bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB071: Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors
Authors: Qie Yaqing , Garavito Emiliano Sanchez , Ulloa Navas Maria J. , Hundal Tanya , Quinones-Hinojosa Alfredo , Qin Hong , Luo Yan 
Published: April 2024

Abstract
Despite its success in treating blood cancers, chimeric antigen receptor (CAR) T-cell therapy has not yielded anticipated clinical outcomes in patients with solid tumors. This discrepancy is primarily attributed to the lack of dependable antigens and the immunosuppressive nature of the tumor microenvironment (TME). A pivotal evasion mechanism employed by tumor to counter antitumor immunity involves the upregulation of programmed death ligand 1 (PD-L1), which interacts with PD1 on T cells, deactivating effector T cells. A variety of immunosuppressive cells within the TME employ similar mechanisms to inhibit T-cell functions. These findings provide a rationale for targeting PD-L1 in both tumors and the immunosuppressive cells. Using a humanized anti-PD-L1 monoclonal antibody, we engineered a second-generation PD-L1 CAR, namely MC9999. MC9999 CAR T-cells exhibited antigen-specific cytotoxicity in vitro and elicited potent in vivo antitumor effects against PD-L1-expressing MDA-MD-232 breast cancer cells. The effectiveness of MC9999 CAR T-cells was confirmed across three other solid tumor models: non-small cell lung cancer, melanoma and glioblastoma (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting the potential to penetrate the blood-brain barrier. In addition to targeting tumor cells, MC9999 CAR T-cells exhibited cytotoxicity against three immunosuppressive cell models, including HMC3 microglia cells, M2 macrophages, and importantly, primary tumor-associated macrophages (TAMs) isolated from GBM. Furthermore, we engineered patient-derived MC9999 CAR T-cells and demonstrated their effectiveness against two primary tumor cell lines derived from GBM tumors and HMC3 cells. Collectively, these proof-of-principle study findings substantiate the viability of targeting PD-L1 against both tumors and their immunosuppressive microenvironment. This prototype MC9999 CAR lays the groundwork for further development of clinically applicable CAR T-cell therapy against solid tumors.
Citation Format: Yaqing Qie, Emiliano Sanchez Garavito, Maria J. Ulloa Navas, Tanya Hundal, Alfredo Quinones-Hinojosa, Hong Qin, Yan Luo. Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB071.
Abstract LB073: Adoptive transfer of one CD4TCR and one CD8TCR targeting autochthonous neoantigens are essential and sufficient for eradication of naturally heterogeneous solid tumors
Authors: Wolf Steven , Anastasopoulou Vasiliki , Drousch Kimberley , Diehl Markus , Engels Boris , Yew Poh Yin , Kiyotani Kazuma , Nakamura Yusuke , Schreiber Karin , Schreiber Hans , Leisegang Matthias 
Published: April 2024

Abstract
Despite advances in checkpoint blockade therapy or adoptive transfer of tumor-infiltrating lymphocytes (TILs), achieving cure remains challenging, but success of immunotherapy seems to depend on recognition of tumor-specific antigens (neoantigens). We aimed to determine how many neoantigens need to be recognized by how many different TCRs for eradication of solid tumors. Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). Investigated were effects of TCR-engineered CD8+ T cells, TCR-engineered CD4+ T cells or a combination of both. The targeted tumors were established for at least three weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. CD8TCR-therapy was only effective against homogenous tumors and relapse was common in heterogeneous tumors, even when targeting multiple different autochthonous neoantigens. By contrast, a combination of CD8TCR-therapy with CD4TCR-therapy, each targeting an independent neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8TCR-therapy was essential for cure. Thus, two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous neoantigens.
Citation Format: Steven Wolf, Vasiliki Anastasopoulou, Kimberley Drousch, Markus Diehl, Boris Engels, Poh Yin Yew, Kazuma Kiyotani, Yusuke Nakamura, Karin Schreiber, Hans Schreiber, Matthias Leisegang. Adoptive transfer of one CD4TCR and one CD8TCR targeting autochthonous neoantigens are essential and sufficient for eradication of naturally heterogeneous solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB073.
Abstract LB082: A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer
Authors: Bullock Kennady K. , Hasaka Thomas , Days Emily , Bauer Joshua , Richmond Ann 
Published: April 2024

Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype broadly characterized by the lack of hormone receptor (HR) and HER2 expression. Compared to HR+ breast cancers, TNBCs typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI). The results from KEYNOTE-355 and KEYNOTE-522 trials led to the approvals of anti-PD-1 in combination with physician’s choice chemotherapy for the treatment of TNBC in adjuvant and neoadjuvant settings. However, few patients achieve a durable response, and there remains a need to optimize combination strategies to enhance the benefits of ICI in TNBC. Therefore, we developed a high-throughput co-culture screening assay to identify compounds enhancing T-cell-mediated cytotoxicity. Co-cultures included three cell types: mKate2-labeled PyMT tumor cells expressing the OVA antigen, BPF-labeled PyMT cells, and CD8+ OT-1 T-cells. The screening library included over 400 FDA-approved compounds or agents under investigation for oncology indications. Each compound was evaluated at five concentrations (3µM-12nM) and across three-time points (24hr, 48hr, and 72hr) to provide insight into the kinetics. Cell viability was assessed via image analysis at each time point, and enhanced cell death in the PyMT-OVA cells compared to the non-OVA PyMT cells was considered evidence of enhanced T-cell mediated cytotoxicity. Five chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, kinesin-inhibitor, ABT-751, and etoposide. We are exploring the dose dependency of MHC-I and MHC-II induction, as well as the minimum dose required to cause immunogenic cell death. We further found that low doses of these agents do not negativity affect CD8+ T-cell proliferation, whereas high doses may have deleterious effects on CD8+ T-cell functioning. The results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients and suggest benefit to further investigating the immunostimulatory potential of low dose chemotherapy.
Citation Format: Kennady K. Bullock, Thomas Hasaka, Emily Days, Joshua Bauer, Ann Richmond. A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB082.
Abstract LB127: A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model
Authors: Zhang Yifu , Shang Chengzhang , Guo Chaoshe , Yang Yi 
Published: April 2024

Abstract
Folate receptor alpha (FOLR1) is specifically overexpressed in malignant tumors of epithelial origin, including ovarian, lung and breast cancers. While antibody-drug conjugate (ADC) therapies targeting FOLR1 have shown promise in clinical trials, there is still a large proportion of patients, particularly those with low FOLR1 expression, who do not respond, indicating new therapeutic strategies are needed. MUC1 is another tumor-associated antigen that is likewise overexpressed in epithelial ovarian cancer, breast cancer, and NSCLC, among other cancers; analysis of ovarian PDX tumors by immunohistochemistry (IHC) suggests that FOLR1 and MUC1 are both highly expressed in this cancer type. We therefore hypothesized that dual targeting of FOLR1 and MUC1 could provide therapeutic benefit in ovarian cancer as well as a broad range of tumors. We generated a FOLR1 x MUC1 bispecific antibody (bsAb) from anti-FOLR1 and anti-MUC1 monoclonal antibodies that were produced using RenLite® fully human common light chain mice. These parental monoclonal antibodies recognize both human and cynomolgus monkey antigens. Anti-FOLR1 antibodies were highly specific for FOLR1, as they did not recognize other FOLR family members. The anti-MUC1 antibody was previously confirmed to target MUC1-C, the juxtamembrane domain of MUC1, ensuring tumor cell recognition regardless of MUC1 cleavage. Assessment of the novel FORL1 x MUC1 bsAb indicates binding to several ovarian, breast and NSCLC cell lines, and shows enhanced internalization in MDA-MB-468 and T47D cell lines when compared to parental antibodies. Subsequently, the FORL1 x MUC1 bsAb was conjugated to vcMMAE with a DAR of 4, to generate a bispecific ADC, BCG023. BCG023 exhibited superior tumor growth inhibition compared to benchmark ADCs conjugated with the same payload and DAR in a low FOLR1-expressing NSCLC PDX model. These data suggest that targeting FOLR1 and MUC1 with a bispecific ADC is a promising therapeutic strategy for the treatment of ovarian and other tumors.
Citation Format: Yifu Zhang, Chengzhang Shang, Chaoshe Guo, Yi Yang. A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB127.
Abstract LB199: Condensate modulator sequesters beta-catenin into depot condensates and demonstrates competitive anti-tumor activity in animal models ofcolorectal cancer
Authors: Salojin Costa , Baumann Douglas , Talbot Adam , West Kip , Durand-Reville Thomas , Klein Isaac , Boija Ann 
Published: April 2024

Abstract
Constitutive activation of beta-catenin is a well-known driver of malignancy. However, traditional drug discovery approaches have proven challenging and largely unsuccessful in identifying therapeutic agents to modulate the function of beta-catenin. Biomolecular condensates have recently been demonstrated to play key roles in regulating most cellular processes and biological pathways by compartmentalizing biomolecules in membranelles organelles, thus lending novel opportunities to drug previously “undruggable” targets. Here, we leverage condensate biology to discover small molecules that reverse the hyperactive function of beta-catenin in colorectal cancer by entrapping it into depot condensates. We developed a high-throughput phenotypic assay that identifies beta-catenin condensate-modifying compounds (c-mods). Through condensate screening and functional secondary assays, we have identified c-mods that sequester beta-catenin into depots, induce selective cancer cell killing, and reverse oncogenic beta-catenin specific gene expression programs. C-mods identified in our screen are effective in genetically diverse colorectal cancers and a range of Wnt-associated cancers, providing the opportunity to treat a broad patient population. Furthermore, oral dosing of lead c-mod demonstrates competitive tumor growth inhibition as a single agent in xenograft and PDX models of colorectal cancer. Taken together, these results highlight the promise of condensate biology in drugging previously intractable high-value targets in oncology and developing novel treatments for patients suffering from diseases of high unmet need.
Citation Format: Costa Salojin, Douglas Baumann, Adam Talbot, Kip West, Thomas Durand-Reville, Isaac Klein, Ann Boija. Condensate modulator sequesters beta-catenin into depot condensates and demonstrates competitive anti-tumor activity in animal models ofcolorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB199.
Abstract LB251: Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer
Authors: Burgman Brandon , Pan Xingxin , Agrawal Anjali , Sahni Nidhi , Yi S. Stephen 
Published: April 2024

Abstract
Clinical evidence suggests that right-sided colorectal cancer (CRC) tends to have a worse prognosis compared to left-sided CRC. The distinct functional mechanisms underlying this “sidedness” remain cryptic and poorly understood. Thus, molecular classification of CRC is of paramount in targeting specific subtypes and personalizing treatment for patients. To identify targetable molecular features to improve treatment regimens, we performed multi-faceted network analyses of a large number of CRC patients. In our network model, differential expression of transcript abundance, epigenetic features, and mutational frequency were used to identify widespread gene dysregulation and perturbed pathways to reveal disrupted networks distinct to right or left sided colorectal cancer. We discovered histone related genes and distinct epigenetic signals are at play in right-sided CRC. Additionally, our studies reveal “at risk” patient characteristics suggestive of survival differences, to improve diagnostic predictors based on CRC sidedness. Overall, our integrative approach serves to link molecular profiles distinct between left and right sided colorectal cancer, while paving the way towards identifying more effective treatment alternatives from a previously overlooked, readily characterized subtype of colorectal cancer.
Citation Format: Brandon Burgman, Xingxin Pan, Anjali Agrawal, Nidhi Sahni, S. Stephen Yi. Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB251.
Abstract LB259: Cell context-dependent role of KDM5D in ATR and CHK1 inhibitor sensitivity in prostate cancer
Authors: Zheng Wenxiao , Chen Yuzhou , Wang Qiming J. 
Published: April 2024

Abstract
Epigenetic regulation plays an important role in prostate cancer progression and metastasis. KDM5D is a male-specific histone-modifying enzyme encoded on the Y chromosome that demethylates di- and tri-methylated forms of lysine 4 in histone H3, resulting in transcriptional repression of certain genes. In this study, we investigated the role of KDM5D in resistance to inhibitors targeting the G2/M cell cycle checkpoint kinase CHK1. Loss of KDM5D expression was associated with reduced cell proliferation and resistance to the CHK1 inhibitor SRA737 in castration-resistant (CRPC) and neuroendocrine (NEPC) prostate cancer cell lines. In KDM5D expressing cells, depletion of KDM5D differentially impacted the proliferation of prostate cancer cell lines. The androgen-sensitive LNCaP cell line was particularly sensitive to the knockdown of KMD5D. On the other hand, in CRPC cell line 22Rv1, the knockdown of KDM5D caused resistance to both inhibitors, indicating a dual role of KDM5D in mediating ATR and CHK1 inhibitor sensitivity and cell proliferation in prostate cancer cells. Further analysis demonstrated a self-regulatory cycle between CHK1 and KDM5D in 22Rv1 cells, where depletion of KMD5D reduced CHK1 mRNA, while decreased CHK1 caused upregulation of KDM5D and overexpression of KDM5D resulted in increased CHK1 expression. The relevance of this regulatory mechanism to ATR and CHK1 inhibitor sensitivity is currently under investigation, along with several potential mediators of the differential responses to these inhibitors. Additional ATR and CHK1 inhibitors will also be examined in this context. This study may uncover novel biomarkers for ATR and CHK1 inhibitors that are currently in clinical trials for various cancers. KDM5D may be used to stratify prostate cancer patients receiving these highly potent anticancer agents.
Citation Format: Wenxiao Zheng, Yuzhou Chen, Qiming J. Wang. Cell context-dependent role of KDM5D in ATR and CHK1 inhibitor sensitivity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB259.
Abstract LB280: Enhancing glioblastoma radiotherapy by COMT inhibition
Authors: Jiao Meng , Pirozzi Christopher J. , Yu Chen , Bao Xuhui , Hu Mengjie , Pan Dong , Littleton Sejiro , Reynolds Nathan , Saban Daniel R. , Li Fang , Li Chuan-yuan 
Published: April 2024

Abstract
There is an urgent unmet medical need to discover novel therapeutics to enhance the efficacy of glioma radiotherapy. Here we assessed the roles of catechol - o - methyltransferase COMT, a key enzyme in dopamine metabolism and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in glioma versus normal brain tissues. Inhibition of COMT by genetic knockout or FDA - approved COMT inhibitors significantly sensitized glioma cells to radiotherapy in vitro and murine glioma in vivo. Mechanistically, COMT inhibition in glioblastoma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral dsRNA sensing pathway and type I IFN response. Elevated type I IFNs stimulated microglial cells′ phagocytic capacity, enhancing radiotherapy efficacy. Because of the long - established safety record of the COMT inhibitors, our findings provide a solid rationale to evaluate them in combination with radiotherapy in glioma patients.
Citation Format: Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-yuan Li. Enhancing glioblastoma radiotherapy by COMT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB280.
Abstract LB291: High-plexy intracellular and surface CITE-Seq offers multiomic insights into cell function
Authors: Campbell Tracy L. , Wright Adam , Lee Ying Wah , Tran Anne , Chen Yan , Olives Joe , Song Hye-Won , Wang Larry 
Published: April 2024

Abstract
CITE-Seq allows researchers to combine high-plex protein information with whole transcriptome sequencing to gain insights about individual cell states. Due to the harsh fixation and permeabilization required for intracellular (IC) antibody staining, only a few studies have recovered mRNA expression profiles alongside IC protein detection.
This experiment utilized a novel IC CITE-Seq assay that enables robust profiling of multiple IC protein targets in combination with mRNA and high-plex surface proteins. In this study, we stimulated human peripheral blood mononuclear cells (PBMCs) alongside a resting control. After stimulation, we stained the surface proteins with a 40-plex BD® AbSeq Panel, including the Immune Discovery Panel and human Single-Cell Multiplexing Kit (SMK). Resting and stimulated cells were pooled, and a portion of the sample pool immediately underwent cell capture as a live control using a BD Rhapsody™ single-cell microwell system. The other portion of the pool was stored in BD® OMICS-Guard Sample Preservation Buffer for either 5 minutes or 24 hours followed by permeabilization, IC staining with a 10-plex IC AbSeq Panel (50-plex total, surface and IC), and cells captured on the the same system. We show IC protein detection for the expected positive targets, including pH2AX, actCaspase-3, and cPARP in the stimulated population, as well as T-Bet, Granzyme B and Helios in the resting lymphocytes. Analysis shows excellent correspondence between IC CITE-Seq protein and transcriptome for T-Bet, Granzyme B and Helios. The gene expression correlation for surface antigen and mRNA between the IC and live control each had R2 values &gt; 0.9. The mRNA sensitivity for the IC sample compared to live control was within whole transcriptome analysis (WTA) assay variation at 86–89% and 95–97% median molecules and genes per cell.
Our data showed that the new IC CITE-Seq assay can provide rich single-cell multiomics information including mRNA and surface and intracellular proteins.
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Citation Format: Tracy L. Campbell, Adam Wright, Ying Wah Lee, Anne Tran, Yan Chen, Joe Olives, Hye-Won Song, Larry Wang. High-plexy intracellular and surface CITE-Seq offers multiomic insights into cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB291.