bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5007: Ex vivo evaluation of mRNA lipid nanoparticle cancer vaccines
Authors: Lidström Tommy , Arauzo Mara Blanco , Karlowatz Nickolas , Johansson Mikael , Forsell Mattias , Nilsson Jonas 
Published: March 2024

Abstract
Lipid nanoparticle vaccines have recently been developed broadly against pathogens and recently, in precision medicine targeting mutations in different tumors. Evaluating vaccine candidates typically require animal models using orthotopic or allogenic transplantations to evaluate efficiency. Evaluating vaccine efficacy using ex vivo systems is faster and less technically demanding. Here we aim to develop individualized cancer vaccines based on neoantigen identified within established human organoids or directly from patient tissue. The selected neoantigens are enriched for epitopes identified on gene fusions. Identified gene fusions encoding predicted immunogenic proteins are inserted into a vaccine backbone and used to make mRNA lipid nanoparticle vaccines. The neoantigen candidates are then evaluated in a personalized ex vivo testbed. Within the ex vivo testbed personal tumor neoantigens are tested on the patients own isolated CD8+ T cells and monocytes. Monocytes are in vitro differentiated into monocyte derived dendritic cells (moDCs), which specialize in antigen cross presentation. The moDCs are inoculated with mRNA lipid nanoparticle vaccines or loaded with peptides. The moDCs are then co-cultured with syngeneic T cells. Vaccine candidates are evaluated based on CD8+ T cell activation and cytotoxicity in the co-culture ex vivo testbed. Our pipeline offers a fast and efficient means of evaluating individualized vaccine candidates. Effective vaccines developed through this process can be administered as a standalone therapy or in combination with checkpoint inhibitors, to generate a strong durable immune response against a variety of solid tumor types.
Citation Format: Tommy Lidström, Mara Blanco Arauzo, Nickolas Karlowatz, Mikael Johansson, Mattias Forsell, Jonas Nilsson. Ex vivo evaluation of mRNA lipid nanoparticle cancer vaccines [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 5007.
Abstract 504: Anticancer effects of kaempferol through cell cycle arrest and the inhibition of proliferation in genetically distinct triple-negative breast cancer cells
Authors: Kaur Sukhmandeep , Mendonca Patricia , Soliman Karam F. A. 
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is one of the most known aggressive subtypes of breast cancer, affecting 1 in 3 newly diagnosed cancers in women. TNBC affects African-American women disproportionally in comparison to Caucasian women. Due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER-2), it poses direct challenges to the efficacy of standard hormonal therapies. The current TNBC treatments present higher toxicity and multiple side effects. An alternative would be using natural compounds that have emerged as potential anticancer agents. Kaempferol is a major flavonoid aglycone found in many fruits, vegetables, and herbs, including grapes, tomatoes, broccoli, tea, and ginkgo biloba leaves. In this study, we investigated the differential effect of kaempferol on cell toxicity, cell growth, and underlying mechanisms in inducing cell cycle arrest in genetically different TNBC cells from Caucasian (MDA-MB-231) and African American (MDA-MB- 468) women. Kaempferol significantly inhibited cell growth in both the cell lines with a more profound effect against MDA-MB-231 (IC50: 43.86 µM) compared to MDA-MB-468 cells (IC50: 53.47 µM). Also, kaempferol treatment induced cell cycle arrest at S-phase in both cancer cell subtypes. The MDA-MB-231 cells showed a kaempferol effect at lower concentrations (6.25µM and 12.5µM), while MDA-MB-468 cells showed the same effect at higher concentrations (25µM and 50µM). Kaempferol also modulated CDK gene expression associated with cell cycle progression in breast cancer cells. The inhibition at S-phase is important in cancer treatment because it targets the highly proliferative nature of cancer cells characterized by uncontrolled cell division. This study indicates that, by inducing cell cycle arrest at the S-phase, kaempferol may interfere with cancer cell growth and proliferation by inhibiting DNA replication, offering potential therapeutic benefits. This approach could reduce side effects and increase treatment efficacy, providing hope for more effective interventions in the fight against TNBC.
Citation Format: Sukhmandeep Kaur, Patricia Mendonca, Karam F. A. Soliman. Anticancer effects of kaempferol through cell cycle arrest and the inhibition of proliferation in genetically distinct triple-negative breast cancer cells [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 504.
Abstract 5050: Germline variants in CDKN2A wild-type melanoma prone families
Authors: Knappskog Stian , Iversen Gjertrud T. , Loeng Marie , Holth Amalie L. , Lonning Per E. , Geisler Jurgen 
Published: March 2024

Abstract
The presence of germline pathogenic variants in CDKN2A is a well-established underlying cause of familial malignant melanoma. While pathogenic variants in several other genes have also been linked to melanoma development, many familial cases remain unexplained. We analyzed for pathogenic germline variants in a panel of 360 cancer related genes in a set of 56 Norwegian melanoma prone families. The index cases and families were selected based on familial history of melanoma and/or multiple primary melanomas in the same individual, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants. These variants were found in BRCA2, MRE11, ATM, MSH2, CHEK2 and AR. In addition, one family member with a melanoma diagnosis (not index case) carried a pathogenic variant in MAP3K6. In genes typically linked to xeroderma pigmentosum, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance. In particular the XPCL48F variant was found in 8 out of 56 indexes, thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (p-values from 0.007 to 0.014). Similarly, we found presumed benign or uncertain variants in MC1R to be significantly enriched or numerically higher in index cases versus comparable healthy populations (p-values from 0.009 to 0.1). The common MC1RArg151Cys variant was highly enriched in our cohort (p=0.001).In conclusion, we found that several melanoma prone families harbored pathogenic variants in genes not usually linked to melanoma.
Citation Format: Stian Knappskog, Gjertrud T. Iversen, Marie Loeng, Amalie L. Holth, Per E. Lonning, Jurgen Geisler. Germline variants in CDKN2A wild-type melanoma prone families [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 5050.
Abstract 5069: Retrospective analysis of acute myeloid leukemia using next generation cytogenomics identifies variants missed at diagnosis
Authors: Eacker Stephen , Malig Maika , Wood Mary , Muratov Alexander , Sala-Torra Olga , Liachko Ivan , Yeung Cecilia , Radich Jerald 
Published: March 2024

Abstract
Cytogenetics forms the cornerstone of diagnostic genetic testing in leukemia, providing both prognostic and diagnostic information to help guide treatment. Currently, standard-of-care cytogenetics in acute myeloid leukemia (AML) is composed of a combination of karyotyping, FISH testing, and in some cases chromosomal microarray analysis, each test offering a unique combination of advantages and weaknesses. A particular challenge for this combination of tests is the delivery of results in a timely and comprehensive manner. To overcome these limitations, we have developed OncoTerra, a proximity-ligation-sequencing based method which can rapidly detect all classes of variants detected by cytogenetics tests in a single assay. We applied OncoTerra to a cohort of more than 100 samples from a SWOG AML trial (S0106), benchmarking sensitivity and specificity of the variants. We observed an overall &gt;0.95 sensitivity and a specificity of 1 for the variants identified by cytogenetics and identified numerous cryptic variants. Overall, we identified variants that changed the diagnostic risk stratification of 15% of the patient involved in the trial based on the ELN 2022 criteria. This translated into better overall prediction of outcomes of patients in the trial and has identified both known and novel variants missed by standard-of-care tools.
Citation Format: Stephen Eacker, Maika Malig, Mary Wood, Alexander Muratov, Olga Sala-Torra, Ivan Liachko, Cecilia Yeung, Jerald Radich. Retrospective analysis of acute myeloid leukemia using next generation cytogenomics identifies variants missed at diagnosis [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 5069.
Abstract 5243: CAR B cells to accelerate antigen presentation in cancer
Authors: Molloy Mary Ellen , Balero Jessica , Contreras-Sandoval Ana , Selby Mark , Park Hangil , Kothakota Srinivas , Boyle Kathleen , Romano Rosa , Rajendiran Smrithi , Hernandez Moises , Pios Ariel , Williams Rusty 
Published: March 2024

Abstract
Engineered B cells hold promise for multiple therapeutic applications. Walking Fish Therapeutics is engineering B cells to produce replacement proteins for deficiency diseases, antibodies of defined specificity and effector function, and Chimeric Antigen Receptor (CAR) B cells with and without therapeutic payloads for use in the oncology setting. B cells are professional antigen presenting cells (APCs) with the ability to present antigen to CD4+ T cells. Recent studies have found the presence of tumor infiltrating B cells are associated with favorable outcomes across multiple cancer types. Adoptive transfer of B cells has demonstrated antitumor activity in a syngeneic mouse model. B cells from OVA-vaccinated transgenic luciferase mice were adoptively transferred to mice bearing EG7.OVA-tumors. We observed B cells migrating to the tumor and tumor draining lymph node (TDLN), locations where B cells can engage with antigen. Further, we observed a strong anti-tumor response in mice receiving B cells from OVA-vaccinated donors. Based on these results, we hypothesized that B cells engineered to target tumor specific antigens may engage and activate the immune system leading to an enhanced antitumor immune response. We generated CAR B cells expressing synthetic BCRs with tumor-antigen specific scFvs fused to designated B cell signaling motifs. Expression of different CAR constructs were confirmed in both human and mouse B cells. Upon antigen engagement CAR B cells release pro-inflammatory cytokines. Importantly, we demonstrate in vitro that antigen-specific CAR B cells can recognize cognate cell surface antigen, leading to uptake, processing, and presentation on MHCII as detected by activation of peptide-specific CD4+ T cells. When administered in vivo by IV administration, we observed a significant increase in mouse CAR B cells at the tumor site compared to unengineered B cells. We are currently investigating additional CAR formats that may lead to enhanced anti-tumor activity.
Citation Format: Mary Ellen Molloy, Jessica Balero, Ana Contreras-Sandoval, Mark Selby, Hangil Park, Srinivas Kothakota, Kathleen Boyle, Rosa Romano, Smrithi Rajendiran, Moises Hernandez, Ariel Pios, Rusty Williams. CAR B cells to accelerate antigen presentation in 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 5243.
Abstract 5278: Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian carcinoma
Authors: Holicek Peter , Vosahlikova Sarka , Moserova Irena , Orsulic Sandra , Mikyskova Romana , Hensler Michal , Kasikova Lenka , Lanickova Tereza , Novotny Ondrej , Reinis Milan , Drozenova Jana , Ryska Ales , Laco Jan , Rob Lukas , Halaska Michael , Cibula David , Spisek Radek , Fucikova Jitka 
Published: March 2024

Abstract
Epithelial ovarian carcinoma (EOC) is among the top five causes of cancer-related death in women. Most women with EOC achieve indeed complete remission after primary or interval cytoreductive surgery combined with chemotherapy based on a platinum-taxane doublet. Homologous recombination (HR) defects imposed by germline or somatic BRCA1 DNA repair-associated (BRCA1) or BRCA2 mutations are not only key determinants of platinum sensitivity in EOC patients but also provide a strong rationale for maintenance therapy based on poly(ADP-ribose) polymerase (PARP) inhibitors, which is generally associated with improved progression-free survival (PFS). Besides direct cytotoxic and cytostatic properties, PARPi have been shown to mediate multipronged immunostimulatory effects, largely reflecting their ability to inhibit DNA repair in malignant cells and indicating the possibility to synergy with immune-check point inhibitors (ICIs). Here, using multiparametric flow cytometry, multiplex immunostaining, single cells transcriptomics and functional studies in experimental syngeneic BR5Brca1-/- mouse model and EOC tumor samples, we discuss PARPi immunomodulatory activity, with a specific focus on molecular and cellular pathways that can be harnessed to develop superior combinatorial regimens for clinical management. Thus, PARPi might enhance the mutational load of EOCs as consequence of unrepaired DNA damage and DAMPs exposure, favoring T cell infiltration, but also appear to drive robust type I IFN secretion downstream of cyclic GMP-AMP synthase and stimulator of IFN response cGAMP interactor 1 activation. In addition, the combination of PARPi with ICIs positively regulate the balance between adaptive anti-tumor immunity and innate myeloid components and significantly improve the cytotoxic T cell profile as shown in both experimental mice model and HGSOC tumor samples. We surmise that rationally designed combinations of PARPi and immunotherapeutic agents might be critical to unlock immunosuppression in the EOC microenvironment in support of clinical efficacy.
Citation Format: Peter Holicek, Sarka Vosahlikova, Irena Moserova, Sandra Orsulic, Romana Mikyskova, Michal Hensler, Lenka Kasikova, Tereza Lanickova, Ondrej Novotny, Milan Reinis, Jana Drozenova, Ales Ryska, Jan Laco, Lukas Rob, Michael Halaska, David Cibula, Radek Spisek, Jitka Fucikova. Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian 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 5278.
Abstract 5304: ABL407, a LILRB4x4-1BB bispecific antibody with a wild type Fc, exhibits potent antitumor activity by modulating immune system in multiple ways involving T cells, myeloids, and regulatory T cells
Authors: Seon Minkyu , Lee Yangsoon , Youn Hyunseong , Park Yelim , Kim Sora , Park Kyungjin , Won Jonghwa 
Published: March 2024

Abstract
Tumor-associated myeloid cells such as myeloid-derived suppressor cells (MDSC) accumulate in the tumor microenvironment (TME) and suppress anti-tumor immune responses in a broad range of cancers. LILRB4 (Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 4), an emerging myeloid target, is specifically expressed in tumor-associated myeloid cells and suppresses the immune response, thus promoting cancer progression and metastasis. ABL407 is a First-in-Class bispecific antibody designed to simultaneously target LILRB4 and 4-1BB, enabling LILRB4 expression-dependent 4-1BB activation. By antagonizing LILRB4 signaling, ABL407 inhibited LILRB4 mediated immunosuppression, restoring T cell activity. In addition, ABL407 inhibited fibronectin, a potential LILRB4 ligand, -mediated suppression of myeloid cells. To evaluate the efficacy of ABL407, we established EL4 murine tumor model overexpressing LILRB4 (EL4/LILRB4) in h4-1BB transgenic mice and hLILRB1/4-h4-1BB triple transgenic mice. We observed LILRB4 was overexpressed in M-MDSC in the blood and liver-metastasized tumors. A significant decrease of M-MDSC population and tumor growth inhibition was observed in mice treated with anti-LILRB4 antibody and ABL407. ABL407 treatment resulted in a proportion increment of T cells. However, the percentage of Treg cells and M-MDSC in the liver and blood was reduced by ABL407 treatment in hLILRB1/4-h4-1BB triple transgenic mice. Mice with complete remission (CR) were further protected from the rechallenge of previously exposed tumor after 3 months of cessation of ABL407 treatment, implicating that immunological memory might be generated. In conclusion, our findings suggest that ABL407, LILRB4x4-1BB bispecific antibody, may be a promising strategy for the treatment of cancer. It can be applied as a "LILRB4 antagonist" as well as a "LILRB4-dependent 4-1BB agonist" across a broad spectrum of cancers.
Citation Format: Minkyu Seon, Yangsoon Lee, Hyunseong Youn, Yelim Park, Sora Kim, Kyungjin Park, Jonghwa Won. ABL407, a LILRB4x4-1BB bispecific antibody with a wild type Fc, exhibits potent antitumor activity by modulating immune system in multiple ways involving T cells, myeloids, and regulatory T cells [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 5304.
Abstract 535: Resistant PDO models: Unraveling drug resistance mechanisms for discovering new drug targets
Authors: Abouleila Yasmine , Doorn Mayke , Verkerk Roel , Maas Joris , Verissimo Carla , Boj Sylvia 
Published: March 2024

Abstract
Resistance to cancer treatment remains a significant obstacle in curing patients with cancer. Despite recent advancements in novel drug targets for cancer therapeutics, patients often develop treatment resistance even after initial disease remission, leading to tumor relapse. To investigate the mechanisms responsible for developing resistance to standard-of-care therapies, it is essential to gain insights into the stepwise progression leading to complete resistance. Recent research has revealed that cancer cells can evade the effects of chemotherapy and targeted therapy by entering a reversible and slow proliferation state known as the drug-tolerant persister (DTP) state. This DTP state allows cancer cells to survive drug therapy long enough for additional mechanisms of acquired drug resistance to develop. HUB Organoids® or patient-derived organoid (PDO) models are derived from patient tissues, making them more physiologically relevant than traditional cell lines. Thus, studying drug persistence and resistance in PDO models is more likely to reflect in vivo conditions. This study demonstrates the successful development of persistent and resistant CRC PDO models to standard-of-care therapies. All models were characterized using whole exome sequencing and RNA sequencing to confirm their persistent or resistant state and to identify possible pathways involved in developing therapy resistance, as well as potential new drug targets. In conclusion, developing persistent and resistant PDO models is crucial for understanding drug resistance mechanisms, enabling the development of more effective and personalized cancer treatments, and advancing our overall knowledge of how resistance develops in cancer patients.
Citation Format: Yasmine Abouleila, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia Boj. Resistant PDO models: Unraveling drug resistance mechanisms for discovering new drug targets [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 535.
Abstract 536: Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model
Authors: Fang Yuan , Wang Huiyi , Xing Jun , Yang Lu , Zhao Jing , Gao Xiang , Ju Cunxiang 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) are compounds that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxic payload of toxic substances. In recent years, ADCs have rapidly developed in the field of cancer therapy, particularly in the treatment of HER2-positive breast cancer. One representative example is Trastuzumab deruxtecan (Enhertu), which has become a new benchmark for anti-HER2 ADCs due to its excellent performance in clinical trials. Despite the impressive clinical outcomes of ADCs, some tumors in patients may still develop resistance to these drugs. Therefore, it is crucial to understand the mechanisms of resistance and develop strategies to overcome ADCs resistance. To achieve these goals, it is essential to establish and utilize preclinical models to study these resistance mechanisms. Preclinical models of resistance to ADCs have mainly been generated using human cultured cell lines. JIMT-1 is a HER2-positive breast cancer cell line that exhibits primary resistance to the anti-HER2 antibody trastuzumab and also shows resistance to trastuzumab-derived ADC T-DM1. However, we found that Enhertu significantly inhibited tumor growth in JIMT-1 xenograft models. We subjected JIMT-1 tumor tissues to continuous passage in mice and administered long-term drug induction. The tumor growth rate gradually increased, and the drug sensitivity decreased, resulting in the acquisition of an Enhertu-resistant tumor model. The obtained resistant tumor tissues not only include tumor cells themselves but also comprise fibroblasts, extracellular matrix, and other cellular components, enabling a more comprehensive investigation into the interactions between different cells within the tumor microenvironment (TME). We believe that the establishment of preclinical Enhertu-resistant models helps predict resistance that has not yet emerged clinically and provides references for future drug development.
Citation Format: Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. Breaking through ADCs resistance: Constructing preclinical enhertu-induced resistant model [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 536.