bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6697: The role of microbiomes in pediatric cancer prevention: A survey of population awareness
Authors: Elmoneim Abeer Abd , Alshanqiti Mona Alhassan , Aljohani Yara Saad , Alomari Lubna Hosain 
Published: March 2024

Abstract
Background: Gut microbiome includes the genome of all gut microorganisms; it plays a crucial role in the body’s nutritional, metabolic, physiological, and immunological processes. Persistent imbalance of the gut microbial community is associated with the onset of metabolic and inflammatory disorders, including cancer. The environment has a major role in the great variability of microbiome composition among different people. This high heterogeneity between individuals may be a source of differences in susceptibility to disease. Dietary and lifestyle choices as well as social interactions play a significant role in makeup and function of the gut microbiota, which may affect microbiome-associated diseases. Therefore, strategies that might favorably modulate the gut microbiota to reduce the risk of cancer through diet and lifestyle changes are of great interest.
Aim: To detect and increase self-awareness about gut microbiota and its relation to diet and lifestyle habits.
Methods: A survey questionnaire is provided asking for microbiome knowledge and lifestyle habits and distributed among the population in Madina city in Saudi Arabia. Study population are the children aged 2-18 years. Data gathered from older children or the parents/guardian of young children.
Results: A profile involving each participant’ diet, physical activity, and sociodemographic characteristics through self- reporting questionnaire is obtained.
Discussion: Gut microbiota can regulate many functions of the tumor-bearing meta-organism, typically through immunomodulation. Known microbial mechanisms can alter non-hematopoietic and hematopoietic components of the gut epithelial barrier, modulate lymphoid organ activities, and regulate immune tone of the tumor microenvironment (TME).
Conclusion: Understanding information about microbiome and its role in causing diseases as well as each participant’ diet, physical activity and other sociodemographic characteristics help to raise participants’ awareness about the importance of taking care of their gut health.
Citation Format: Abeer Abd Elmoneim, Mona Alhassan Alshanqiti, Yara Saad Aljohani, Lubna Hosain Alomari. The role of microbiomes in pediatric cancer prevention: A survey of population awareness [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 6697.
Abstract 6728: Preclinical development of QL325, a novel T cell engager targeting CLEC12A-positive AML
Authors: Gu Shenda , Tran Hieu V. , Chen Shihao , Liu Ke , Zhang Xin , Jia Linchao , Ma Ruixue , Fu Jiayu 
Published: March 2024

Abstract
Despite advancement in targeted therapies, treatment options for patients with acute myeloid leukemia (AML) that provide a tolerable and durable response remain elusive. We have developed a CD3 bispecific antibody, QL325, targeting CLEC12A, a c-type lectin protein that is highly expressed on AML blasts. Normally, CLEC12A expression is mostly confined to the CD34+CD38- progenitor population and largely absent on normal and regenerating bone marrow stem cells. Our bispecific antibody is configured in a 2 + 1 format, with bivalent avidity binding to CLEC12A, monovalent low affinity binding to CD3, and an effector-null Fc for extending half-life. In our preclinical studies, QL325 induced CLEC12A -dependent activation and proliferation of T cells. Redirected T cell-dependent cytotoxicity mediated by QL325 was restricted to AML cancer cells expressing CLEC12A. QL325 demonstrated dose dependent suppression of tumor growth in xenograft models of AML, significantly more potent than a clinical benchmark antibody. In non-human primates, QL325 was tolerated up to 0.03 mg/kg for IV dosing and under 0.1 mg/kg for SC dosing, well above the predicted effective therapeutic dose. A phase 1 clinical trial is currently ongoing to determine the safety and early efficacy in patients with refractory or relapsed AML.
Citation Format: Shenda Gu, Hieu V. Tran, Shihao Chen, Ke Liu, Xin Zhang, Linchao Jia, Ruixue Ma, Jiayu Fu. Preclinical development of QL325, a novel T cell engager targeting CLEC12A-positive AML [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 6728.
Abstract 6741: Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer
Authors: Yu Tao , Van der Jeught Kevin , Zhu Haiqi , Zhou Zhuolong , Sharma Samantha , Liu Sheng , So Ka Man , Eyvani Haniyeh , Wang Xiyu , Sandusky George E. , Liu Yunlong , Opyrchal Mateusz , Cao Sha , Wan Jun , Zhang Chi , Zhang Xinna 
Published: March 2024

Abstract
Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy.
Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in colorectal 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 6741.
Abstract 6743: Identifying new cellular adjuvants for cancer vaccines and immunotherapies
Authors: Rucker Joseph , Nwogu Nnenna , Molino Nicholas M. , Snyder Ami , Sullivan Jonathan T. , Doranz Benjamin J. 
Published: March 2024

Abstract
Background: Cancer vaccines represent a promising strategy for antitumor immunotherapy. Despite considerable research efforts and progress, the effectiveness of cancer vaccines remains a challenge. This is primarily due to relatively low immune responses against tumors, stemming from issues of poor immunogenicity and the immunosuppressive microenvironment commonly found in many solid tumors. Use of an optimal adjuvant can augment immune responses against tumor antigens and guide them towards a specific adaptive immune enhancement. Dendritic cells (DCs) play a primary role in initiating immunes response to vaccines, often through activation of toll-like receptors (TLRs). Identifying novel immunomodulatory proteins that regulate DCs or TLR activation can identify novel adjuvant candidates with applications for cancer immunotherapy.
Methods: We constructed a Membrane Proteome Array (MPA) encompassing ~6,000 structurally intact human membrane proteins in their native conformation (94% of the entire membrane proteome) and used it to screen for cellular proteins that can modulate response to vaccination through DCs and TLRs. To identify proteins that interact with TLRs, the library was expressed in live TLR reporter cells, and these cells were tested for response to known activators. In addition, cells expressing the MPA were presented to DCs to identify membrane proteins that modulate DC activity. TLR-expressing cell activation was measuring using an NF-kB-activated luciferase reporter, while DC assays used upregulation of cell surface markers (CD80, CD83, and MHCII) to measure the activation of immature monocyte-derived dendritic cells.
Results: Screening of TLR2, TLR3, and TLR5 reporter cell lines identified both known and novel regulators of TLR activation. Activators common to several TLRs were identified as well as activators unique to individual TLRs. Screening of primary human DCs likewise identified known regulators of activation (for example CD40L) and several novel targets. Putative novel regulators of DC activation are being further investigated to determine their biological significance.
Conclusion: Discovering novel immunomodulatory targets and proteins that regulate DCs and TLR activation can identify novel adjuvant candidates with targeted immune outcomes, such as immune stimulating and anti-cancer responses. This study identified novel regulators of immune activation which are being further investigated as adjuvant candidates for cancer vaccines.
Citation Format: Joseph Rucker, Nnenna Nwogu, Nicholas M. Molino, Ami Snyder, Jonathan T. Sullivan, Benjamin J. Doranz. Identifying new cellular adjuvants for cancer vaccines and immunotherapies [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 6743.
Abstract 676: The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma
Authors: Liu Yang , Lee Heng-Huan , McIntosh Joseph , Li Yijing , Zhang Tianci , Wang Wei , Kostura Matthew J. , Wang Michael 
Published: March 2024

Abstract
Successive generations of BTK inhibitors and CAR T-cell therapy have transformed the treatment of mantle cell lymphoma (MCL). However, treatment resistance has inevitably emerged, creating significant medical need. Recently a novel, clinical stage small molecule, BTM-3566, has been described that targets a mitochondrial process essential for Diffuse Large B-cell lymphoma (DLBCL) survival. BTM-3566 activates the mitochondrial protease OMA1, triggering the ATF4 integrated stress response (ISR). BTM-3566 has robust in vitro efficacy in DLBCL cell lines irrespective of genomic background and elicits complete tumor regression in multiple CDX and PDX mouse models of DLBCL. Based on the activity observed in DLBCL, we further explored the effectiveness of BTM-3566 in MCL models in vitro and in xenograft mouse models in vivo. BTM-3566 inhibited cell proliferation across a panel of MCL cell lines, irrespective of resistance status to ibrutinib and venetoclax (IC50s of 142.5-687.6 nM). Following a 24-hour treatment with BTM-3566, a dose-dependent increase in apoptosis was observed in four tested MCL cell lines—JeKo-1, JeKo-IBN-R, Mino, and Mino-VEN-R, as determined by increased caspase-3 activation and PARP cleavage. Similarly, western blot analysis revealed dose-dependent reductions in MCL-1 and c-MYC, accompanied by an increase in the transcription factor ATF4, indicative of activation of the stress response. We evaluated the in vivo efficacy of BTM-3566 in the JeKo-CDX mouse model. Daily oral administration of BTM-3566 at 10, 20 and 30 mg/kg (n = 5 for each group) in a 5-day on and 2-day off schedule resulted in tumor regression at all three doses (Treatment vs. Vehicle, p &lt; 0.01). We expanded our investigation to PDX mouse models, including those derived from patients resistant to multiple therapies. Four PDX models encompassing naive, rituximab-resistant, BTKi-CAR T dual-resistant and BTKi-VEN-CAR T triple-resistant models were evaluated. BTM-3566 treatment results in nearly complete tumor growth inhibition associated with robust reductions in tumor burden in treated mice across all four PDX models (reduction in tumor weight at the study endpoint, p &lt; 0.001). Notably, no toxicity was observed during the treatment period. In summary, BTM-3566 is effective in treating MCL in vitro and in vivo in preclinical studies.
Citation Format: Yang Liu, Heng-Huan Lee, Joseph McIntosh, Yijing Li, Tianci Zhang, Wei Wang, Matthew J. Kostura, Michael Wang. The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma [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 676.
Abstract 6811: IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages
Authors: Cannon Anthony , Kaplan Mark H. 
Published: March 2024

Abstract
A defining characteristic of cancer is its ability to evade detection by immune cells through the generation of a myeloid cell-dependent immunosuppressive tumor microenvironment. Arginine is utilized by Arginase 1 (ARG1) or nitric oxide synthase in tumor-associated macrophages to respectively elicit pro-tumor or anti-tumor activity. The balance between these enzymes is regulated by extracellular cytokines including Interleukin 9 (IL-9), a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab identified that IL-9 promotes tumor development in the lung by expanding interstitial macrophage populations and inducing ARG1. Lung tumor growth is attenuated in mice with myeloid cell deficiency of Arg1. Similarly, macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and alter macrophage populations in the lung toward an immunostimulatory phenotype. However, an understanding of the mechanism by which IL-9R/ARG1+ interstitial macrophages drive tumor progression remains incomplete. Here, using a B16F10 lung metastasis model in mixed-bone marrow chimeric mice, we demonstrate that IL-9-responsive interstitial macrophages are intrinsically altered at the transcriptomic level toward an ARG1-dependent immunosuppressive phenotype. Furthermore, our research shows that the absence of IL-9 signaling or ARG1 expression in macrophages has a notable impact on the levels of arginine and its metabolites in the lung tissue and bronchoalveolar lavage fluid of tumor-bearing mice. These alterations subsequently lead to an enhanced anti-tumoral immune response, reflected by changes in Interferon-gamma expression in both lung macrophages and T cells. Thus, our work suggests that the IL-9R/ARG1/interstitial macrophage axis promotes lung tumor development by altering intrinsic arginine metabolism and reprogramming immune cell populations toward an immunosuppressive phenotype.
Citation Format: Anthony Cannon, Mark H. Kaplan. IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages [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 6811.
Abstract 6871: Tumor-infiltrating mregDC restrains anti-tumor immunity to promote cancer relapse in HCC
Authors: Zhang Zefan , Zhou Jian , Fan Jia , Zhong Yu , Wu Liang , Sun Yunfan 
Published: March 2024

Abstract
Background and aims: Cancer relapse is one of the major causes of mortality in patients after curative resection of primary tumors. Furthermore, significant proportion of patients with recurrent tumor lack of effective treatments, thus novel therapeutic strategies are urgently needed. Although there have been several single-cell studies of primary tumor, functional roles and mechanism of tumor-infiltrating immune cells, especially those of myeloid cells in tumor relapse have remained to be elucidated.
Methods: We analyzed the RNA profile of 16498 cells from 12 primary and 6 early-relapse HCC cases. Digital pathology, multiplex immunofluorescent staining and digital spatial profiling (DSP) of paired primary and relapsed tumors from 41 HCC patients were also performed as our validation set. The molecular mechanisms associated with DCs was further tested through ex vivo and in vivo experiments.
Results: We performed single-cell clustering and visualized 3 DC clusters (cDC1, cDC2, and DC3). Compared with the other two subsets, the enrichment of DC3 in relapsed HCC was correlated with a higher second recurrence rate. Deeper inspections of the signature genes indicated this subset as ‘mregDC’, a DC subset enriched in maturation and regulatory molecules. Our results demonstrated that mregDC recruited CD161+CD8+ T cells that had an innate-like, low-cytotoxic, and low-clonal-expansion phenotype. CD161+CD8+ T cells secreted large amounts of TNF to activate non-canonical NF-κB pathway via tumor necrosis factor receptor 2 (TNFR2) and promoted the differentiation of immature DC into mregDC. This positive feedback loop between mregDC and CD161+CD8+ T cells shaped a dysfunctional anti-tumor immunity, facilitating cancer relapse in HCC. In vivo assay further indicated that therapy combining anti-TNFR2 and PD-L1 antibodies significantly inhibited HCC tumor growth via impeding the infiltration of mregDC compared with anti-PD-L1 monotherapy. We also found mregDC recruited FCN1+ monocyte, a MDSC-like cell population to create an immunosuppressive niche of relapsed HCC.
Conclusions: We identified this population of mregDC with immunomodulatory function in recurrent HCC and demonstrated the role of these special DCs in shaping the immunosuppressive microenvironment of recurrent tumors. Our study suggests that mregDC may be a new target for the treatment of recurrent HCC in the future.
Citation Format: Zefan Zhang, Jian Zhou, Jia Fan, Yu Zhong, Liang Wu, Yunfan Sun. Tumor-infiltrating mregDC restrains anti-tumor immunity to promote cancer relapse in HCC [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 6871.
Abstract 6895: Application of MiniPDX® in clinical indication identification and anti-tumor drug development
Authors: Xie Bin , Chen Hongkui , Zhao Shizhu , Li Le , Xi Song , Di Yu , Liu Yang , Chen Xinlei , Gu Xiaorong , Bi Zhenle , Hu Kaimeng , Van Loc , Caggiula Josh , Tang Candice , Wen Danyi 
Published: March 2024

Abstract
MiniPDX® (Mini-patient-derived xenograft) is a novel, rapid (7~10days), and accurate method for drug sensitivity testing in vivo. It was referred as in vivo version of organoid assy. The testing material can be fresh patient tumor samples or tissues from established PDX models. We have systematically evaluated and compared the response rates of MiniPDX® assays and PDX assays pairwise in 26 PDX models across 3 types of cancers to 12 clinically relevant regimens for chemical and targeting drugs. The results demonstrate a high correlation between drug responses of the two assays, with sensitivity of 80% and specificity of 93%. More and more studies showed that MiniPDX® drug sensitivity test results were consistent with clinical responses in most patients, which indicated MiniPDX® models have great potential in guiding personalized medicine. LIDE has successfully conducted over 3,000 MiniPDX® tests for clinical precision medicine, covering more than 50 indications. The application of MiniPDX® extends beyond therapeutic selection, facilitating the prioritization of approved pharmacological interventions and informing the discovery pipeline for novel agents. Importantly, the MiniPDX® Mouse Trial using fresh tumor samples generated from the clinic is beneficial for determination of potential clinical indications. Only thousands of fresh cells leftover from MiniPDX® preparation are sufficient to get genomic and transcription data by OncoVee ® K-cell technology. The combination of MiniPDX® assay and omics data would be very useful for determination of potential biomarkers to distinguish responders and non-responders in population with certain indication(s) and leveraged for patient stratification and selection criteria in clinical trial design. In addition, we have developed a new version of MiniPDX® assay for immunotherapy (IO-FIVE, Immuno-Oncology Fast In Vivo Efficacy test) by using fresh patient cancer cells with autologous immune cells to maximally mimic human tumor microenvironment before seeding in immune-deficient mice. This assay allows for the tracking of cellular viability and phenotype pre- and post-treatment, thus providing a robust metric of in vivo immunotherapeutic efficacy within a fortnight.
Citation Format: Bin Xie, Hongkui Chen, Shizhu Zhao, Le Li, Song Xi, Yu Di, Yang Liu, Xinlei Chen, Xiaorong Gu, Zhenle Bi, Kaimeng Hu, Loc Van, Josh Caggiula, Candice Tang, Danyi Wen. Application of MiniPDX® in clinical indication identification and anti-tumor drug development [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 6895.