bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1730: A novel chimeric virus-like drug conjugate (VDC) for the potential treatment of HPV-positive tumors
Authors: Kines Rhonda C. , Savinainen Anneli , Pinos Elisabet de los , Schiller John T. 
Published: April 2023

Abstract
Introduction: Human papillomavirus (HPV) virus-like particles (VLPs) bind to a wide variety of tumor types via modified glycosaminoglycans (GAGs) found on the tumor cell surface. This finding led to the development of the investigational virus-like drug conjugate (VDC) belzupacap sarotalocan (bel-sar, formerly AU-011), an HPV-derived VLP conjugated to a light-activated cytotoxic payload. When activated by near-infrared light, bel-sar induced rapid tumor necrosis resulting in pro-immunogenic cell death, release of tumor neoantigens and long-term anti-tumor immunity in the TC-1 tumor model. When E6 and E7 expressing TC-1 mouse tumors were treated with the VDC, E7-specific T-cells were detected in the absence of provided tumor antigens. A novel chimeric VDC (cVDC) is now in development, in which E6 and E7 are fused to the L2 capsid protein as a means to potentially further enhance the observed anti-tumor response. This cVDC could allow for the targeted cytotoxicity of HPV-positive tumors in addition to the release of supplemental tumor antigens E6 and E7 within the now pro-immunogenic tumor milieu, potentially leading to a long term anti-tumor response.
Methods: The detoxified sequences of E6 and E7 were engineered as one fusion polypeptide on the C-terminus of the L2 minor capsid protein. Both L2/E6/E7 and L2/E7/E6 protein expression vectors were generated to determine if the order of the proteins impacted L2’s ability to co-assemble with L1, the major capsid protein. The plasmids were co-expressed alongside L1 using the mammalian 293TT expression system.
Results: Both the L2/E6/E7 and L2/E7/E7 fusion proteins were expressed and co-assembled with L1 into chimeric VLPs. Fusion protein expression was validated by western blots for L2, E6 and E7, and VLPs were confirmed by electron microscopy.
Conclusions: Preliminary data indicate that chimeric VDCs containing E6 and E7 can successfully be generated using the 293TT mammalian expression system. Studies evaluating the cytotoxicity and E6 and E7 immunogenicity of the cVDC as well as the impact on tumor targeting are underway.
Citation Format: Rhonda C. Kines, Anneli Savinainen, Elisabet de los Pinos, John T. Schiller. A novel chimeric virus-like drug conjugate (VDC) for the potential treatment of HPV-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1730.
Abstract 1746: Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma
Authors: Leung Carmen Oi , Yang Yang , So Karl Kam , Zhao Qian , Lee Terence Kin 
Published: April 2023

Abstract
Lenvatinib is the FDA-approved targeted drug for advanced hepatocellular carcinoma (HCC), but the efficacy is modest due to drug resistance. Tumor kinome re-wiring governs drug resistance in resistant cancer cells, which is an obstacle for efficient cancer therapy. Therefore, identification of the kinases critical for this rewiring process in HCC is crucial. Upon mass spectrometry analysis using a lysine-targeted sulfonyl fluoride probe named XO44, CDK6 was identified to be the most upregulated kinase in lenvatinib-resistant HCC cell lines. Lentiviral-based overexpression and knockdown approaches were performed to characterize functional roles of CDK6 in regulation of cancer stemness and lenvatinib resistance. The upregulation of CDK6 in lenvatinib-resistant HCC cells is found to be mediated by the ERK/YAP signaling cascade. CDK6 is crucial in the regulation of acquired lenvatinib resistance via augmentation of cancer stemness and the overexpression of CDK6 led to poorer patient survival. We identified a novel noncanonical pathway of CDK6 in which it binds and regulates the activity of GSK3β, leading to activation of the Wnt/β-catenin signaling pathway. CDK6 inhibition by CDK4/6 inhibitor palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with lenvatinib in vitro. Interestingly, palbociclib not only exerts the maximal growth suppressive effect with lenvatinib in lenvatinib-resistant HCC xenografts and Trp53KO/MYCOE-induced HCC models but also reshapes the tumor immune microenvironment. CDK6 blockade impedes the lenvatinib-induced activation of the ERK/YAP/CDK6/β-catenin signaling cascade. Targeting CDK6 with palbociclib in combination with lenvatinib may be a novel therapeutic strategy against HCC.
Citation Format: Carmen Oi Leung, Yang Yang, Karl Kam So, Qian Zhao, Terence Kin Lee. Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1746.
Abstract 1769: A combination approach of a cellular library and single cell microfluidics analysis for the rapid selection of CAR-T cells
Authors: Boga Eren , Berger Luisa , De Roia Alice , Zörnig Inka , Embacher Robert , Eichmüller Stefan B. , Jäger Dirk , Harbottle Richard , Schmidt Patrick 
Published: April 2023

Abstract
Within the last decade CAR-T cells have changed the landscape of treatment regimen for leukemia and myeloma, which is reflected by the first FDA approval of this class of living drugs in 2017. As of today, the clinical trial situation aims on CAR-T applicability in solid tumors, which is more arduous due to antigen heterogeneity and limited CAR-T persistence. More personalized and multi-target oriented cellular products may offer a solution to overcome these problems but then CAR identification and selection display the major bottleneck in the drug development process. Usually, matching scFvs are selected from targeting screens of a phage-display library and hits are subsequently cloned in CAR backbones and tested for functionality and possible limiting factors as the occurrence of tonic signaling. This makes the whole process very time consuming and laborious. Within this project, we propose a novel CAR-T selection method that rapidly shortens the discovery procedure. We have developed a full length CAR library in nS/MARt DNA vectors that is electroporated in a Jurkat reporter cell line reflecting entirely its full diversity. By this, we can quickly identify the amount of tonic signaling CARs and exclude them from further selection. For on-target selection we first perform a bulk pre-selection followed by a single cell functionality screening using the Berkeley Lights Lightning™ device. This allows us to export hits as clonal viable cells that undergo long length Nanopore CAR-RNA sequencing. Our findings show the feasibility of our approach and that it can shorten the timeframe needed for the full selection process from weeks to days.
Citation Format: Eren Boga, Luisa Berger, Alice De Roia, Inka Zörnig, Robert Embacher, Stefan B. Eichmüller, Dirk Jäger, Richard Harbottle, Patrick Schmidt. A combination approach of a cellular library and single cell microfluidics analysis for the rapid selection of CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1769.
Abstract 178: Establishment of patient-derived organoid of breast cancer
Authors: Ryu Won-Ji , Park Shinyoung , Lee Jeong Dong , Hwang Yumi , Jo Seongyeon , Yong Kweon Tae , Koo Ja Seung , Kim Min Hwan , Sohn Joo Hyuk , Park Hyung Seok 
Published: April 2023

Abstract
A patient-derived organoid (PDO) is an in vitro three-dimensional model which shows similar features in phenotypic and genetic aspects with primary tissue from patients. PDOs are useful for preclinical studies including drug sensitivity tests of tumors from individual patients as well as development of novel targeted agents. Collectively, PDOs are recently introduced as an emerging platform for personalized medicine. We obtained a total of 100 surgical specimens from 100 patients with breast cancer at the Yonsei Cancer Center, Severance Hospital, Seoul, Korea. One of the tissue specimens was acquired from a breast cancer patient-derived xenograft model. We dissociated the tissues and isolated breast cancer primary tumor cells from the samples, and then the cells were cultured in basement membrane-like matrix in 3D manner with growth medium with supplements. We defined successful establishment of PDOs as continuous growth after 3 passaging. Among all 100 cases, 32 cases failed to culture or passage, however, 41 cases were successfully cultured over 3 passages. In addition, the remaining 27 cases are still in progress of establishment. Success rate of PDO was 68% (68/100). Subtypes of primary tumors of the PDO were 33.8% (23/68) of luminal A, 26.5% (18/68) of luminal B, 26.5% (18/68) of triple-negative, 5.9% (4/68) of triple-positive and 7.4% (5/68) of HER2-enriched. Success rates of each subtype were 69.7% (23/33) of luminal A, 72.0% (18/25) of luminal B, 66.7% (18/27) of triple-negative, 66.7% (4/6) of triple-positive and 55.6% (5/9) of HER2-enriched. Pathologic evaluation using immunohistochemistry revealed that PDOs showed similar morphologic and immunohistochemical features with primary tumors. The selective sensitivity of PARP inhibitor, olaparib, was confirmed in PDOs harboring mutant BRCA1/2 compared with BRCA1/2 wild-type PDOs. Overall, PDOs can be used as a real-time platform for drug sensitivity and screening analyses, and a robust tool for preclinical studies in breast cancer.
Citation Format: Won-Ji Ryu, Shinyoung Park, Jeong Dong Lee, Yumi Hwang, Seongyeon Jo, Kweon Tae Yong, Ja Seung Koo, Min Hwan Kim, Joo Hyuk Sohn, Hyung Seok Park. Establishment of patient-derived organoid of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 178.
Abstract 1793: Single-cell RNA analysis reveal effector-like CD8+ CAR-T cell subpopulations associated with response in lymphoma patients
Authors: Sarén Tina , Ramachandran Mohanraj , Gammelgård Gustav , Lövgren Tanja , Wikström Kristina , Hashemi Jamileh , Freyhult Eva , Mirabello Claudio , Björklund Åsa K , Ahlström Håkan , Amini Rose-Marie , Hagberg Hans , Loskog Angelica , Enblad Gunilla , Essand Magnus 
Published: April 2023

Abstract
Although CD19-targeting CAR T cell therapy has shown remarkable success against B cell malignancies there is still room for improvement. To improve long-term responses amongst lymphoma patients, mechanisms underlying initial response and tumor relapses must be addressed. Recent studies have highlighted the importance of the quality of the starting cell material for CAR T cell production and the composition of the CAR T cell infusion product for clinical response. In our study, we have evaluated the clinical response to third generation anti-CD19 CAR T cell therapy in 23 patients with B cell lymphoma. Further, we evaluated the CAR T cell infusion products using targeted single-cell RNA sequencing and multi-color flow cytometry to find potential T cell subsets associating with clinical response. Patients were divided into responders (CR + PR) and non-responders (SD + PD) at the 1-month follow-up after treatment. The CAR T cell products of both responding and non-responding patients were dominated by CD8+ CAR T cells. When comparing cells from the two patient groups we found that the presence of effector-like CD8+ CAR T cells with a high cytotoxic and cytokine secretion and low dysfunction gene expression profile were associated with clinical response. Furthermore, CD8+ CAR T cells of responders displayed a higher polyfunctional gene expression profile, which has previously been shown to associate with clinical response. In contrast, CD8+ CAR T cells from the infusion products of non-responders displayed an elevated dysfunction gene expression profile. Our study reveals that single-cell RNA expression analysis of individual CAR T cell infusion product can identify subsets of effector cells correlating with clinical response. This can be used as a guidance in the CAR T cell production processes, to obtain CAR T cells with the desired characteristics.
Citation Format: Tina Sarén, Mohanraj Ramachandran, Gustav Gammelgård, Tanja Lövgren, Kristina Wikström, Jamileh Hashemi, Eva Freyhult, Claudio Mirabello, Åsa K Björklund, Håkan Ahlström, Rose-Marie Amini, Hans Hagberg, Angelica Loskog, Gunilla Enblad, Magnus Essand. Single-cell RNA analysis reveal effector-like CD8+ CAR-T cell subpopulations associated with response in lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1793.
Abstract 1800: An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade
Authors: Lee Seung Joon , Lee Won Suk , Go Eun-Jin , Yang Hannah , Kim Hong Ro , Kim Bong-Seog , Kim Chan , Chon Hong Jae 
Published: April 2023

Abstract
Background: PI3Kδ and PI3Kγ are mainly expressed in leukocytes, indicating that they are involved in immune modulation of the tumor microenvironment (TME). Additionally, DNA-dependent protein kinase (DNA-PK) plays a pivotal role as a mediator in repairing DNA damage in cancer cells. Here, we developed a triple inhibitor of PI3Kδ/γ and DNA-PK, BR101801, to promote antitumor immune responses and thereby enhance therapeutic efficacy of the PD-1 immune checkpoint inhibitor.
Methods: CT26 and MC38 colon tumor-bearing immunocompetent mice were treated with BR101801 (50 mg/kg, PO) daily and/or anti-PD-1 (8 mg/kg, IP) twice a week. The tumors were comprehensively analyzed using flow cytometry, multiplex tissue imaging, and NanoString profiling methods.
Results: Oral administration of BR101801 suppressed tumor growth without significant toxicities. The optimal schedule for BR101801 was determined by activation of T cell immunity in the TME. BR101801 monotherapy significantly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells, while no changes were observed in tumor-associated macrophages. Moreover, BR101801 increased AH-1+ tumor-specific CD8+ T cells within BR101801-treated CT26 tumors. BR101801 induced extensive immune remodeling of the TME by altering immune-related genes. Notably, gene signatures related to DNA damage and inflammatory responses were more enriched in BR101801-treated tumors. Furthermore, the combination immunotherapy of BR101801 and anti-PD-1 antibody strongly suppressed tumor growth and improved antitumor immunity within the TME, leading to complete tumor regression.
Conclusion: Our study demonstrates that BR101801, an oral triple inhibitor of PI3Kδ/γ and DNA-PK, effectively elicited anticancer immune responses within the TME and potently inhibited tumor progression in combination with immune checkpoint blockade.
Citation Format: Seung Joon Lee, Won Suk Lee, Eun-Jin Go, Hannah Yang, Hong Ro Kim, Bong-Seog Kim, Chan Kim, Hong Jae Chon. An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1800.
Abstract 1821: Discovery of XNW21015, a novel, potent HPK1 inhibitor with excellent immune modulatory activity
Authors: Wu Yuchuan , Hao Rui , Chen Xi , Liu Xiao , Xie Yonghua , Wang Shihua , Gao Bingquan , Wen Jichun , Wu Zhenwei , Wang Wengui , Wei Haiyang , Hu Yonghan , Liu Xiaojun , Le Meijie , Qiang Jing 
Published: April 2023

Abstract
Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the STE20 family of serine/threonine kinases, and restrictedly expressed in hematopoietic cells. In T cells, HPK1 negatively regulated TCR signaling by phosphorylating the adaptor protein SLP76 on Ser376, which leads to the dissociation of the SLP-76/LAT signalosomes and downregulation of T cell priming and activation. HPK1 knockout (KO) or kinase-inactive (KI) mice spontaneously reject tumors with an enhanced immune response compared to wild-type ones. Thus, HPK1 is a novel immuno-oncology (I/O) target. In this work, we described the discovery of a potent HPK1 inhibitor starting from comprehensive SAR-based design with guidance from X-ray crystallography and computational modeling. These efforts led to identification of the potent azaindole inhibitor XNW21015, with excellent kinase selectivity and promising PK profile of low clearance and sufficient exposure for in vivo animal studies. XNW21015 dose-dependently inhibited phosphorylation of SLP76(Ser376) in vitro and in vivo in response to anti-CD3 agonist antibody, with concomitant enhancement in T cell activation. Oral administration of XNW21015 in mouse syngeneic tumor models showed favorable PK profile and robust anti-tumor activity as both single agent and in combination with immune checkpoint inhibitors. In a humanized PDX (patient-derived xenograft) model, XNW21015 enhanced tumor-infiltrated lymphocytes (TIL). In summary, we have discovered a novel, highly potent and selective HPK1 inhibitor XNW21015 as promising small molecule I/O agent, as monotherapy or in combination with immune checkpoint inhibitors.
Citation Format: Yuchuan Wu, Rui Hao, Xi Chen, Xiao Liu, Yonghua Xie, Shihua Wang, Bingquan Gao, Jichun Wen, Zhenwei Wu, Wengui Wang, Haiyang Wei, Yonghan Hu, Xiaojun Liu, Meijie Le, Jing Qiang. Discovery of XNW21015, a novel, potent HPK1 inhibitor with excellent immune modulatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1821.
Abstract 1876: NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of potent payload by counteracting MUC16/CA125 effects
Authors: Grasso Luigi , Kline J. Bradford , Nicolaides Nicholas C. 
Published: April 2023

Abstract
Subsets of tumor-produced proteins, referred to as Humoral Immuno-Oncology (HIO) factors, can bind to IgG1 antibodies and suppress their immune-effector activities. Antibody-drug conjugates (ADCs) targeting tumor cell surface antigens can internalize and kill target cells upon liberation of their cytotoxic payload. Binding of the antibody component of an ADC by a HIO factor may potentially hamper the efficacy of a bound ADC. To assess any suppression of ADC’s activity by HIO factors, we evaluated the efficacy of a HIO-refractory ADC, NAV-001, and a HIO-bound ADC, SS1, both targeting mesothelin. The HIO factor MUC16/CA125 protein, which binds to SS1 ADC, was shown to have a negative effect on its internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of tumor cells regardless of MUC16/CA125 expression in vitro (EC50 ~20 pM) as well as in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor as a payload, demonstrated good stability in vitro and in vivo as well as robust bystander activity against tumor and stromal cells not expressing the target antigen mesothelin, while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenograft models from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed for NAV-001 and warrants NAV-001-PNU’s advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.
Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of potent payload by counteracting MUC16/CA125 effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1876.
Abstract 1980: Integrating common and rare genetic variants to predict cancer risks in diverse populations
Authors: Elmas Abdulkadir , Kittrell Hannah , Huang Kuan-lin 
Published: April 2023

Abstract
Inherited germline genetic factors contribute substantially to cancer risk. Large-scale DNA-Sequencing (DNA-Seq) studies have identified rare pathogenic variants in 5~10% of adult cancer cases, while genome-wide association studies (GWAS) have revealed hundreds of common variants that require aggregation using polygenic risk scores (PRS). However, rare and common genetic variants are often assessed separately and prohibit accurate risk assessments. Here, we developed methods to combine common and rare variants for improved cancer risk predictions using the diverse Mount Sinai BioMe population cohort of 49,854 individuals, including 22% African Americans, 1.9% Asian, 34% Latinx/Hispanic, 32% Europeans, and 11% of Other self-reported ancestries. By linking and analyzing EHR data, we identified over 4,000 cancer cases and another 815 individuals with family history, and analyzed 14 solid tumor types with at least 50 cases with pass-QC whole-exome sequencing (WES) data. The landscape of pathogenic variants differs across ancestries and highlighted multiple founder variants, while PRSs predict cancer risks in major cancer types across different ancestries. Notably, we detect significant interactions of common and rare genetic variants contributing to risks of selected cancer types. Machine learning models that combine both common and rare variants show higher predictive accuracy than using common or rare variants alone. Overall, our study underscores the importance of jointly considering common and rare genetic factors to provide accurate cancer risk assessment for diverse individuals.
Citation Format: Abdulkadir Elmas, Hannah Kittrell, Kuan-lin Huang. Integrating common and rare genetic variants to predict cancer risks in diverse populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1980.