tbuckley/cabot-search huggingface dataset:
Abstract 6082: Enhanced NK cell reactivity with Fc-optimized B7-H3 antibody for colorectal and non-small cell lung cancer
Authors: Sylwia Anna Stefanczyk, Xenija Kaiser, Samuel J. Holzmayer, Ilona Hagelstein, Latifa Zekri, Susanne Jung, Melanie Märklin
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) are among the deadliest cancers worldwide, especially in advanced stages with limited treatment options. While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown significant potential, their efficacy is limited to a small subset of CRC patients with microsatellite instability-high (MSI-H) tumors, and their use in NSCLC is often limited by severe side effects, further restricting their applicability. This underscores the urgent need for alternative immunotherapeutic approaches employing novel targets to expand clinical benefit. Here, we present a novel strategy exploiting natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) using a monoclonal antibody (mAb) targeting B7-H3 (CD276). B7-H3, a B7 family immune checkpoint protein, is overexpressed in several tumor types, including CRC and NSCLC, but minimally expressed in normal tissues, making it an ideal target for cancer immunotherapy. Our engineered B7-H3 mAb, 8H8, was modified by introducing amino acid substitutions (S239D/I332E) in the Fc region to create the Fc-optimized variant 8H8-SDIE. This variant shows increased affinity for CD16 on NK cells, thereby enhancing ADCC potential. Preclinical characterization demonstrated robust B7-H3 expression and specific binding of 8H8-SDIE to CRC (n=5) and NSCLC (n=3) cell lines, with saturation at approximately 1 µg/mL. Co-culture of allogeneic peripheral blood mononuclear cells (PBMCs) with B7-H3-positive CRC and NSCLC cells confirmed that 8H8-SDIE significantly activated NK cells, as evidenced by increased expression of CD69 and CD25. Upregulation of CD107a further indicated NK cell degranulation. Additional analyses showed that 8H8-SDIE treatment promoted the secretion of IFNγ, TNF, and effector molecules such as granzyme A, granzyme B, granulysin, and perforin, thereby enhancing NK cell-mediated cytotoxicity. In short-term, mid-term and long-term cytotoxicity assays, 8H8-SDIE induced potent target cell-restricted lysis of CRC and NSCLC cell lines, while the iso-SDIE control showed no effect. In conclusion, 8H8-SDIE is a potent immunotherapeutic candidate that effectively induces NK cell anti-cancer reactivity and represents a promising treatment option for CRC and NSCLC. Citation Format: Sylwia Anna Stefanczyk, Xenija Kaiser, Samuel J. Holzmayer, Ilona Hagelstein, Latifa Zekri, Susanne Jung, Melanie Märklin. Enhanced NK cell reactivity with Fc-optimized B7-H3 antibody for colorectal and non-small cell lung 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 6082.
Abstract 5863: Mapping tumor metastasis and EMT-associated immune changes in HNSCC through spatial transcriptomic analysis
Authors: Chih-Hung Chung, Muh-Hwa Yang
Journal: Cancer Research (2025)

Abstract Head and neck squamous cell carcinoma (HNSCC) is a globally prevalent malignancy. Standard treatments typically include surgical resection, radiation therapy, and chemotherapy. However, for patients with recurrent or distantly metastatic tumors where surgery or radiation is no longer feasible, the primary treatment strategy shifts to combining targeted therapies with chemotherapy or immune checkpoint blockade (ICI) therapy. Despite these approaches, the overall prognosis remains poor. Therefore, identifying key changes in immune cell composition within the tumor microenvironment of malignant or metastatic tumors is crucial for improving the management and outcomes in HNSCC therapy. The aim of this study is to analyze changes in the immune microenvironment composition across different HNSCC specimens. We utilized tools including the GeoMx Digital Spatial Profiler (DSP) for imaging-based digitized gene expression analysis. We identified region of interesting (ROI) from distinct tumor regions, such as the tumor invasive front, tumor core, and paired lymph node metastases. Through the Cancer Transcriptome Atlas (CTA) analysis, we identified two distinct epithelial-mesenchymal transition (EMT) gene signatures, which were highly expressed in particularly aggressive tumor tissues. Additionally, within the myeloid activation signature, we observed that immune cell composition in primary tumor site was predominantly neutrophil-activated, whereas in lymph node metastases, macrophages were the dominant immune cells. To further validate these observations, we applied other spatial transcriptomics tools, including 10x Visium and 10x Xenium, to analyze specimens from six HNSCC patients. Transcriptomic trajectory analysis and ligand-receptor pair analysis revealed significant changes in the immune microenvironment of malignant HNSCC tissues. These results provide crucial insights into head and neck cancer treatment strategies tailored to different tumor microenvironment (TME) characteristics. Citation Format: Chih-Hung Chung, Muh-Hwa Yang. Mapping tumor metastasis and EMT-associated immune changes in HNSCC through spatial transcriptomic analysis [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 5863.
Abstract 5206: ADC efficacy and safety evaluation based on organoid models
Authors: Yuhui Wang, Junwen Zhang, Jiawen Xu, Lin Feng, Junjie Zhu, Pengwei Pan, Fang He
Journal: Cancer Research (2025)

Abstract Introduction: Antibody-drug conjugates (ADCs) are effective cancer therapies that selectively deliver cytotoxic payloads to tumors. For the discovery of new ADCs, in vitro efficacy testing with organoids is crucial, as they replicate the 3D structure of tumors, providing a more accurate model for assessing the complex mechanism of action of ADCs. In this poster, we present an organoid-based ADC testing platform suitable for high-throughput screening. We demonstrate its application through a case study targeting human epidermal growth factor receptor 2 (HER2) to predict ADC efficacy and safety. Method: We established multiple PDX-derived organoid (PDXO) models from different cancer types with low, medium or high expression levels of HER2, which we verified by RNA-seq and immunohistochemistry. Responses to four groups of HER2-targeted ADC drugs were evaluated in these models by assessing cell viability, including Trastuzumab deruxtecan, Trastuzumab duocarmazine, Trastuzumab emtansine, Trastuzumab MMAE, and their corresponding payloads (with or without linker). Furthermore, we conducted additional safety studies to assess the intestinal toxicity of these drugs using human intestinal organoids (HIO) derived from normal intestinal tissues. Results: The HER2 expression levels in the in vitro cultured PDXO models were almost consistent at both RNA and protein levels, and they accurately reflected the expression status of the original tissues. The ADC screening revealed a differential sensitivity of organoids based on HER2 expression levels, with high HER2 expression correlating with increased sensitivity to ADC treatment, while low expression indicated resistance. Interestingly, normal organoid models were insensitive to ADC treatment, suggesting a potential for minimal side effects. However, the payloads alone demonstrated strong, unbiased cytotoxic activity against all models. In addition, the cytotoxic efficacy of payloads connected to linkers was significantly reduced, likely because the linkers hindered the payloads from entering the cells. Summary: Our organoid-based ADC screening platform offers a rapid and reliable method for early high-throughput screening, pharmacology, and efficacy research that help bridge the gap between in vitro and in vivo studies. The translational results enhance the development process of ADCs through more accurate assessments of their potential effectiveness and safety. Citation Format: Yuhui Wang, Junwen Zhang, Jiawen Xu, Lin Feng, Junjie Zhu, Pengwei Pan, Fang He. ADC efficacy and safety evaluation based on organoid 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 5206.
Abstract 6503: Preclinical insights into chemotherapy-induced alopecia: a focus on mouse and rat models
Authors: Simonetta I. Gaumond, Isabella Kamholtz, Caroline A. Crowley, Claudia Kersting, Joaquin J. Jimenez
Journal: Cancer Research (2025)

Abstract Chemotherapy-induced alopecia (CIA) is a prevalent and distressing side effect of cancer treatment, significantly affecting patients’ quality of life and highlighting the critical need for preclinical models to investigate its mechanisms and develop effective interventions. Murine models, including both rat and mouse species, are indispensable in advancing our understanding of CIA. This review explores the use of murine models in CIA research, focusing on the most commonly used strains, chemotherapies, and administration methods. Rat models primarily utilized Fischer, Long-Evans, and Sprague-Dawley strains, treated with chemotherapeutic agents such as cyclophosphamide, cytarabine, doxorubicin, and etoposide. Most of these chemotherapies were injected intraperitoneally (IP), with occasional intravenous (IV) or subcutaneous (SQ) injections. Mouse models primarily involved C57/BL mice, with chemotherapy also administered predominantly via IP injection, along with a few IV and one SQ method. The primary agents responsible for inducing alopecia in these models included cyclophosphamide, doxorubicin, and, less frequently, 5-fluorouracil, cytosine arabinoside, etoposide, and paclitaxel. The assessment of alopecia progression relied on visual evaluation, photography, and histological analysis. While these models provide critical insights into CIA mechanisms, variability in outcomes underscore the need for standardized protocols to enhance reproducibility and translational relevance in preclinical CIA research. Citation Format: Simonetta I. Gaumond, Isabella Kamholtz, Caroline A. Crowley, Claudia Kersting, Joaquin J. Jimenez. Preclinical insights into chemotherapy-induced alopecia: a focus on mouse and rat 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 6503.
Abstract 6073: IDP-002 is a PD-1xCD6 bispecific antibody that enables complete PD-1 receptor occupancy and enhances cytotoxic over regulatory T cell responses
Authors: Marc Gavin, Tsadik Habtetsion, Christie Mortales, Hayley Ma, Aniruddh Saxena, Mikaela Rusnak, Jing Song, Ben Setter, Robert Gene, Heath Klock, Carina Xu, Ertan Eryilmaz, Pamela Holland, Scott Lesley
Journal: Cancer Research (2025)

Abstract High response rates observed with PD-1/L1 antagonists have advanced immunotherapy to the forefront of treatment options for multiple cancer types; however, a substantial proportion of partial and non-responders warrants development of novel and more effective approaches. Poor responses to current PD-1/L1 antagonists may result from incomplete receptor occupancy, partial reversal of T cell exhaustion, and proliferative responses in PD-1+ FOXP3+ immunosuppressive regulatory T cells (Tregs) which will suppress anti-tumor effector T cell responses. Importantly, the recently demonstrated superiority of the PD-1xVEGF bispecific antibody (bsAb) ivonescimab over pembrolizumab in PD-L1+ advanced NSCLC suggests greater PD-1 receptor occupancy (achieved through high-avidity PD-1 binding of ivonescimab/VEGF multivalent complexes) leads to significantly deeper clinical responses. Enhanced PD-1 receptor occupancy may also be achieved with cis-acting bsAbs that target PD-1 and an abundant T cell surface protein, enabling more efficient PD-1 blockade compared to that achieved with conventional mAbs. Furthermore, candidate co-targets can be evaluated not only by expression level, but also for co-stimulatory capacity and differential cell subset expression. For example, low co-target expression on Tregs or co-target signaling that attenuates Treg fitness would skew PD-1 antagonist activity towards effector T cells and reduce therapy-induced Treg responses. Here, we present IDP-002, a PD-1xCD6 bsAb that facilitates complete PD-1 receptor occupancy and promotes greater proliferative and cytotoxic responses in vitro and in tumor-bearing humanized mice compared to current PD-1 antagonist mAbs. Tregs, which express lower levels of CD6, proliferate less efficiently than effector CD4 and CD8 T cells in response to IDP-002. Enhanced effector T cell responses observed with IDP-002 derive from a combination of complete PD-1 blockade and the engagement of unique signaling pathways downstream of CD6. IDP-002 has the potential to become a leading therapeutic option for the next generation of PD-1 antagonists. Citation Format: Marc Gavin, Tsadik Habtetsion, Christie Mortales, Hayley Ma, Aniruddh Saxena, Mikaela Rusnak, Jing Song, Ben Setter, Robert Gene, Heath Klock, Carina Xu, Ertan Eryilmaz, Pamela Holland, Scott Lesley. IDP-002 is a PD-1xCD6 bispecific antibody that enables complete PD-1 receptor2 occupancy and enhances cytotoxic over regulatory T cell responses [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 6073.
Abstract 6045: MHC II+ VEGFA+ neutrophils induce expansion of regulatory T cells and confer colorectal cancer peritoneal metastasis
Authors: Shuang Deng, Shaoqiu Liu, Jian Zheng
Journal: Cancer Research (2025)

Abstract Peritoneal metastasis is a fatal mode of cancer metastasis that is accompanied by extensive stromal fibrosis and poor prognosis. Increasing evidence suggests that tumor associated neutrophils (TANs) constitute a major component of tumor-infiltrating cells in many types of cancer and contribute to tumor immunity; however, how TANs are connected to adaptive immunity and clinical relevance in peritoneal metastasis remains unclear. Here, we generated and integrated single-cell RNA and spatial transcriptomes in primary tumor, adjacent normal tissues and metastases from 7 cancer types that tend to develop peritoneal metastasis (235 samples from 124 patients). Neutrophils exhibited distinct states in different tissue types. Specially, a terminally differentiated MHC II + VEGFA+ neutrophil population with antigen presenting and oncogenic phenotype termed TAN-2 portended peritoneal metastasis and could further induce mesothelium to mesenchymal transition. These fibrotic mesothelial cells exhibit higher CXCL12 levels and recruited more TAN-2 cells via CXCR4. Notably, the antigen-presenting TAN-2 could invoke expansion of regulatory T cells in an antigen-specific manner and was associated with worse survival. Importantly, in vivo TAN-2 depletion or in combination with immune checkpoint inhibitors effectively attenuates peritoneal metastasis. Taken together, we elucidate how MHC II+ VEGFA+ TANs contribute to peritoneal metastasis, provide novel insights on innate and adaptive immunity, and demonstrate new strategies to enhance cancer immunotherapy effects. Citation Format: Shuang Deng, Shaoqiu Liu, Jian Zheng. MHC II+ VEGFA+ neutrophils induce expansion of regulatory T cells and confer colorectal cancer peritoneal metastasis [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 6045.
Abstract 5214: Nuclear APC maintains colon homeostasis and mitigates inflammation
Authors: Anika James, Kristi Neufeld
Journal: Cancer Research (2025)

Abstract Adenomatous polyposis coli (APC) is critical for maintaining intestinal homeostasis. Although widely recognized for its cytoplasmic tumor suppressor functions, the roles of APC in other subcellular compartments and inflammation are less defined. To investigate nuclear APC functions, we developed a mouse model with compromised nuclear Apc import (ApcmNLS/mNLS mice). ApcmNLS/mNLS mice displayed lower levels of mucin-2 (MUC2) RNA, the primary component of the intestinal mucus barrier, and had significantly thinner colonic mucus layers. These mice were more susceptible to experimentally induced colitis than their wild-type littermates. Importantly, male ApcmNLS/mNLS mice exhibited significantly increased weight loss and higher colitis scores compared to female mice. Therefore, we hypothesize that nuclear APC promotes gut barrier integrity by upregulating MUC2 expression. In cultured human colon cells, APC positively regulates MUC2 RNA levels and inhibits NF-κB signaling. Overall, this study provides evidence that nuclear APC upregulates colonic MUC2 expression, increases the mucus barrier, and inhibits colonic inflammation. Furthermore, our results reveal notable sex-specific differences in colitis susceptibility. Citation Format: Anika James, Kristi Neufeld. Nuclear APC maintains colon homeostasis and mitigates inflammation [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 5214.
Abstract 1959: Variant Origin Prediction (VOP) determines the tumor-somatic, germline, or clonal hematopoiesis (CH) origin of short variants (SVs) detected in liquid biopsy (LBx)
Authors: Derek W. Brown, Alexander D. Fine, Daokun Sun, Hanna Tukachinsky, Michael McDevitt, Kerriann Pontbriand, Eliana Polisecki, Angela Kou, Mingyue Li, Shumeng Zhang, Zheng Kuang, Aparna Aiyer, Bahar Yilmazel, Brennan Decker, Jason Hughes, Chang Xu
Journal: Cancer Research (2025)

Abstract Introduction: Distinguishing the origin of variants detected by LBx is essential as tumor-somatic and germline, but not CH variants, can provide prognostic insights and inform treatment decisions. We describe a machine learning model that generates variant origin predictions for SVs (including base substitutions and short indels) detected by LBx. Method: For all SVs detected in the FoundationOne®Liquid CDx (F1LCDx) assay, VOP generates a 3-way probability that the variant originated as germline, CH, or tumor-somatic. Tumor-somatic and germline probabilities can be summed to predict that the SV is in the tumor. This model was trained using 1977 F1LCDx results for which matched buffy coat (BC) DNA was also sequenced to equal depth. A variety of features, including fragmentomics and variant allele frequency, but no patient demographics, were used to train the classification model. Probability cutoffs were applied to pathogenic SVs and validated for accuracy from paired BC (658) and reproducibility using LBx replicates. Results: VOP made accurate best call predictions (&amp;gt;50% probability cutoff) for pathogenic SVs across all origin types, with high sensitivity and high positive predictive value of tumor and CH (PPA &amp;gt; 93%, PPV &amp;gt; 91%). Critically, VOP performs well for SVs with VAFs ≤ 1% (PPV &amp;gt; 90%), as well as in genes known to harbor both CH and tumor-somatic SVs, such as TP53 (PPV &amp;gt; 88%). For a use case requiring higher confidence in tumor origin, an 80% tumor cutoff maintained high PPA (90%) while increasing PPV overall (99%), including low VAF and TP53 SVs (PPV &amp;gt; 96%). These cutoffs were assessed in 31 unique samples across 546 replicates and showed high reproducibility (Table). Conclusion: VOP is a highly accurate and reproducible method to predict the origin of SVs from LBx alone. VOP performs well even when VAF ≤ 1% and in heavily confounded genes such as TP53. Increased confidence in variant origin is valuable for improving clinical care. Citation Format: Derek W. Brown, Alexander D. Fine, Daokun Sun, Hanna Tukachinsky, Michael McDevitt, Kerriann Pontbriand, Eliana Polisecki, Angela Kou, Mingyue Li, Shumeng Zhang, Zheng Kuang, Aparna Aiyer, Bahar Yilmazel, Brennan Decker, Jason Hughes, Chang Xu. Variant Origin Prediction (VOP) determines the tumor-somatic, germline, or clonal hematopoiesis (CH) origin of short variants (SVs) detected in liquid biopsy (LBx) [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 1959.
Abstract 5208: The use of human small intestinal organoids as a preclinical screening tool to assess gastrointestinal toxicity induced by CDK inhibition
Authors: Frida Ponthan, Thomas Kedward, Valentina Ubertini, Gary Beale, Cath Booth
Journal: Cancer Research (2025)

Dysregulated cell division is one of the most important hallmarks of cancer. Cyclindependent kinases (CDKs), involved in cell cycle regulation, have been identified to be overexpressed in many cancers. The development of CDK inhibitors has emerged as a promising and novel approach for cancer treatment in both solid and hematological malignancies. However, first generation pan-CDKIs, which initially showed reliable results in vitro and in Phase I trials, lacked selectivity. Many were discontinued due to adverse effects, including Gastrointestinal (GI) toxicity, and reduced efficacy in vivo. The development of specific CDKIs, which can provide optimum therapeutic outcomes with good efficacy and reduced off-target effects are therefore needed. In this study, we have used a human small intestinal organoid model (adapted from Sato et al. 2009), as a screening tool to predict GI toxicity and subsequent mucosal regeneration. The culture conditions have been designed to mimic the stem cell niche and allow cell differentiation and proliferation to occur. All intestinal lineages were present in the organoids and resembled the frequency of linage observed in vivo. The effect of several clinically available CDKIs, such as Dinaciclib, Palbociclib and Abemaciclib, some of them known to induce GI toxicity were assessed. Treatment was applied on Day 3 after plating of fragments, when the organoid structures had formed. On Day 5, the number of dead, viable unbranched and branched organoids were counted and IC50 values were calculated. Furthermore, morphometric analysis of acquired images were performed. To compare the toxicity profiles on a molecular level, organoids were harvested for RNA-seq. The second generation pan-CDK inhibitor Dinaciclib was the most toxic. Whereas Palbociclib was the least toxic compound within the human organoid assay, reflecting clinical data that shows the lowest incidence of severe diarrhea. We conclude that organoids are a predictive preclinical model that can be used to identify potential on-target, off-tissue GI toxicities induced by novel therapeutics such as CDKIs. Toxicity and mechanism of action (MOA) can all be addressed in vitro to potentially reduce in vivo experimentation. Citation Format: Frida Ponthan, Thomas Kedward, Valentina Ubertini, Gary Beale, Cath Booth. The use of human small intestinal organoids as a preclinical screening tool to assess gastrointestinal toxicity induced by CDK inhibition [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 5208.