SC1. Objective We investigated which patient groups need surveillance beyond SC1. Design Retrospective analysis of patients who underwent colonoscopy with polypectomy at 17 UK hospitals, mostly from 2000 to 2010, and had ≥1 surveillance colonoscopies. Cancer and death data were collected through 2017. We examined patients in groups defined by risk at baseline and SC1, applying risk definitions from the 2020 UK postpolypectomy surveillance guidelines: ‘low risk, low risk’ (LR-LR), ‘high risk, low risk’ (HR-LR), ‘low risk, high risk’ (LR-HR) and ‘high risk, high risk’ (HR-HR). We examined CRC incidence after SC1, censoring at any second surveillance colonoscopy (SC2), and after SC2 through end of follow-up. We compared incidence with general population incidence using standardised incidence ratios (SIRs). Results Analyses included 10 508 patients: LR-LR=6587 (63%), HR-LR=3272 (31%), LR-HR=248 (2%) and HR-HR=401 (4%). Median follow-up from SC1 was 8.0 years and 151 CRCs were diagnosed. Compared with the general population, CRC incidence after SC1 was lower in the LR-LR group (SIR 0.48, 95% CI 0.34 to 0.67), non-significantly different in the HR-LR (SIR 1.17, 0.85 to 1.58) or LR-HR (SIR 2.51, 0.81 to 5.85) groups, but higher in the HR-HR group (SIR 2.84, 1.30 to 5.39). After SC2, CRC incidence in the HR-HR group was no longer higher than in the general population (SIR 1.86, 0.89 to 3.42). Conclusion Patients with high-risk findings at both baseline and SC1 needed an SC2, while those with low-risk findings at SC1 did not, regardless of their baseline findings.