tbuckley/cabot-search huggingface dataset:
Abstract 2734: RC148, a novel bispecific antibody targeting PD-1 and VEGF for cancer immunotherapy
Authors: Jianmin Fang, Dong Li, Kaiyue Wu, Sisi Wang, Du Li, Guorui Zhao, Shenjun Li, Jing Jiang
Journal: Cancer Research (2024)

Abstract Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors in modulating tumor microenvironment (TME), and the concentration of VEGF in TME is significantly higher than that of peripheral. Inhibiting VEGF can improve immunotherapy efficacy by modulating the TME, preventing angiogenesis and regulating immune cell populations. Combined anti-VEGF and anti-Programmed cell death protein 1 (PD-1)/Programmed cell death ligand (PD-L1) therapies have exerted potent antitumor effect in preclinic and clinic studies. Therefore, we developed a novel humanized IgG1 silenced bispecific antibody RC148 to target VEGF and PD-1. RC148 allows dimeric VEGF crosslinking and gradually enhances PD-1 binding activity, potentially reduces systemic toxicity of anti-VEGF therapy and enhances antitumor potency via VEGF trigged enrichment in tumor areas. In preclinical studies, RC148 blocks the binding of VEGF to VEGFR and PD-1 to PD-L1, prevents the growth and migration of human umbilical vein endothelial cells, enables efficient T cell activation, exhibited synergistic antitumor effects in rodent models and showed safety profiles in non-human primate studies. Citation Format: Jianmin Fang, Dong Li, Kaiyue Wu, Sisi Wang, Du Li, Guorui Zhao, Shenjun Li, Jing Jiang. RC148, a novel bispecific antibody targeting PD-1 and VEGF for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2734.
Abstract 14: Identification of tumor-reactive T cell receptors through functional single cell interaction analyses for personalized T cell therapy
Authors: Tim Robin Wagner, Niklas Kehl, Simon Steiger, Michael Kilian, Bruno Schönfelder, Tamara Boschert, Katharina Lindner, Patrick Schmidt, Karsten Rippe, Hartmut Goldschmidt, Marc-Steffen Raab, Michael Platten, Mirco Friedrich, Stefan B. Eichmüller
Journal: Cancer Research (2024)

Abstract Innovative immunotherapy approaches such as adoptive transfer of chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes (TILs) have shown great success in the treatment of solid tumors and hematological malignancies. Although treatment of multiple myeloma with CAR T cells can induce deep responses, relapses frequently occur due to antigen escape and limited CAR T cell persistence. TCR-engineered T cells may show prolonged persistence in vivo and could mediate sustained antitumor effects. A further benefit of TCR transgenic T cells is the ability to target intracellular antigens that are inaccessible to CAR T cells, expanding the range of potential targets for immunotherapy. In our project, we propose to identify T cell receptors (TCRs) specifically targeting autologous myeloma cells. Tumor-reactive T cells were identified using the Bruker Cellular Analysis Lightning® platform, allowing simultaneous functional analysis of up to 1500 individual T cell/target cell interactions on a chip. Reactive T cells were identified upon detection of secreted cytokines (IFNγ, TNFα, IL2) and measurement of 4-1BB (CD137) surface expression. Tumor-reactive T cells showing various cytokine secretion patterns and 4-1BB expression profiles were detected in each myeloma patient (on average 11.9 T cells out of 1243 cells tested per assay run). Individual tumor-reactive T cells have been isolated and their TCRs were sequenced. TCR sequences of tumor-reactive T cells were mapped to single-cell RNA sequencing data of T cells from the same patiens to reveal a gene expression signature of myeloma-reactive T cells. TCR genes of reactive T cells were cloned and overexpressed in autologous T cells for functional validation and analysis of tumor derived neoepitope specificity. In summary, we present a pipeline allowing identification of myeloma-recognizing T cells and recovery of bona fide tumor-reactive TCRs eligible for patient-individualized T cell therapy. Citation Format: Tim Robin Wagner, Niklas Kehl, Simon Steiger, Michael Kilian, Bruno Schönfelder, Tamara Boschert, Katharina Lindner, Patrick Schmidt, Karsten Rippe, Hartmut Goldschmidt, Marc-Steffen Raab, Michael Platten, Mirco Friedrich, Stefan B. Eichmüller. Identification of tumor-reactive T cell receptors through functional single cell interaction analyses for personalized T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 14.
Abstract 3032: Generation of a FOXC2-deficient melanoma cell line using CRISPR-Cas9 gene editing
Authors: Devanand M. Clark, Patrick D. Conde, Kristian M. Hargadon
Journal: Cancer Research (2024)

Abstract Melanoma, a cancer derived from pigment-producing melanocytes of the skin, is a highly aggressive cancer characterized by rapid growth and metastasis. FOXC2 is a forkhead box transcription factor family member that is often dysregulated in various cancers, including melanoma, where its expression correlates with metastatic progression and drug resistance. To gain insight into the oncogenic activity of FOXC2 in melanoma, we have employed CRISPR-Cas9 gene editing technology to generate a novel FOXC2-deficient B16-F10 murine melanoma cell line. This model will be a useful tool for studying the tumor-promoting functions of FOXC2. Citation Format: Devanand M. Clark, Patrick D. Conde, Kristian M. Hargadon. Generation of a FOXC2-deficient melanoma cell line using CRISPR-Cas9 gene editing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3032.
Abstract 3324: Discovery of a novel SOS1 inhibitor, AIG01012, targeting pan-KRAS mutant cancers
Authors: Jihye Kim, Sejeong Park, Sunkyu Kim, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee
Journal: Cancer Research (2024)

Abstract Targeting the SOS1-KRAS interaction represents a pivotal strategy in mitigating aberrant KRAS signaling, which is implicated in numerous malignancies. At AIGEN Sciences, Inc., we have harnessed an advanced human-in-the-loop (HITL) AI-based drug discovery platform (AIGEN ChemTailor). This innovative platform allows online learning through expert feedback, optimizing our drug development endeavors. We designed a potent SOS1 inhibitor, AIG01012 using AIGEN ChemTailor in combination with fragment-based drug discovery (FBDD) and molecular modeling techniques. We conceived numerous compounds and shortlisted the leading candidates for extensive testing after meticulous computer simulations. AIG01012 manifested substantial inhibitory effects against several KRAS mutant interactions with SOS1, specifically SOS1-KRAS WT, SOS1-KRAS G12C, SOS1-KRAS G12D, SOS1-KRAS G12V, and SOS1-KRAS G13D. However, its inhibitory capacity did not extend to the SOS2-KRAS G12C interaction. AIG01012 demonstrated remarkable inhibitory effects in 3D cell proliferation assays across various cell lines, including H358, MIA-PaCa2, SW837, AsPC-1, A427, SW620, Capan-2, A549, DLD-1, MKN-1, and H1666. Moreover, AIG01012 showed synergistic antiproliferative effects when combined with approved drugs such as sotorasib (for lung cancer with KRAS mutations), trametinib (a MEK inhibitor), and Osimertinib (targets specific EGFR mutations) in either H358 or PC-9 cell lines. Mouse studies further confirmed its favorable pharmacological properties, and its efficacy was evaluated in subsequent mouse tumor model. In summary, utilizing our human-in-the-loop (HITL) AI platform, AIGEN ChemTailor, we have efficiently derived AIG01012 as a potent SOS1 inhibitor that targets a wide range of KRAS interactions. With its notable in vitro and in vivo outcomes, AIG01012 is set for further exploration and prospective clinical trials as a significant contender in KRAS-targeted cancer treatments. Citation Format: Jihye Kim, Sejeong Park, Sunkyu Kim, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee. Discovery of a novel SOS1 inhibitor, AIG01012, targeting pan-KRAS mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3324.
Abstract 7180: Tumor growth modeling to support dose justification of Dato-DXd in hormone receptor positive, HER2 negative breast cancer (HR+HER2-BC) subjects
Authors: Zoey Tang, Yu Jiang, Haitao Yang, David Dai, Chang Gong, Linda Irons, Yuzhuo Pan, Ying Hong, Shuang Liang, Song Ren, Alex Phipps, Diansong Zhou
Journal: Cancer Research (2024)

Abstract BACKGROUND: Dato-DXd, a TROP2-directed antibody-drug conjugate, has demonstrated efficacy and a manageable safety profile in multiple tumor types. A dosing regimen of 6 mg/kg every three weeks (Q3W) has been proposed as the optimal schedule based on phase I data in patients with non-small cell lung cancer (NSCLC)1. Dato-DXd demonstrated statistically significant and clinically meaningful improvement in PFS compared with ICC in patients with HR+HER2-BC in TROPION-Breast012. A tumor growth inhibition (TGI) model was developed to support dose justification at 6 mg/kg in HR+HER2-BC subjects. METHODS: A tumor growth inhibition (TGI) model was developed based on tumor size data from HR+HER2-BC patients received 6 mg/kg Dato-DXd Q3W in a Phase I study (N = 39, Data cutoff July 2022). The TGI model described the tumor size as the result of an exponential tumor growth, a tumor shrinkage that was driven by Dato-DXd cycle-specific AUC, and a resistance term suggesting that the shrinkage effect by Dato-DXd decreases over time. Cycle-specific Dato-DXd AUC was derived based on the AUC and time at each cycle for each individual. Simulations were conducted using the TGI model to compare tumor size change from baseline at 4, 6, and 8 mg/kg in HR+HER2-BC patients, with consideration of dropouts. RESULTS: The TGI model well-described tumor size data with reasonable parameter estimations. Simulated time-courses of tumor sizes at Dato-DXd 4, 6, and 8 mg/kg suggested that Dato-DXd at 6 mg/kg may lead to greater tumor shrinkage effect than that at 4 mg/kg in HR+/HER2-BC patients. At approximately 180 days post first treatment, tumor shrinkage at 6 mg/kg was almost 2-times greater than at 4 mg/kg (-51% vs. -25%, respectively). CONCLUSION: Simulations based on the TGI model suggested greater tumor size reduction at Dato-DXd 6 mg/kg compared to 4 mg/kg in HR+HER2-BC patient population. Reference: 1 ACoP13 2022 2 ESMO 2023. Citation Format: Zoey Tang, Yu Jiang, Haitao Yang, David Dai, Chang Gong, Linda Irons, Yuzhuo Pan, Ying Hong, Shuang Liang, Song Ren, Alex Phipps, Diansong Zhou. Tumor growth modeling to support dose justification of Dato-DXd in hormone receptor positive, HER2 negative breast cancer (HR+HER2-BC) subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7180.
Abstract 2698: TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma
Authors: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke
Journal: Cancer Research (2024)

Abstract Tissue-resident immune cells reside within the gastrointestinal tract known as intraepithelial lymphocytes (T-IELs), including αβ and γδ T-IELs. This unique population of T cells constantly survey and are critical in maintaining the gastrointestinal epithelium. We show that T-IELs in various regions of the gastrointestinal tract have distinct features. T-IELs in the small intestine exhibit high expression of cytotoxic molecules important for cancer defense while colon T-IELs are distinctively regulated by the transcription factor, TCF-7/TCF-1, which suppresses their effector and cytotoxic properties, including reduced expression of granzymes, and their abundance is dependent on the microbiome. Targeted deletion of TCF-1 in γδ T-IELs using pre-clinical mouse models resulted in a distinct effector profile and reduced colon tumor burden. Furthermore, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers compared with normal healthy colon, strongly correlating with an enhanced γδ T-IEL effector phenotype and improved patient survival. Further investigation aims to elucidate diverse mechanisms by which TCF-1 controls tissue-specific anti-tumor immunity and uncover the important factors controlling TCF-1 expression. Our study underscores the necessity to consider tumor and organ microenvironment-specific factors in optimizing immunotherapy, advancing our understanding of T cell function in the colon to pave the way for innovative CRC treatments. Citation Format: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke. TCF-1 is a critical regulator of intraepithelial lymphocytes in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2698.
Abstract 7253: Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver cancer
Authors: Chad M. Moles, Peter Weijmarshausen, Rupsa Basu, Brenda Ho, Manal Farhat, Taylor Flaat, Bruce F. Smith, Michael Whitt, Sarah E. Woodfield, Sanjeev A. Vasudevan
Journal: Cancer Research (2024)

Abstract Background: Humane Genomics is pioneering multi-factored authenticated oncolytic virotherapy (OVT) using glycoprotein receptor matching and aptazyme technology to positively control replication in cytoplasm. Using VSV as a platform the OVTs show excellent safety and remain highly lytic. Sindbis virus glycoprotein was mutated to eliminate natural infectivity and retargeted to GPC3 with a codon optimized nanobody. An aptazyme was used to regulate viral replication. As far as we are aware, this was the first report of a functional ON switch using a cancer biomarker. Methods: 293T cells were used for virus rescue and titration by TCID50. Identity was confirmed by Nanopore sequencing. We evaluated safety on off-target SK-Hep-1 and NCI-H28 cell lines, and efficacy on target HepG2 and patient derived HB17 cells. Cell health and GFP was measured at multiple timepoints up to 72 hours. Results: Safety testing of HGI498 on SK-Hep-1 (GPC3 negative) and NCI-H28 (GPC3 negative, biomarker negative) showed no virus induced cell cytopathic effects in a range of 0.01 ≤ MOI ≤1. HGI498’s efficacy testing on HepG2 and HB17 showed tumor cytotoxicity at MOI 0.01 (p&amp;lt;0.001). Endpoint dilution assay showed a 159-fold and 316-fold difference between off-target NCI-H28 and on-target HepG2 and HB17, respectively. We incorporated an optimized aptazyme with the GPC3 targeted glycoprotein (HGI572), which was similarly rescued, titered, and evaluated for selectivity. HGI572 demonstrated approximately 1000-fold higher titer on target HepG2 and HB17 cells than off-target cells. Initial in vivo MTD study shows that both HGI498 and HGI572 are well tolerated, and are currently being investigated in vivo for efficacy on Hep3B in NSG mice. HGI498 has shown no seroprevalence (in vitro) and is stable at cryostorage for a minimum of 11 months. Conclusion: We have successfully engineered a two-factor authentication enabled OVT to address an unmet need for a therapy for liver cancer. As far as we are aware, this is the first report of an ON switch using a cancer protein to control viral replication, and the ON/OFF control is the highest to date. Citation Format: Chad M. Moles, Peter Weijmarshausen, Rupsa Basu, Brenda Ho, Manal Farhat, Taylor Flaat, Bruce F. Smith, Michael Whitt, Sarah E. Woodfield, Sanjeev A. Vasudevan. Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7253.
Abstract 7169: A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions
Authors: Asli Küçükosmanoglu, Silvia I. Scoarta, Bart Westerman
Journal: Cancer Research (2024)

Abstract Purpose: Combination-therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in an real-world setting. Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Complex adverse-event frequencies of drugs or their combinations were visualized as heatmaps onto a 2D UMAP grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heatmaps. Additionally, statistical synergy analyses were performed based on BLISS independence or Chi-square testing. Results: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse-event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. Conclusion: Our study provides a framework for analyzing adverse events and suggest that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice. Citation Format: Asli Küçükosmanoglu, Silvia I. Scoarta, Bart Westerman. A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7169.
Abstract 3033: Oncogenic ETS transcription factors avoid repression by EZH2 and FOXO1 in prostate cancer and Ewing sarcoma
Authors: Nicholas F. Downing, Kaitlyn M. Mills, Peter C. Hollenhorst
Journal: Cancer Research (2024)

Abstract ETS transcription factors play roles throughout development, aiding in hematopoiesis, blood vessel formation and cell fate. The ETS family is composed of 28 members, all of which share an ETS DNA-binding domain. Chromosomal rearrangements that lead to the overexpression of specific ETS promote oncogenic transformation and tumor development. More than half of prostate tumors are driven by aberrant expression of an ETS protein. Our lab has demonstrated that oncogenic ETS form essential interactions with a ubiquitous RNA-binding protein, EWS, to promote prostate tumorigenesis. A similar mechanism exists in Ewing sarcoma (ES). ES tumors are driven by the expression EWS/ETS fusion proteins. This project focuses on the similarities and differences between oncogenic ETS in prostate cancer and EWS/ETS fusions in Ewing sarcoma. We compared biological functions of the most common oncogenic ETS in prostate cancer, ERG, and the most common fusion in ES, EWS/FLI1. Both ERG and EWS/FLI1 promoted migration and clonogenic survival in normal prostate epithelial cell lines, RWPE1 and PNT2. These data suggest that the EWS-ERG complex and EWS/FLI1 fusion protein can function similarly in prostate cells. Knockdown of endogenous EWS/FLI1 in the ES cell line, A673, reduced anchorage-independent colony formation in soft agar. Rescue with exogenous EWS/FLI1 or EWS/ERG restored colony formation relative to control. Wildtype ERG was unable to rescue colony formation in A673. This suggests that ERG and EWS/FLI1 function differently in A673 cells. Pulldown assays from A673 lysates reveal that ERG interacts with EZH2 and FOXO1. Our lab has established that ERG acts as a transcriptional repressor through the formation of an ERG-EZH2-PRC2 complex. Others demonstrate that FOXO1 represses ERG activity by reducing its recruitment to the target sites. Both the N-terminal truncation of ERG and phosphorylation of ERG at S96 disrupted these interactions and rescued anchorage independent growth in A673 ES cells. These data suggest that EWS/ETS fusions avoid transcriptional repression in Ewing tumors due to loss of the N-terminus of the ETS protein. Citation Format: Nicholas F. Downing, Kaitlyn M. Mills, Peter C. Hollenhorst. Oncogenic ETS transcription factors avoid repression by EZH2 and FOXO1 in prostate cancer and Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3033.