tbuckley/cabot-search huggingface dataset:
Abstract LB126: Shp-1 regulates the activity of low affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition
Authors: Joseph G. Matous, Andrew G. Ramstead, Krystal R. Charley, Elizabeth M. Kolawale, Jacob N. Kisiolek, Brian D. Evavold, Matthew A. Williams
Journal: Cancer Research (2025)

Abstract The presence of activated CD8 T cells in the tumor microenvironment (TME) is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominately targets high affinity T cells, which are exhaustion-prone and may be less abundant in tumors with few neoantigens. Low affinity T cells are abundant during many anti-tumor responses, and there is a need to better understand their contribution to the ICI-induced response and to determine the mechanisms controlling their activation. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1, Shp-1 (PTPN6), in combination with ICI lowers the T cell activation threshold and enhances the ability of low affinity T cells to mount a productive anti-tumor response. In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice, as the resulting tumors are ICI-resistant and lack abundant neo-antigens. Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector (PD-1+ Gzb+ Tbet+) and reduced exhaustion characteristics (2b4+ PD-1+). In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2180-188. We utilized a micropipette-based 2D affinity assay to measure the T cell receptor (TCR) affinity of TRP-2-specific T cells in the tumor following treatment. We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity. We conclude that approaches for altering TCR signaling threshold are effective in enhancing the anti-tumor response of low affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neo-antigens are not available to drive anti-tumor responses. Citation Format: Joseph G. Matous, Andrew G. Ramstead, Krystal R. Charley, Elizabeth M. Kolawale, Jacob N. Kisiolek, Brian D. Evavold, Matthew A. Williams. Shp-1 regulates the activity of low affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition [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 LB126.
Abstract LB156: Early mutation-mediated detection of cancers via biomarker production
Authors: Shengyue Piao, Miller Harris, Kevin McHugh
Journal: Cancer Research (2025)

Abstract Background: Cancer remains one of the leading causes of mortality worldwide, with early detection pivotal to improving patient outcomes. Current diagnostic methods often lack the sensitivity and specificity to identify cancers at their earliest stages, especially for KRAS-driven cancers such as pancreatic cancer and non-small cell lung cancer (NSCLC). This challenge is further exacerbated for high-risk populations, where invasive biopsies, imaging, or endogenous biomarkers fail to meet clinical needs. There is a critical need for non-invasive, reliable, and continuous cancer detection methods capable of diagnosing tumors at nascent stages. To address this, we developed a mutation-mediated synthetic biomarker-based blood test specifically targeting early-stage cancers with KRAS G12 mutations. This study evaluates its performance in detecting KRAS-driven cancers using synthetic biomarkers and controls. Methods: A CRISPR-based gene editing system was designed to insert synthetic biomarker genes, such as Gaussia luciferase (GLuc), into cancer cells harboring KRAS G12 mutations. Using Gibson assembly, we constructed a donor plasmid carrying the GLuc gene alongside a plasmid encoding Cas9 VQR and sgRNA targeting the KRAS G12V locus. These plasmids were co-transfected into NCI-H727 human lung tumor cells. Single-cell sorting yielded 29 clonal lines with stable GLuc expression. Sequencing confirmed precise knock-in at the KRAS G12V target in 21 lines, with qPCR verifying exclusive insertion. GLuc secretion was measured via luciferase assays, and limits of detection (LOD) were assessed in vitro. To test biomarker detection in vivo, GLuc-expressing tumor cells were inoculated into SCID/NOD mice at varying numbers. Serum GLuc levels were measured using luciferase assays at defined time points. Results: In vitro, the LOD for GLuc-expressing cancer cells was 5,775 cells/mL. In vivo, SCID/NOD mice injected with GLuc-expressing tumor cells showed time-dependent increases in serum luminescence. Two weeks post-inoculation with 106 cells, serum luminescence in the experimental group was 8.24-fold higher than controls (8.24 ± 0.32), with a tumor lesion size of 29.86 ± 7.26 mm3. Conclusion: This mutation-mediated synthetic biomarker platform detected tumor lesions as small as millimeter-scale in vivo with high sensitivity and specificity after a single injection. Its non-invasive, scalable design offers the potential to transform early detection and monitoring of KRAS-driven cancers, addressing critical unmet needs for high-risk populations. Citation Format: Shengyue Piao, Miller Harris, Kevin McHugh. Early mutation-mediated detection of cancers via biomarker production [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 LB156.
Abstract LB083: Decoding systemic circadian regulation across multi-tissues in response to tumor stress
Authors: Chuqian Liang, Zunpeng Liu, Tao Zhang, Qi Zhang, Bingqiu Xiu, Gongwei Wu, Stuart Benjamin Fass, Li-Lun Ho, Manolis Kellis, Myles A. Brown
Journal: Cancer Research (2025)

Abstract Emerging evidence suggests that tumors produce molecular signals to subvert and perturb circadian-regulated immune system functions. Elucidating the mechanisms of tumor-mediated circadian disruption will promote the development of new therapies targeting tumor remote regulatory abilities. Claudins, the structural backbone of tight junctions (TJs), play a pivotal role in tumor progression, metastasis, stemness, chemotherapy resistance, and crosstalk with signaling pathways in breast cancer, making them potential biomarkers for detection, diagnosis, and treatment. To explore how tumors remotely govern immune responses across tissues in a circadian manner in triple-negative breast cancer (TNBC), we generate a diurnal transcriptome in high (4T1) and low (E0771) claudin TNBC mouse models. We generated 528 transcriptomes from liver, spleen, thymus, bone marrow, PBMC, adjacent fat pad, distal fat pad, and control mammary fat pad, at four time points within a 24-hour cycle to understand tissue-wide and cell-type-specific responses to tumor stress. We found that tumor stress impacts gene expression across tissues. Key pathways are dysregulated in response to tumor stress irrespective of claudin levels, with upregulation in immune response and cell cycle regulation, and downregulation in metabolic pathways (DNA, lipid, monocarboxylic acid, and amino acid metabolism) across multiple tissues and tumor models. Rhythmicity analysis revealed that tumor stress-responsive tissues such as the spleen in 4T1 models and the thymus in E0771 models, exhibited shifts in circadian gene expression in tumor-bearing groups, with an increase in circadian-enhanced genes during the night. Our results suggest that tumor stress alters circadian gene regulation across tissues, triggering remote, cross-tissue interactions that disrupt tissue-specific functions in a coordinated, circadian-dependent manner. Citation Format: Chuqian Liang, Zunpeng Liu, Tao Zhang, Qi Zhang, Bingqiu Xiu, Gongwei Wu, Stuart Benjamin Fass, Li-Lun Ho, Manolis Kellis, Myles A. Brown. Decoding systemic circadian regulation across multi-tissues in response to tumor stress [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 LB083.
Abstract CT253: HERIZON-BTC-302: A phase 3 trial of zanidatamab with standard-of-care therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer
Authors: James J. Harding, Teresa Macarulla, Xiaotian Wu, Phillip M. Garfin, Takuji Okusaka, Shubham Pant
Journal: Cancer Research (2025)

Abstract Background: Zanidatamab, a dual HER2-targeted bispecific antibody, received accelerated approval from the United States Food and Drug Administration for adults with previously treated, unresectable, or metastatic HER2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer (BTC) based on the results from the single-arm, phase 2 HERIZON-BTC-01 trial. This phase 3 trial is assessing zanidatamab plus standard-of-care (SOC) therapy vs SOC alone for the first-line treatment of patients with HER2-positive advanced/metastatic BTC. Methods: This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced/metastatic HER2-positive BTC. HER2-positive BTC is defined by an IHC score of 3+ or an IHC score of 2+ with HER2 gene amplification by in situ hybridization. Additional eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic BTC and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer &amp;gt;5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight &amp;lt;70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD-1/L1 inhibitor or CisGem alone ± a PD-1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The trial is currently recruiting patients. Citation Format: James J. Harding, Teresa Macarulla, Xiaotian Wu, Phillip M. Garfin, Takuji Okusaka, Shubham Pant. HERIZON-BTC-302: A phase 3 trial of zanidatamab with standard-of-care therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer [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 CT253.
Abstract LB009: Safety profile assessment for IND-enabling studies: Bispecific antibodies and antibody-drug conjugates (ADCs)
Authors: Laura Ratcliffe, Sophie Vermond, Sophie Hill, Sabrina de Munnik, Gijs van Puijvelde, Benita Quist, Rachel Pooley, Katherine Carr, Nick Brown, Mark Aspinall-O'Dea, Ludovico Buti, Namrata Jayanth
Journal: Cancer Research (2025)

Abstract Developing antibody-based therapeutics requires balancing potency and safety. Off-target effects can cause adverse events, necessitating precise target engagement and comprehensive safety profiling during early development. The work presented outlines a systematic approach to identify and mitigate off-target interactions for antibodies and ADCs. This de-risking roadmap which spans 12-16 weeks, evaluates on-target and off-target interactions, ensuring thorough vetting before IND-enabling studies. The de-risking platform uses two primary approaches: (1) Off-target analysis via Retrogenix® Cell Microarray Technology (2) Off-target liability evaluation in human primary tissue cells. The Retrogenix® Cell Microarray Platform is a unique platform that screens over 6,500 human plasma membrane and secreted proteins expressed in HEK cells, providing comprehensive primary and off-target binding analysis. Widely used in regulatory submissions, it helps identify suitable leads and derisk biologics. Analysis of screens from over 300 molecules showed ∼50% had at least one off-target binding, highlighting the importance of early screening. In vitro safety profiling in human primary tissue cells, comprise of robust assays to evaluate off-target liabilities, where the biologics are tested for effects on cell viability and cytokine release using over 70 optimized human primary and iPSC-derived cell types. These assays investigate: (1) Off-target liabilities from Retrogenix® screens in relevant primary cells (2) On-target liabilities from target antigen expression in normal tissues (3) Safety profiles using human tissue cells when animal models are unavailable. The integrated approach to off-target analysis and safety profiling presented provides crucial insights for IND-enabling studies, facilitating safer, more effective antibody-based therapeutics development. Citation Format: Laura Ratcliffe, Sophie Vermond, Sophie Hill, Sabrina de Munnik, Gijs van Puijvelde, Benita Quist, Rachel Pooley, Katherine Carr, Nick Brown, Mark Aspinall-O'Dea, Ludovico Buti, Namrata Jayanth. Safety profile assessment for IND-enabling studies: Bispecific antibodies and antibody-drug conjugates (ADCs) [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 LB009.
Abstract LB105: Integrated molecular profiling of pediatric brain tumors: Insights into subtypes and biomarker discovery
Authors: Sonali Arora, Nicholas Nuechterlein, Matt Jensen, Gregory Glatzer, Srinidhi Varadharajan, Stephen Mack, Philipp Sievers, Andrey Korshunov, Felix Sahm, Michael Taylor, Eric Holland
Journal: Cancer Research (2025)

Abstract Introduction: Medulloblastoma and ependymoma are common pediatric brain tumors, characterized by considerable molecular and clinical diversity. To create a comprehensive reference for these tumors, we gathered bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma samples. Approach: After correcting for batch effects, normalizing the data, and performing dimensionality reduction and clustering, we developed a unified landscape to analyze gene expression, signaling pathways, gene fusions, and copy number alterations. The observed UMAP clusters were validated with known gene expression, known copy number alterations, and known gene fusions from the literature for each subtype. Results: Our findings revealed distinct clustering patterns, such as two major ependymoma subgroups, EPN-E1 and EPN-E2, each with unique molecular features and gene fusions. In medulloblastoma, we achieved precise categorization of Group 3/4 tumors by subtype, and of SHH tumors based on patient age. Both known gene expression patterns and novel pathways identified by our bulk RNA-seq landscape were validated using single-cell transcriptomics in medulloblastoma patients. Additionally, we developed a pipeline that lands uncharacterized tumor samples onto the landscape, enabling the prediction of their subtype. Conclusion: This landscape offers a critical resource for discovering biomarkers, enhancing diagnoses, and allows the mapping of new patient RNA-seq data onto the reference framework to ensure accurate subtype classification. The landscape is available on Oncoscape, an interactive platform, which supports global access and exploration. Citation Format: Sonali Arora, Nicholas Nuechterlein, Matt Jensen, Gregory Glatzer, Srinidhi Varadharajan, Stephen Mack, Philipp Sievers, Andrey Korshunov, Felix Sahm, Michael Taylor, Eric Holland. Integrated molecular profiling of pediatric brain tumors: Insights into subtypes and biomarker discovery [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 LB105.
Abstract LB031: A modular framework for cell and gene therapy assessment in preclinical mouse models
Authors: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Iris Nkamba, Sébastien Tabruyn, Dan Georgess
Journal: Cancer Research (2025)

Abstract The development of cell and gene therapies (CGTs) and biologics relies on designing custom preclinical strategies that provide high-confidence data using predictive animal models. To help investigators navigate navigating the increasingly complex and customizable preclinical landscape, we present a modular design framework for the preclinical evaluation of oncology therapies using traditional and next-generation mouse models. This guide illustrates how investigational requirements specific to each therapeutic candidate influence the selection of model features, including tumor characteristics (such as indication, markers, and engraftment site), immune system status (immunodeficient, immunocompetent, humanized), and compatible readouts. Through a series of proof-of-concept studies, we demonstrate optimal strategies for evaluating persistence, biodistribution, efficacy, safety, and in vivo mechanisms of action of various CGTs such as extracellular vesicles, CAR-NKs, TCR-Ts, and CAR-Ts in autologous and allogeneic settings. The dissemination of such expertise-based frameworks coupled with the increased availability and affordability of custom and/or humanized immune system mice, is poised to mitigate drug candidate attrition in oncology clinical trials. Modularity of the disease feature in this framework, e.g. swapping the tumor for infectious or inflammatory agent, further expands it impact to immuno-inflammatory and infectious disease areas. Citation Format: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Iris Nkamba, Sébastien Tabruyn, Dan Georgess. A modular framework for cell and gene therapy assessment in preclinical mouse models [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 LB031.
Abstract LB036: TIGIT blockade promotes intratumoral Treg cells with less suppressive and more effector-like phenotype to support antitumor responses
Authors: Eugene Chiang, Ellen Duong, Karl Banta, Sunny Wu, Thomas Wu, Katie Nutsch, Lili Adams, Stephanie Mittman, Yan Qu, Ira Mellman
Journal: Cancer Research (2025)

Abstract Therapeutic checkpoint blockade of TIGIT (T cell immunoreceptor with Ig and ITIM domains) in combination with PD-1/PD-L1 pathway blockade has been shown to eradicate large established tumors in preclinical mouse models by enhancing anti-tumor cytotoxic CD8+ T cell responses. In addition to CD8+ T cells, TIGIT is also expressed on other immune cells, with particularly high expression on immunosuppressive regulatory T (Treg) cells. Here, we explored the functional consequences of TIGIT blockade on Treg cells in syngeneic mouse tumor models. In contrast to treatment with Fc-active anti-CTLA-4 which significantly reduced Treg cell frequencies and numbers in tumors, Treg cells were modestly reduced or even increase in tumors with Fc-active anti-TIGIT, indicating that anti-TIGIT was not driving depletion of the bulk Treg cell population. Treg cells had reduced suppressive characteristics and increased effector-like properties, suggesting modulation of the Treg cell phenotype by TIGIT blockade. This effect on Treg cell phenotype was dependent on Fc competency of the anti-TIGIT antibody as well as CD226, the activating counterreceptor to TIGIT. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) demonstrated that anti-TIGIT altered the epigenetic and transcriptional regulatory programs involved in generation and maintenance of suppressive Treg cells. Single-cell RNA sequencing (scRNAseq) revealed four distinct Treg cell clusters and provided resolution of the gene expression shifts away from suppressive function mediated by anti-TIGIT. Our data demonstrate that co-blockade of TIGIT and PD-1 reprograms Treg cells from a pro-tumor immunosuppressive phenotype to an anti-tumor effector-like cell that participates in the response against tumors. Citation Format: Eugene Chiang, Ellen Duong, Karl Banta, Sunny Wu, Thomas Wu, Katie Nutsch, Lili Adams, Stephanie Mittman, Yan Qu, Ira Mellman. TIGIT blockade promotes intratumoral Treg cells with less suppressive and more effector-like phenotype to support antitumor responses [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 LB036.