tbuckley/cabot-search huggingface dataset:
Abstract 3760: Local activation of immune cells and depletion of Tregs by tumor collagen-binding checkpoint immunotherapy
Authors: Jun Ishihara
Journal: Cancer Research (2025)

Abstract Checkpoint inhibitor immunotherapy has demonstrated limited efficacy in 'immunologically cold' tumors, necessitating innovative approaches to treat over 80% of CPI-unresponsive cancer patients. Our research developed a groundbreaking drug delivery strategy using tumor collagen-binding domain (CBD), derived from von Willebrand Factor A3 domain, recombinant fusion with checkpoint inhibitors to target tumors after intravenous injections.By engineering a novel CBD-anti-CTLA4 construct, we achieved precise tumor microenvironment targeting through the unique property of accumulating in tumor stroma's exposed collagen. This molecular engineering approach dramatically reduces systemic toxicity such as liver toxicity while enhancing anti-tumor efficacy of anti-CTLA4 antibody across multiple cancer types including breast cancer, glioblastoma, colon cancer, and melanoma models. The technology's strength is that after intravenous injection, we observe tumor as the primary site of drug accumulation.The specificity of localization within tumor tissues leads to minimizing off-target effects characteristic of traditional checkpoint inhibitors. CBD-anti-CTLA4 antibody demonstrates superior cancer treatment capabilities, including complete tumor regression in glioblastoma, previously unresponsive models. Very interestingly, CBD-anti-CTLA4 antibody can infiltrate into the tumors very deeply into the tissues although normal anti-CTLA4 antibody did not. Thus, we observed very efficient Treg depletion in the tumors, which normal anti-CTLA4 antibody could not do. Key translational achievements include developing a humanised version validated as safe in preclinical studies. This innovative drug delivery strategy to deep tumor tissues represents a significant advancement in antibody delivery, offering hope for more effective, targeted interventions in challenging tumor environments. Specifically, Treg depletion within the tumors will become more efficient by this technology, unlocking the full potential of anti-CTLA4 antibody. By reimagining checkpoint inhibitor delivery, we create potential pathways to overcome current limitations in cancer immunotherapy. Citation Format: Jun Ishihara. Local activation of immune cells and depletion of Tregs by tumor collagen-binding checkpoint immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3760.
Abstract 6294: Motif-independent Identification of functional transcription factors from single-cell multiomics data
Authors: Hongpan Zhang, Jingyi Wang, Zhenjia Wang, Chongzhi Zang
Journal: Cancer Research (2025)

Abstract Transcription factors (TF) are proteins that control when and how genes are turned on or off in a cell by binding to specific DNA sequences. The activation of one TF may induce gene expression cascade of other TFs or genes, suggesting the critical role of TFs in cell differentiation and cancer development. Techniques such as ChIP-seq, CUT&amp;RUN and CUT&amp;Tag are widely used to examine TFs’ genomic binding activity, but only one or a few TFs can be examined at once, making them low-efficient considering that hundreds of TFs can be typically expressed in a cell. Recently emerging single-cell genomic technologies provide an alternative approach, using computational tools to predict functional TFs from single-cell transcriptomics or chromatin accessibility assays. However, most existing computational methods share similar limitations, including the use of static TF binding motifs and the inability of considering distal enhancer regulation. We developed BARTsc, a precise and time-efficient TF prediction tool for clustered single-cell genomics data and it overcomes aforementioned pitfalls. BARTsc leverages differential features between cell clusters and does model-based predictions of cis-regulatory profiles based on given feature sets. Association scores were then calculated between the predicted cis-regulatory profiles and a collection of TF binding profiles derived from published ChIP-seq datasets. BARTsc implemented a set of handy downstream analysis modules that reveal the TFs that lead to signature gene expression in each cell type, the relative TF activity across cell types and the key regulators for each cell type. By benchmarking against other methods in predicting key regulators, we showed that BARTsc exhibits superior performances in various contexts. A promising impact of this work is that BARTsc can facilitate more precise identification of key regulators driving cancer development and can lead to discovery of new therapeutic targets. Citation Format: Hongpan Zhang, Jingyi Wang, Zhenjia Wang, Chongzhi Zang. Motif-independent Identification of functional transcription factors from single-cell multiomics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6294.
Abstract 2488: Employing RNA base editors to engineer personalized tumor-specific neoantigens
Authors: Rona Merdler-Rabinowicz, Netanel Landesman, Eytan Ruppin, Erez Levanon
Journal: Cancer Research (2025)

Abstract Enhancing the quantity and effectiveness of neoantigens in tumors is essential for advancing immunotherapy and developing targeted cancer vaccines. Crafting neoantigens presents a challenge due to the need to specifically modify peptide translation in tumor cells while avoiding effects on normal cells. To tackle this challenge, we introduce a novel method that enables the editing of selected nucleotides in the mRNA of cancer cells in order to produce potent neoantigens. The method is built on the use of Endogenous-ADAR base-editors, an established technology that allows for precise RNA-level edits, which is safer than DNA-level modifications and eliminates the need for external peptides by leveraging the native ADAR enzyme. The algorithm designs a guide RNA tailored to each tumor unique genetic profile and the patient’s HLA type, ensuring a precise and personalized approach to induce edits that are predicted to generate potent neoantigens in the cell. By targeting tumor-specific somatic mutations, our method ensures that edits are confined to tumor cells, sparing normal cells, thus offering a safer, more effective strategy for generating personalized neoantigens. We tested our computational algorithm on thousands of tumor samples available in The Cancer Genome Atlas (TCGA) database, demonstrating its capability to produce neoantigens across a broad spectrum of cases and cancer-types. As Endogenous-ADAR technology advances and delivery methods improve, the algorithm we present shows great promise as a valuable complement to immunotherapy and cancer vaccines. Citation Format: Rona Merdler-Rabinowicz, Netanel Landesman, Eytan Ruppin, Erez Levanon. Employing RNA base editors to engineer personalized tumor-specific neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2488.
Abstract 4786: A humanized monoclonal antibody targeting the Ig-like V1-C1 domains of B7-H3 suppresses the growth of breast cancer
Authors: Fengjuan Zhang, Qi Zhao
Journal: Cancer Research (2025)

Abstract Breast cancer, characterized by its heterogeneity and complexity, poses a significant threat to life. Current monoclonal antibody drugs for breast cancer primarily target HER2, which is only present in 15%-25% of all breast cancer cases. Recently, immune checkpoint therapy has emerged as a groundbreaking approach to reactivating anti-tumor immune responses. B7-H3 (CD276), a newly identified member of the B7 family, is expressed in various tumor tissues, making it an attractive candidate for therapeutic intervention. Utilizing advanced antibody discovery platforms, we have developed a humanized monoclonal antibody targeting B7-H3. This antibody exhibits specific binding affinity to epitopes in the Ig-like V1-C1 domain and demonstrates significant antibody-dependent cellular cytotoxicity effects on triple-negative breast cancer and trastuzumab-resistant HER2+ breast cells. Furthermore, both HER2+ cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models indicated that this antibody displayed potent in vivo anti-tumor activity. RNA-seq analysis of mouse tumor tissues revealed that the B7-H3 antibody downregulates the MAPK and NF-κB signaling pathways, leading to reduced tumor cell metabolism and migration, as well as diminished inflammation and cytokine release. Our findings indicate that B7-H3 is a viable therapeutic target, supporting the continued development of related therapeutic agents in both preclinical and clinical settings. This work is supported by FDCT/009/2023/RIC. Citation Format: Fengjuan Zhang, Qi Zhao. A humanized monoclonal antibody targeting the Ig-like V1-C1 domains of B7-H3 suppresses the growth of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4786.
Abstract 5677: Targeting G protein-coupled receptors in cancer pharmacotherapy: a comprehensive screening platform establishment and application in drug discovery
Authors: Xiaoyan Wang, Dandan Hu, Ziwei Zhang, Tj (Tiejun) Bing
Journal: Cancer Research (2025)

Abstract G protein-coupled receptors (GPCRs) constitute the largest family of membrane protein family in the human genome with over 800 members. They play an important role in various physiological and physiological processes and, such as proliferation, differentiation, neurotransmission, development and apoptosis. Several studies demonstrated that GPCRs play significant roles in the development of cancer, with their involvement in the initiation, growth, and spread of tumors being well-established. Several drugs targeting different GPCRs have been approved for the treatment of cancers, including CXCR4 (C-X-C chemokine receptor type 4) antagonism has been demonstrated to interfere with the communication between tumors and their surrounding stroma, enhance the susceptibility of cancer cells to chemotherapy, and reduce tumor growth and metastatic burden, GnRH (gonadotropin-releasing hormone) antagonists, which are used to treat hormone-dependent tumors like prostate cancer and breast cancer. Despite the increasing recognition of GPCRs' critical functions in cancer pathogenesis, it is noteworthy that only a small number of GPCR targets have been successfully leveraged for the development of anti-cancer treatments. Consequently, comprehensive compound screening platform is particularly important for highlighting the potential of pharmacologically modulating these GPCRs for the development of novel anti-cancer therapeutics. This research established stable cell lines expressing GPCRs and constructed multiple assay modes for GPCR drug discovery and screening, including in vitro HTRF cAMP assay, calcium flux assay and β-arretin2 NanoBiT assay, which can be used for agonist, antagonist and inverse agonist validation. Meanwhile, several CDX modes are constructed for promisingly conducting in-vivo experiments and biomarker detection. Thus, our GPCR platform can provide comprehensive screening cascade for compound evaluation, support multiple approaches to facilitate anti-cancer drug discovery. Citation Format: Xiaoyan Wang, Dandan Hu, Ziwei Zhang, Tj (Tiejun) Bing. Targeting G protein-coupled receptors in cancer pharmacotherapy: a comprehensive screening platform establishment and application in drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5677.
Abstract 6323: Cancer chemopreventive effects and mechanisms of <i>Citrus depressa</i> leaf extracts
Authors: Zheng-Yuan Su, Hsin-Yu Chiang
Journal: Cancer Research (2025)

Many diseases such as cancer are closely linked to excessive intracellular oxidative stress and chronic inflammatory responses. Studies have demonstrated that dietary interventions can mitigate or prevent the progression of certain chronic diseases, which reinforces the significance of the 'prevention is better than cure' concept. This study evaluated the antioxidant capacity and chemopreventive mechanisms of Citrus depressa leaf (CDL) extracts in mouse JB6 P+ skin cells in inhibiting carcinogenesis induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The preparation of various solvent extracts from CDL revealed a richness in flavonoids, which are key bioactive compounds commonly found in citrus fruits. CDL-WE (water extract) and CDL-95EE (95% ethanolic extract) (5-40 μg/mL) both effectively prevented the anchorage-independent growth of JB6 P+ cells with minimal cytotoxicity, but CDL-95EE was found to have superior effects. In addition, CDL-95EE promoted the expression of UGT1A and HO-1 enzymes at the protein level, enhanced the expression of Nrf2 pathway-related genes in mRNA, and decreased TPA-related ROS levels. The protein expression of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) was also reduced by CDL-95EE, which indicates that it is involved in epigenetic regulation. These findings demonstrate the chemopreventive capacity of CDL and endorse their use in creating agricultural byproducts from this resource. Citation Format: Zheng-Yuan Su, Hsin-Yu Chiang. Cancer chemopreventive effects and mechanisms of Citrus depressa leaf extracts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6323.
Abstract 4655: Identification of non-small cell lung cancer metabolic subtypes and targeting glucose pathway
Authors: Seo-Young Lee, Youngjoo Lee, Park Seog Yun, Beom K Choi, Sohyun Park, Jaemin Kim
Journal: Cancer Research (2025)

Abstract Background- NSCLC accounts for approximately 80% of all lung cancer cases. Despite significant treatment efforts, overall survival rates for NSCLC patients remain low. The NSCLC microenvironment and metabolism are also not fully understood, prompting ongoing research to better understand lung cancer progression and metastasis. To address tumor heterogeneity and define precise metabolic clusters, we applied non-negative matrix factorization (NMF) and discovered that the NMF clusters were significantly associated with clinical outcomes (progression, survival). Method- To investigate metabolic functions in 73 patients who received immunotherapy, we performed NMF clustering to identify subgroups based on significantly differentially expressed genes from NanoString data. After performing NMF, we found 5 subgroups then defined the metabolic function of each cluster using Gene Set Variation Analysis (GSVA) and identified the top 10 marker genes for each cluster using the Wilcoxon test from the Seurat package. Result- We found that clusters 1 and 2 had a higher proportion of immune cells compared to other clusters. Interestingly, while cluster 3 showed a higher proportion of immune cells, it had a lower overall survival rate and progression-free survival rate compared to cluster 1. We identified the key difference between these two clusters as glucose uptake. Moreover, glucose-related genes (SLC2A1, SLC2A3, SLC2A6, SLC2A14, SLC2A8, and SLC2A5) were highly expressed in cluster 2, which exhibited a higher proportion of Tregs and a stronger correlation between the glucose transport pathway and Tregs. Additionally, we found that SLC2A3 expression was significantly associated with overall survival and progression-free survival. To validate our findings and demonstrate their robustness, we corroborated them using GSE161537 data. This study may help identify metabolic pathways and biomarkers that could be targeted in precision oncology. Citation Format: Seo-Young Lee, Youngjoo Lee, Park Seog Yun, Beom K Choi, Sohyun Park, Jaemin Kim. Identification of non-small cell lung cancer metabolic subtypes and targeting glucose pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4655.
Abstract 5676: TFC Quick ‘n’ Clean, a next-gen platform for high-throughput production of true four-chain bispecific antibodies
Authors: Julia Su, Gaozhan Zhang, Xiayan Li, Dawei Zhang, Mengjie Lu, Zhumei Feng, Jiansheng Wu
Journal: Cancer Research (2025)

Introduction: Bispecific antibodies (BsAbs) are a promising class of biologics with substantial therapeutic potential. However, the production of bsAbs, particularly four-chain bsAbs containing two distinct LCs, presents significant challenges. Issues such as LC mispairing, fragmentation, and aggregation complicate purification processes and impact overall yield, purity and throughput. To address these challenges, WuXi Biologics has developed the True Four Chain (TFC) Quick ‘n’ Clean platform. By leveraging the WuXiBody™ backbone, this platform eliminates LC mispairing and enables high-throughput, high-purity production of four-chain bsAbs. This innovative approach accelerates the identification of optimal four-chain bsAb pairings during early-stage drug discovery. Methods: All experiments were conducted at WuXi Biologics’ Protein Sciences Department. Briefly, the codons of DNA sequence were optimized, and the plasmids were constructed into WuXi Biologics’ proprietary plasmid vector. Transient transfection was performed in CHO cells, with the culture medium harvested after 7 days. The harvested culture medium was clarified and subsequently processed using an AKTA Pure system with a tandem purification strategy using Nickel, anti-DYKDDDDK, and SEC columns. Final products were analyzed using SDS-PAGE, SEC-HPLC, Intact Mass, and LAL assays. Results: Using the TFC Quick ‘n’ Clean platform, we successfully produced 15 four-chain bsAbs in 20 mL CHO cell cultures within 3-4 weeks. The platform achieved an average monomer purity of 98.23%, an average yield of 3.34 mg, and an average endotoxin level of 0.06 EU/mg. Intact Mass analysis confirmed the absence of impurities such as homodimers and LC mispairing, with heterodimer purity exceeding 99%. Conclusion: The TFC Quick ‘n’ Clean platform overcomes key challenges associated with four-chain bsAb production by harnessing the WuXiBody™ backbone, high-titer CHO expression systems and advanced tandem purification strategies. This platform provides high-throughput, high-purity production of four-chain bsAbs, enabling the rapid, cost-effective identification of optimal parings to accelerate early-stage drug discovery and development. Citation Format: Julia Su, Gaozhan Zhang, Xiayan Li, Dawei Zhang, Mengjie Lu, Zhumei Feng, Jiansheng Wu. TFC Quick ‘n’ Clean, a next-gen platform for high-throughput production of true four-chain bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5676.
Abstract 4787: BGB-A3055, an afucosylated anti-CCR8 antibody, preferentially depletes intratumoral regulatory T cells and inhibits tumor growth in preclinical models
Authors: Xitao Wang, Yannan Xu, Ming Fang, Ming Jiang, Haolan Li, Mingchao Kang, Xiaomin Song
Journal: Cancer Research (2025)

Abstract Background: Regulatory T cells (Tregs) is a well-known key immune suppressive cell population enriched in tumor microenvironment (TME) that inhibits the anti-tumor immunity. Accordingly, specific depletion of Tregs in TME is considered as an attractive strategy to enhance the efficacy of immunotherapy such as PD-(L)1 treatment. C-C motif chemokine receptor 8 (CCR8), a G-protein coupled receptor, is predominately upregulated in intratumoral Tregs while CCR8 level in peripheral Tregs is relatively low. Therefore, CCR8 is widely explored as a promising therapeutic target for intratumoral Treg depletion. BGB-A3055 is a novel humanized afucosylated immunoglobulin G (IgG) 1 monoclonal antibody against human CCR8 (hCCR8). Here, we present the in vitro and in vivo data of BGB-A3055 in preclinical models. Methods: The cellular binding of BGB-A3055 was determined by fluorescence-activated cell sorting (FACS) on 293T cells that overexpress hCCR8 or primary human Treg cells. The blocking activity of BGB-A3055 on CCL1-CCR8 induced signaling was determined by Path Hunter eXpress HuCCR8 CHO-K1ß-Arrestin GPCR Assay kit. Antibody-dependent cellular cytotoxicity (ADCC) effect was evaluated on primary Treg cells. In vivo intratumoral Treg depletion and anti-tumor efficacy was assessed in GL261 and MC38 syngeneic models using hCCR8 knock-in mice. Results: BGB-A3055 exhibited a potent cellular binding to hCCR8 overexpressing cells and primary human Treg cells. BGB-A3055 can also efficiently block CCL1-CCR8 signaling and induce potent ADCC effect against CCR8 expressing primary Treg cells. Furthermore, in preclinical in vivo models, BGB-A3055 preferentially depleted Tregs in TME, demonstrated potent single agent and synergistic anti-tumor effect in combination with PD-1 antibody. Conclusions: BGB-3055 is a novel fully humanized afucosylated antibody that has high binding affinity to hCCR8, strong CCL1-CCR8 blocking capacity and potent ADCC effect. BGB-A3055 demonstrated strong anti-tumor activity as single agent or in combination with PD-1 antibody. A Ph1 study evaluating BGB-A3055 alone and in combination with Tislelizumab in participants with solid tumor is ongoing (NCT05935098). Citation Format: Xitao Wang, Yannan Xu, Ming Fang, Ming Jiang, Haolan Li, Mingchao Kang, Xiaomin Song. BGB-A3055, an afucosylated anti-CCR8 antibody, preferentially depletes intratumoral regulatory T cells and inhibits tumor growth in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4787.