tbuckley/cabot-search huggingface dataset:
Abstract LB129: VTS105: A novel and potent BCMA/GPRC5D/CD3 trispecific T cell engager (TCE) for the treatment of hematologic malignancies and autoimmune diseases
Authors: Wei (Vivian) Wang, Bo Peng, Man Xu, Xuekun Zhang, Jing Li
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is a genetically complex and heterogeneous malignancy with a poor survival rate. Despite therapeutic advancements, MM remains incurable, and patients ultimately succumb to relapsed disease. Recently approved T cell engagers targeting BCMA (e.g., Teclistamab) and GPRC5D (e.g., Talquetamab) have demonstrated clinical responses; however, high relapse rates persist due to suboptimal complete response (CR) rates and minimal residual disease (MRD). Additionally, BCMA mutations and antigen escape diminish the clinical benefits of BCMA-targeted therapies, including TCEs and CAR-T cells (chimeric antigen receptor T cells). Consequently, broader tumor-associated antigen coverage is urgently needed to address the unmet medical need for effective tumor cell elimination and prevention of resistance due to antigen loss. Here, we present VTS105, a trispecific antibody featuring a proprietary CD3 arm and the capability to target both BCMA and GPRC5D, which are co-expressed or individually expressed on heterogeneous MM cancer cells. VTS105 exhibits potent human PBMC-mediated tumor cell killing across various heterogeneous MM cell lines, outperforming competitors such as JNJ-79635322, IBI3003, and SCR-8572. VTS105 maintains high killing potency against BCMA low MM cells, effectively addressing drug resistance associated with BCMA escape following frontline BCMA-targeted therapies. In CDX models with varying BCMA and GPRC5D expression levels, VTS105 induces complete tumor remission, even at low or very low doses, demonstrating superior efficacy compared to JNJ-79635322. VTS105 activates T cells exclusively in a BCMA- and/or GPRC5D-dependent manner, indicating a promising safety profile. This innovative approach has the potential to significantly improve progression-free survival (PFS) and reduce relapse rates in MM clinical development. In addition, BCMA and GPRC5D expression are upregulated in Systemic Lupus Erythematosus (SLE), particularly in patients with Lupus Nephritis (LN). This suggests that VTS105 can also serve as a promising therapeutic option for SLE treatment. Evaluations in this indication are currently underway. Currently VTS105 is advancing into CMC and toxicology studies, with an Investigational New Drug (IND) filing planned for the second half of 2026. Citation Format: Wei (Vivian) Wang, Bo Peng, Man Xu, Xuekun Zhang, Jing Li. VTS105: A novel and potent BCMA/GPRC5D/CD3 trispecific T cell engager (TCE) for the treatment of hematologic malignancies and autoimmune diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB129.
Abstract LB139: Preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody for the treatment of advanced solid tumors resistant to immune checkpoint inhibitors
Authors: Shi Chen, Shuaixiang Zhou, Yao Xiong, Li Li, Qian Guo, Yucong Lei, Zhimin Zhang, Meng Ni, Zhihai Wu, Bingliang Chen, Kaijie He
Journal: Cancer Research (2025)

Abstract Despite the revolution of therapeutic landscape for solid tumors advanced by immune checkpoint inhibitors (ICIs), primary or acquired resistance to ICI remain major unmet medical challenges in substantial proportion of patients. Activation of antigen presentation and priming may provide feasible solution to the insufficiency of endogenous anti-tumor immune activity in ICI-resistant tumors and cover multiple types of cold tumors. Here we report the first disclosure of preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody that simultaneously activates CD40 and blocks PD-1/L1 interactions. IAR037 incorporates a 2+1 molecule structure, with two anti-CD40 Fab regions and one anti-PD-L1 VHH linked to the C-terminus of Fc region. Fc effector functions are abrogated by LALA mutations to reduce peripheral FcƳR-mediated CD40 clustering and consequent toxicities. IAR037 has shown strong in vitro potency of PD-1/L1 blockade and PD-L1-dependent activation of CD40. IAR037 has also shown significant in vivo anti-tumor efficacy in multiple mice syngeneic models, including PD-1 resistant models. It strongly synergized with IBI363, a clinical-stage PD-1/IL-2v bispecific fusion protein, and demonstrated superior tumor regression in highly PD-1-resistant tumor model. IAR037 showed good safety profile in pilot-toxicology study in cynomolgus monkey and displayed large therapeutic window for further development. Dual functionality of IAR037 enables potential coverage of broad ranges of tumor types and larger patient populations due to widespread expression of PD-L1 in advanced solid tumors. IAR037 could specifically activate immune responses in the tumor microenvironment and tumor-draining lymph node while minimizing systemic side effects, showing unique advantages over other CD40-targeting anti-tumor therapies. In summary, IAR037 presents a novel therapeutic approach for ICI-resistant advanced solid tumors and the IND enabling study of IAR037 is ongoing. Citation Format: Shi Chen, Shuaixiang Zhou, Yao Xiong, Li Li, Qian Guo, Yucong Lei, Zhimin Zhang, Meng Ni, Zhihai Wu, Bingliang Chen, Kaijie He. Preclinical data of IAR037, a novel CD40/PD-L1 bispecific antibody for the treatment of advanced solid tumors resistant to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB139.
Abstract SY36-02: Interrogating how the dialogue between immune cells and fibroblasts impacts radiotherapy outcomes
Authors: Anna Wilkins
Journal: Cancer Research (2025)

Abstract Background: Increased stromal fibroblasts in tumors is associated with inferior radiotherapy responses, however, we lack a mechanistic understanding of how fibroblast reprogramming contributes to radiotherapy outcomes. Methods: Radiotherapy (8Gy) was applied to 5555 BRAF mutant melanoma flank tumors grown in WT and RAG1 KO Bl/6 mice. Tumors were harvested at early (1 week post radiation) and late timepoints. 1D11, which inhibits all three isoforms of TGFβ, or the relevant isotype control, was administered from 24 hours prior to irradiation for one week. Multiplex immunohistochemistry and flow cytometry evaluated biological changes following treatment. A Cre-inducible murine model of podoplanin (PDPN) knockout was used to evaluate the specific role of PDPN expression in fibroblasts. NanoString GeoMx spatial profiling was used to evaluate transcriptional changes in different tumour regions. Results: An extensive peri-tumoral expansion of PDPN+ fibroblasts was observed after radiation in WT mice but not in RAG1 KO mice where tumours grew more rapidly. Radiation induced entry of CD8+ T cells which remained sequestered at the fibroblast/tumor cell interface, with minimal entry into the tumor core. Upregulation of inflammatory signaling was identified in PDPN+ fibroblasts at this interface with tumor cells but not elsewhere. The addition of 1D11 to irradiation promoted T cell entry into the tumor core however a paradoxical increase in TGFβ signaling was observed specifically in PDPN fibroblasts with 1D11. When PDPN knockout was induced shortly before irradiation, a higher rate of spontaneous tumor rejection was observed. The PDPN+ fibroblast phenotype observed in the above pre-clinical models is also seen across a range of human tumors both pre- and post-radiation. Conclusion: Rapid stromal reprogramming after irradiation, involving PDPN+ fibroblast expansion and associated inflammatory signaling, restricts T cell entry into tumors which appears to compromise tumor control Citation Format: Anna Wilkins. Interrogating how the dialogue between immune cells and fibroblasts impacts radiotherapy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY36-02.
Abstract LB087: Inferring single-cell spatial gene expression with tissue morphology via explainable deep learning
Authors: Yue Zhao, Elaheh Alizadeh, Yang Liu, Ming Xu, J Matthew Mahoney, Sheng Li
Journal: Cancer Research (2025)

Abstract The spatial arrangement of cells is vital in developmental processes and organogenesis in multicellular life forms. Deep learning models trained with spatial omics data uncover complex patterns and relationships among cells, genes, and proteins in a high-dimensional space, providing new insights into biological processes and diseases. State-of-the-art in silico spatial multi-cell gene expression methods using histological images of tissue stained with hematoxylin and eosin (H&amp;E) to characterize cellular heterogeneity. These computational techniques offer the advantage of analyzing vast amounts of spatial data in a scalable and automated manner, thereby accelerating scientific discovery and enabling more precise medical diagnostics and treatments. In this work, we developed a vision transformer (ViT) framework to map histological signatures to spatial single-cell transcriptomic signatures, named SPiRiT (Spatial Omics Prediction and Reproducibility integrated Transformer). Our framework was enhanced by integrating cross validation with model interpretation during hyper-parameter tuning. SPiRiT predicts single-cell spatial gene expression using the matched histopathological image tiles of human breast cancer and whole mouse pup, evaluated by Xenium (10x Genomics) datasets. Furthermore, ViT model interpretation reveals the high-resolution, high attention area (HAR) that the ViT model uses to predict the gene expression, including marker genes for invasive cancer cells (FASN), stromal cells (POSTN), and lymphocytes (IL7R). In an apple-to-apple comparison with the ST-Net Convolutional Neural Network algorithm, SPiRiT improved predictive accuracy by 40% using human breast cancer ST-Net dataset. Cancer biomarker gene prediction and expression level are highly consistent with the tumor region annotation. In summary, our work highlights the feasibility to infer spatial single-cell gene expression using tissue morphology in multiple-species, i.e., human and mouse, and multi-organs, i.e., mouse whole body morphology. Importantly, incorporating model interpretation and vision transformer is expected to serve as a general-purpose framework for spatial transcriptomics. Citation Format: Yue Zhao, Elaheh Alizadeh, Yang Liu, Ming Xu, J Matthew Mahoney, Sheng Li. Inferring single-cell spatial gene expression with tissue morphology via explainable deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB087.
Abstract SY29-01: Compartmentalization of proteins and drugs in cancer cells
Authors: Richard A. Young
Journal: Cancer Research (2025)

Abstract New insights into condensate compartments in cell biology promise to advance understanding of disease mechanisms and to improve drug discovery and development for cancer. Cells have evolved mechanisms to distribute ∼10 billion protein molecules to condensate compartments where multiple proteins involved in shared functions must assemble. We have found that proteins possess codes both for folding and for selective compartmentalization in biomolecular condensates. Selective protein-protein and protein-nucleic acid interactions are thought to be the predominant driving force leading to the assembly of specific proteins in subcellular compartments, but there is evidence of distinctive chemical environments within condensates, indicating that these compartments have different solvent properties. Thus, patterns of amino acid sequences in proteins both promote specific folding behaviors and favor residence in compartments compatible with their solvent properties. The observation that small molecule drugs, including widely used anti-neoplastic medicines, selectively concentrate in specific condensates has important implications for drug development and therapeutic efficacy. Citation Format: Richard A. Young. Compartmentalization of proteins and drugs in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY29-01.
Abstract LB069: An agrin mechanotransduction for EGFR-addicted cancers
Authors: Sayan Chakraborty
Journal: Cancer Research (2025)

Abstract Epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), where it senses extracellular matrix (ECM) rigidity. Despite our understanding of the increasing role of tissue rigidity on various hallmarks of cancer development, how the ECM-driven mechanotransductive network impacts EGFR-dependent tumorigenesis remains uncharacterized. Here we show that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. The agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin-EGFR rigidity response to YAP-TEAD mechanosensing is essential for tumorigenesis. Together, we propose that the combined inhibition of EGFR-YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers. Citation Format: Sayan Chakraborty. An agrin mechanotransduction for EGFR-addicted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB069.
Abstract LB079: Expression of C1q by macrophages and fibroblasts in tumor microenvironment is associated with invasion and metastasis of cutaneous squamous cell carcinoma
Authors: Kristina Viiklepp, Jaakko Knuutila, Liisa Nissinen, Elina Siljamäki, Pekka Rappu, Ujjwal Suwal, Teijo Pellinen, Markku Kallajoki, Seppo Meri, Jyrki Heino, Veli-Matti Kähäri, Pilvi Riihilä
Journal: Cancer Research (2025)

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, with a poor prognosis for metastatic cases. We have previously demonstrated that cSCC cells in culture express components of the complement C1qr2s2 complex, specifically C1r and C1s, but not C1q. In this study, we found significantly higher mRNA levels of C1QA, C1QB, and C1QC variants 1 and 2 in cSCC tumors compared to normal skin using the Nanostring Cancer Immune Panel and qRT-PCR. Additionally, C1q production was induced in 3D spheroid co-cultures of cSCC cells, fibroblasts, and macrophages. C1q staining was detected on the surface of cSCC tumor cells, in peritumoral PDGFRbeta-positive activated fibroblasts, and in peri- and intratumoral CD68-positive macrophages using multiplexed immunofluorescence and chromogenic immunohistochemistry. Expression of C1q was higher in cSCCs compared to normal skin, actinic keratosis, and cSCC in situ. C1q expression in fibroblasts and macrophages was significantly more prevalent in metastatic primary cSCCs and cSCC metastases compared to non-metastatic cSCCs. High C1q expression in fibroblasts and macrophages in cSCC correlated with a poor prognosis. These findings provide new evidence for the role of fibroblast- and macrophage-derived C1q in the progression of cSCC. The results also suggest stromal C1q as a molecular marker for cSCC metastasis and a therapeutic target for metastatic cSCC. Citation Format: Kristina Viiklepp, Jaakko Knuutila, Liisa Nissinen, Elina Siljamäki, Pekka Rappu, Ujjwal Suwal, Teijo Pellinen, Markku Kallajoki, Seppo Meri, Jyrki Heino, Veli-Matti Kähäri, Pilvi Riihilä. Expression of C1q by macrophages and fibroblasts in tumor microenvironment is associated with invasion and metastasis of cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB079.
Abstract LB248: SCHEQ Lung Cancer Health Equity Summit learnings: Building a community to address disparities
Authors: Eugene Manley, Rochelle Prosser
Journal: Cancer Research (2025)

Abstract SCHEQ (STEMM &amp; Cancer Health Equity) Foundation held our lung cancer health equity summit, themed “Black and Hispanic Populations Navigating Lung Cancer: Stepping Stones To Equity” to bring together diverse stakeholders across the lung cancer care continuum that are dedicated to addressing disparities. This summit was held at the Philadelphia College of Osteopathic Medicine - Georgia in Suwanee Nov 18-19, 2024, and is the first lung cancer summit that focused on solutions instead of only the challenges. We increased enrollment from 42 to 117 people, had 20 states and Puerto Rico present, had 3 exhibitors, and had 53 different institutions or organizations from across the country. The conference consisted of panel discussions, thematic sessions, a poster session, individual presentations, 5 roundtables and 5 breakout sessions that spanned screening, treatments, biomarkers, clinical trials, and workforce diversity, to name a few. A key requirement was that all of the sessions had to have diverse representation and have no all male panels. In preconference surveys, attendees said their leading goals of attending the conference were to address barriers and disparities (23%) and health equity strategies (16.9%), while they indicated the biggest challenges in lung cancer were access and healthcare delivery (24.7%) and clinical trials (20.6%). Of the solo presentations, the day 1 keynote on structural racism and lung cancer, and the wrap up and closing session had 76% of attendees extremely satisfied. The clinical trial diversity session (76%) and panels on both patient/caregiver experience and community engagement (71%) were the highest rated. The most attended roundtable session was partnerships for increasing clinical trial diversity while the most attended breakout session was on using social media for education and marketing. Attendees noted that this was an encompassing event that addresses the needs of underserved populations, and we have demonstrated that you can create an event that brings together patients, researchers, clinicians, and hospital systems. We will be launching a webinar and working group to amplify the programs reach and impact. Citation Format: Eugene Manley, Rochelle Prosser. SCHEQ Lung Cancer Health Equity Summit learnings: Building a community to address disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB248.
Abstract LB057: Metabolic vulnerabilities in non-small cell lung cancer metastasis
Authors: Mayher Kaur, Massar Alsamraae, Nia G. Hammond, Robert Cameron, Brianna Chang, Brandon Faubert
Journal: Cancer Research (2025)

Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, largely due to its propensity to metastasize to distant organs. To identify new treatment strategies, there is a need to better understand the biological factors, such as metabolic reprogramming, that enable the survival of NSCLC cells throughout the metastatic cascade. However, standard cell culture media have non-physiological levels of key nutrients, limiting the ability to translate these findings in vivo. Here, we integrated physiological in-vitro and in-vivo approaches to reveal how metabolic plasticity drives NSCLC progression. Culturing NSCLC cells in a Human-Plasma-Like Medium versus conventional culture media revealed a marked reduction in glucose- and glutamine-derived carbon oxidation in the tricarboxylic acid (TCA) cycle. Next, we utilized non-adherent conditions to mimic extracellular matrix detachment and circulating tumor cells. We identified that NSCLC cells increased their reliance on lactate import and contribution to TCA cycle intermediates, demonstrating both a capacity to shift fuel sources under selective pressure and the influence of physiological nutrient environments on cancer cells. To assess how metabolic reprogramming supports NSCLC progression in-vivo, we utilized patient-derived xenografts with novel capacity for spontaneous metastasis. Inhibition of lactate import significantly reduced metastatic spread without substantially affecting primary tumor growth, suggesting a shift to lactate reliance in metastatic NSCLC cells. Together, these data suggest that circulating NSCLC cells' survival relies on metabolic flexibility, with key alterations of nutrient contribution to the TCA cycle. These data underscore the therapeutic potential of targeting metabolic dependencies to hinder NSCLC progression. Citation Format: Mayher Kaur, Massar Alsamraae, Nia G. Hammond, Robert Cameron, Brianna Chang, Brandon Faubert. Metabolic vulnerabilities in non-small cell lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB057.