bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2449: Case report: DETECT-A participants with pre-malignant conditions
Authors: Choudhry Omair A. , Kharge Angana , Rego Seema P. , Elias Paul Z. , Buchanan Adam H. , Lennon Anne Marie , Papadopoulos Nickolas , Diehl Frank , Beer Tomasz M. 
Published: March 2024

Abstract
Background: Blood based tests for multi-cancer early detection (MCED) are being developed to facilitate the earlier detection of various cancer types. The Detecting cancers Earlier Through Elective mutation-based blood Collection and Testing (DETECT-A) study evaluated the CancerSEEK MCED test, an early version of the Exact Sciences MCED test in development, in 9,911 women, age 65-75, without previous history of cancer (Lennon et al., Science 2020). The degree to which MCED testing will facilitate detection of precancerous conditions or incidental findings is unclear. Here we focus on DETECT-A participants who had pre-cancerous conditions diagnosed during a diagnostic work-up for a positive CancerSEEK MCED test.
Methods: In a post-hoc analysis, we report on the detection of precancerous conditions consequent to CancerSEEK MCED testing and follow-up. Electronic health records were reviewed for diagnostic procedures performed, details of premalignant and cancer diagnoses, and vital status.
Results: In three individuals, mutations in PIK3CA, TP53, or KRAS genes led to a positive CancerSEEK MCED test result. The prescribed imaging protocol using 2-deoxy-2[fluorine-18] fluoro-D-glucose positron emission tomography-computed tomography (18-FDG PET-CT), revealed a 10.3 × 9.8 × 7.8(cm) ovarian mucinous cystadenoma, a 0.8 cm appendiceal mucinous neoplasm, and 3 colonic polyps displaying high-grade dysplasia. All three participants were diagnosed with clinically significant pre-cancerous lesions, subsequently underwent surgical treatment, and remain alive and cancer-free as of February 2023 (Table 1).
Conclusion: The diagnostic evaluation of a positive MCED test may occasionally reveal clinically significant pre-cancerous conditions amenable to interventions. The frequency of such findings and their clinical impact warrants further study.
Citation Format: Omair A. Choudhry, Angana Kharge, Seema P. Rego, Paul Z. Elias, Adam H. Buchanan, Anne Marie Lennon, Nickolas Papadopoulos, Frank Diehl, Tomasz M. Beer. Case report: DETECT-A participants with pre-malignant conditions [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 2449.
Abstract 2460: Receptor antibody conjugated engager (RACE): A novel bispecific 4-1BB engager platform for enhanced immuno-oncology therapy
Authors: Lee DaeHee , Yoon Jihye , Jeong Jonggwan , Bak Jeonghyeon , Son KkaBi , Kim Heechan , Jang Seil , Kim Minseok S. 
Published: March 2024

Abstract
Background: Traditional immuno-oncology strategies, such as checkpoint blockade therapy, are evolving to immune cell engagers as a smarter strategy. The early successes of Blincyto, a CD3 engager, demonstrated its capacity to activate host pan-T cells irrespective of their TCR-pMHC restriction status. However, this broad activation has been linked to off-target immunotoxicities, thus limiting its therapeutic applicability. In response, targeting immune co-stimulatory receptors like CD28 or 4-1BB has gained attention by their expression being induced on activated immune effector cells, presenting a more targeted approach to cancer therapy.
Methods: We developed RACE, a novel bispecific 4-1BB engager. This platform fuses a 4-1BB ligand (4-1BBL) trimer with antibody F(ab’)2 fragments, excluding Fc domains. A Key and lock design on the 4-1BBL trimer interface facilitates asymmetric assembly of 4-1BBL dimer and monomer in the endoplasmic reticulum, achieving over 95% assembly efficiency in mammalian systems.
Results: RACE differs from conventional 4-1BB agonistic antibodies in its ability to form natural hexagonal hyper-clusters of 4-1BB receptors, enhancing NF-κB signal transduction. Unlike first-generation 4-1BB antibodies, which incurred off-tumor hepatotoxicity, RACE selectively activates 4-1BB receptors only in the presence of tumor antigens. Enhanced cytotoxicity requires successful TCR signaling complex formation between T cells and cancer cells. In CT26 and MC38 tumor models, RACE not only induced strong anti-tumor effects without hepatic or systemic toxicities but showed synergistic efficacy with anti-PD-1 antibodies as well.
Conclusion: The novel RACE platform represents a potent as well as safe immuno-oncology strategy, demonstrating significant potential for clinical application.
Citation Format: DaeHee Lee, Jihye Yoon, Jonggwan Jeong, Jeonghyeon Bak, KkaBi Son, Heechan Kim, Seil Jang, Minseok S. Kim. Receptor antibody conjugated engager (RACE): A novel bispecific 4-1BB engager platform for enhanced immuno-oncology 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 2460.
Abstract 2474: Antitumoral efficacy of ASKG812, a Smartkine® based bifunctional PD-1-eIL-2 molecule, through enhancing T effector cis agonism
Authors: Yu Chunxiao , Shanebeck Kurt , Yu Shiguang , Ruiz Jeanine , Li Shichang , Shi Stone D.-H , Ma Hong , Lu Yuefeng 
Published: March 2024

Abstract
Cytokines are potent molecules, yet their broad application as therapeutics has been significantly hampered due to short PK, severe systemic toxicity, and narrow therapeutic window. To improve the developability of cytokines, AskGene has invented a proprietary cytokine platform (Smartkine®) to achieve its overarching objective of modulating immune reactions at a disease site in a selective and controlled manner. Several antibody-cytokine fusion molecules using the SmartKine® platform have been moving into preclinical and clinical development. ASKG812 is a unique fusion molecule composed of anti-PD-1 antibody and engineered IL-2 (eIL-2). The eIL-2 moiety also comprises a specific mask such that the eIL-2 molecule binding biases towards PD-1+ T effector cells in a cis agonism manner for improved efficacy and therapeutic window. In ex vivo human PBMC assays, we demonstrated that ASKG812 significantly reduced activity in PD-1− T and NK cells, and enhanced activity in PD-1+ T cells judged by levels of pSTAT5, Ki67 and Granzyme B. In a cytotoxicity assay, ASKG812 can efficiently induce PBMC-mediated killing of MDA-MB-231 tumor cells in a dose-dependent manner. Moreover, in both anti-PD-1 therapy responsive and non-responsive syngeneic mouse tumor models, ASKG812 showed robust efficacy; without noticeable toxicity compared to a reference anti-PD-1-IL-2v fusion molecule. In conclusion, these findings provide the basis for the development of this new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the clinical treatment of cancer.
Citation Format: Chunxiao Yu, Kurt Shanebeck, Shiguang Yu, Jeanine Ruiz, Shichang Li, Stone D.-H Shi, Hong Ma, Yuefeng Lu. Antitumoral efficacy of ASKG812, a Smartkine® based bifunctional PD-1-eIL-2 molecule, through enhancing T effector cis agonism [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 2474.
Abstract 2487: KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma
Authors: Budczies Jan , Romanovsky Eva , Kirchner Martina , Neumann Olaf , Blasi Miriam , Schnorbach Johannes , Shah Rajiv , Bozorgmehr Farastuk , Savai Rajkumar , Stiewe Thorsten , Peters Solange , Schirmacher Peter , Michael Thomas , Kazdal Daniel , Christopoulos Petros , Stenzinger Albrecht 
Published: March 2024

Abstract
PD-L1 protein expression is the most important predictive biomarker for immune checkpoint inhibition (ICI) in advanced non-small cell lung cancer (NSCLC), but has limited sensitivity and specificity. We analyzed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas of the Thoraxklinik Heidelberg who were negative for actionable EGFR and ALK/RET/ROS1 alterations. Two external cohorts of patients treated with immunotherapy (SU2C-ICI: n=247, MSK-ICI: n=135) and two external cohorts of surgical early stage patients were additionally analyzed (TCGA-LUAD: n=417, MSK-LUAD: n=394). Therapy benefit was assessed stratified by KRAS and TP53 mutations. RNA-Seq data of TCGA were analyzed to reveal the molecular characteristics of KRASmut/TP53mut tumors. Analyzing overall survival, an interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses (HR=0.56, p=0.0044 and HR=0.53, p=0.0021). KRASmut/TP53muts tumors performed better than tumors not harboring the dual mutation configuration (HR=0.71, CI 0.55-0.92). This observation could be confirmed in the external cohorts of immunotherapy patients (SU2C-ICI: HR=0.54, CI 0.28-1.03 and MSK-ICI: HR=0.35, CI 0.14-0.88), whereas KRASmut/TP53mut was not associated with prolonged survival in the surgical cohorts. Tumor mutational burden, proliferation (measured by TOP2A mRNA expression), and PD-L1 mRNA were significantly higher in TP53mut compared with TP53wt tumors, regardless of KRAS status. Genome-wide mRNA expression analysis revealed 64 genes including the chemokine CX3CL1 (fractalkine) as specific transcriptomic characteristic of KRASmut/TP53mut tumors. In summary, KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumor features. Further validation studies are warranted. Mutation testing of the two genes can be easily implemented using small gene panels or even single gene analyses.
Citation Format: Jan Budczies, Eva Romanovsky, Martina Kirchner, Olaf Neumann, Miriam Blasi, Johannes Schnorbach, Rajiv Shah, Farastuk Bozorgmehr, Rajkumar Savai, Thorsten Stiewe, Solange Peters, Peter Schirmacher, Thomas Michael, Daniel Kazdal, Petros Christopoulos, Albrecht Stenzinger. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma [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 2487.
Abstract 2497: Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for disease monitoring in patients with pancreatic ductal adenocarcinoma
Authors: Halder Kuntal , Jameson Gayle , Borazanci Erkut , Lin Wei , Cridebring Dereck , Von Hoff Daniel , Han Haiyong 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge in the realm of oncology, characterized by its aggressive nature and resistance to treatment. Several therapeutic regimens have been shown to extend patient survival, but the majority of the patients become refractory to the treatments in a short period of time. Hence, it is critical to monitor a patient’s response to treatment in a timely manner so that different treatment regimens can be considered promptly. Currently, CA19-9 is the most common blood-based marker being used to monitor disease burden in patients with PDAC. However, 15-20% of patients with PDAC do not have elevated blood CA19-9 levels. In this study, we sought to determine the utility of two circulating extracellular vesicle (EV) based protein biomarkers, ALPPL2 (Alkaline phosphatase, placental-like 2) and THBS2 (Thrombospondin 2), for disease monitoring in patients with PDAC. We first established and optimized EV assays using the ExoViewTM platform for detecting and quantifying the number of ALPPL2+ or THBS2+ EVs in serum samples. We then determined the concentrations of ALPPL2+ or THBS2+ EVs in samples from healthy individuals and longitudinal samples from patients with Stage IV PDAC undergone treatment. The longitudinal samples were from 26 patients of which 16 were CA19-9 secretors (defined as &gt;35 U/ml) and 10 were CA19-9 non-secretors (defined as &lt;35 U/ml) that were treated with various regimens for 4-24 months with monthly blood sample collection and CT scans (a total of 305 samples). We found that the concentrations of ALPPL2+ and THBS2+ EVs are on average 1,737 and 1,113 times higher in PDAC patients than in the healthy controls, respectively. Correlation analysis using the mixed linear model showed that the concentrations of both ALPPL2+ and THBS2+ EVs significantly correlate with changes in tumor size (based on RECIST measurements) in the longitudinal samples of CA19-9 non-secretors or secretors. In CA19-9 non-secretors the correlation p values are 0.003 and 0.006 for ALPPL2+ and THBS2+ EVs, respectively, whereas in CA19-9 secretors, the p values are 0.014 and 0.016 for ALPPL2+ and THBS2+ EVs, respectively. Our data indicates that EV based ALPPL2 and THBS2 could potentially serve as biomarkers for disease monitoring in patients with PDAC. (This work was supported in part by the Dorrance Family Fund and the Flinn Foundation)
Citation Format: Kuntal Halder, Gayle Jameson, Erkut Borazanci, Wei Lin, Dereck Cridebring, Daniel Von Hoff, Haiyong Han. Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for disease monitoring in patients with pancreatic ductal adenocarcinoma [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 2497.
Abstract 2601: Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker
Authors: Liubomirski Yulia , Tiram Galia , Scomparin Anna , Gnaim Samer , Das Sayantan , Gholap Sachin , Ge Liang , Yeini Eilam , Shelef Omri , Zauberman Arie , Berger Nir , Kalimi Doron , Toister-Achituv Mira , Schröter Christian , Dickgiesser Stephan , Tonillo Jason , Shan Min , Deutsch Carl , Sweeney-Lasch Stanley , Shabat Doron , Satchi-Fainaro Ronit 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer therapeutics, with 14 ADCs already approved worldwide. We developed unique linker technologies for the bioconjugation of drug molecules with controlled-release applications. We synthesized cathepsin-cleavable ADCs using a dimeric prodrug system based on a self-immolative dendritic scaffold, resulting in a high drug-antibody ratio (DAR) with the potential to reach 16 payloads due to its dendritic structure, increased stability in the circulation and efficient release profile of a highly cytotoxic payload at the targeted site. Using our novel cleavable linker technologies, we conjugated the anti-human epidermal growth factor receptor 2 (anti-HER2) antibody, trastuzumab, with topoisomerase I inhibitors, exatecan or belotecan. The newly synthesized ADCs were tested in vitro on mammary carcinoma cells overexpressing human HER2, demonstrating a substantial inhibitory effect on the proliferation of HER2-positive cells. Importantly, a single dose of our trastuzumab-based ADCs administered in vivo to mice bearing HER2-positive tumors, showed a dose-dependent inhibition of tumor growth and survival benefit, with the most potent antitumor effects observed at 10 mg/kg, which resulted in complete tumor regression and survival of 100% of the mice. Overall, our novel dendritic technologies using the protease-cleavable Val-Cit linker present an opportunity for the development of highly selective and potent controlled-released therapeutic payloads. This strategy could potentially lead to the development of novel and effective ADC technologies for patients diagnosed with HER2-positive cancers. Moreover, our proposed ADC linker technology can be implemented in additional medical conditions such as other malignancies as well as autoimmune diseases that overexpress targets, other than HER2.
Citation Format: Yulia Liubomirski, Galia Tiram, Anna Scomparin, Samer Gnaim, Sayantan Das, Sachin Gholap, Liang Ge, Eilam Yeini, Omri Shelef, Arie Zauberman, Nir Berger, Doron Kalimi, Mira Toister-Achituv, Christian Schröter, Stephan Dickgiesser, Jason Tonillo, Min Shan, Carl Deutsch, Stanley Sweeney-Lasch, Doron Shabat, Ronit Satchi-Fainaro. Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker [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 2601.
Abstract 2615: Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors
Authors: Xiao Liang , Lian Wei , Song Shuai , Liu Qigang , Zong Qing , Stann Sasha , Cai Jiaqiang , Xue Tongtong 
Published: March 2024

Abstract
cMET (mesenchymal-epithelial transition factor), which belongs to the MET family, is a type of receptor tyrosine kinase that is expressed on the surfaces of various epithelial cells. The elevation of cMET can promote the development and progression of multiple cancers. cMET- ADCs have shown promising clinical activity with highest cMET levels, indicating tumor cMET levels may be limited for efficacy. YL211, a novel cMET-ADC was developed by leveraging on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform), which could release the payload both in the tumor cell and in the tumor microenvironment. YL211 is comprised of an anti-cMET humanized monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker. The novel linker-payload and site-specific conjugation of YL211 results in a homogeneous product with a DAR (Drug-to-Antibody Ratio) of 8. Furthermore, the advancement in linker-payload design has facilitated the development of more hydrophilic ADCs, which exhibit minimal impact on the antibody's characteristics while being less prone to aggregation and showcasing lower systematic clearance. Along with release of the payload in the tumor microenvironment extracellularly, upon binding to cMET on tumor cell surfaces, the antigen-ADC complexes are internalized to lysosomal vesicles and subsequently release the toxic payload. The cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. These findings translated in vivo where YL211 showed superior efficacy in causing tumor regressions and good tolerability in both cell lines and patient-derived xenograft (CDX and PDX) mouse models with both low to high cMET expression levels (H358, CR5088, ect.). The in vivo pharmacokinetics in monkeys showed that YL211 is highly stable with less than 0.1% (molar ratio) payload released in circulation. GLP safety evaluations demonstrated good safety profiles and no off-target toxicity in monkeys. These non-clinical data suggest the stability of the linker in circulation as well as efficient release of the payload in tumors with improved therapeutic window. Taken together, preclinical data suggest that YL211 could be a promising treatment strategy for cMET positive cancer patients.
Citation Format: Liang Xiao, Wei Lian, Shuai Song, Qigang Liu, Qing Zong, Sasha Stann, Jiaqiang Cai, Tongtong Xue. Preclinical development of a next generation antibody drug conjugate (ADC) targeting cMET for treatment of solid tumors [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 2615.
Abstract 2639: Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response
Authors: Fischetti Irene , Laura Botti , Sulsenti Roberta , Cancila Valeria , Enriquez Claudia , Ferri Renata , Bregni Marco , Crivelli Filippo , Tripodo Claudio , Colombo Mario P. , Jachetti Elena 
Published: March 2024

Abstract
Castration resistant prostate cancer (CRPC) is a fatal disease. Androgen receptor pathway inhibitors, like enzalutamide, are initially effective but resistance eventually occurs, often associated to the emergence of aggressive neuroendocrine variants (NEPC). Even immunotherapy induced limited results in prostate cancer, governed by an immunosuppressive microenvironment. Therefore, effective therapies are needed. We here investigate in preclinical models a new approach aimed to revert castration resistance and simultaneously turn the immune milieu from “cold” to “hot”, through the combination between enzalutamide and the drug GSK-126, which inhibits the epigenetic modulator EZH2. We show that enzalutamide and GSK-126 can synergize to restrain the growth of CRPC in vitro and in vivo. Moreover, this therapeutic combination efficiently reduced NEPC differentiation, in both subcutaneous and autochthonous in vivo models, increasing the rate of cured mice with regressed lesions. The antitumor efficacy observed in immunocompetent mice bearing subcutaneous syngeneic CRPC tumors was lost in immunodeficient mice, indicating a contribution of immune cells. Additional experiments in the TRAMP spontaneous mouse model revealed that the combination of enzalutamide and GSK-126 significantly induced cytotoxic activity and IFNγ production by tumor-specific CD8+ T cells, otherwise tolerant, and increased IL-17 production by CD4+ T cells. The two drugs did not directly modulate T cell activity in vitro, suggesting the importance of microenvironment accomplices in triggering these effects. These results promote the combined use of enzalutamide and GSK-126 to restrain CRPC growth and NEPC differentiation, and, simultaneously, to awake antitumor T cell response, opening new possibilities for immunotherapy in prostate cancer.
Citation Format: Irene Fischetti, Botti Laura, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P. Colombo, Elena Jachetti. Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response [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 2639.