bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2854: Logic gates controlled by priming receptors increase specificity and potency of CAR T cells
Authors: Williams Jasper , Martinez Kevin , Boroughs Angela , Lim Laura , Sandoval Marian , Sue Cate , Drever Matthew , Yao Anzhi , Choe Joseph , Sidorov Maxim , Phillips Sophia , Polyak Dina , Mohanty Suchismita , Santoro Stephen , Cooper Aaron , Haining W. Nicholas 
Published: June 2022

Abstract
CAR T cell therapies for solid tumors are limited by a paucity of tumor-specific single target antigens and insufficient potency due to limitations of CAR T biology. Logic gated (LG) CARs increase control of cell therapy activation and target cell killing by requiring recognition of two or more antigens through AND or AND-NOT Boolean logic. They represent an attractive strategy for cell therapy to improve the therapeutic index by increasing specificity for tumor antigens.
We created an AND logic gate cassette deliverable by CRISPR-mediated, non-viral, site-specific integration into human T cells. This logic gate activates expression of a MSLN-targeting CAR upon ALPP/G binding of a priming receptor (PrimeR) within high-grade serous carcinoma ovarian tumors. The PrimeR triggers proteolytic release of a chimeric, fully human transcription factor, which then translocates to the nucleus to induce expression of a minigene encoding a CAR. The PrimeR is built only from human protein sequences, reducing theoretical risk of cell therapy immunogenicity and rejection within a patient.
In order to test the specificity of our LG CARs, we integrated LG cassettes into a defined site in the T cell genome, and then co-cultured T cells with K562 cells engineered with only one target antigen (K562-ALPG or K562-MSLN), both target antigens (K562-ALPG/MSLN), or neither target antigen (K562). LG CAR T cells only killed K562-ALPG/MSLN cells. The specificity of this LG was also demonstrated in vivo in a dual-flank K562 model, in which only the ALPG/MSLN tumor was inhibited by LG CAR T cells. CAR expression was not observed on LG CAR T cells recovered outside the ALPG/MSLN tumor, and no growth inhibition was observed in K562-MSLN tumors, unlike a constitutive CAR T control. To model priming antigen heterogeneity expected in tumors, we mixed K562-MSLN cells with varying proportions of K562-ALPG/MSLN cells. We found that the presence of only 5-15% ALPG/MSLN cells was sufficient to effect killing of all target cells by the induced MSLN CAR. The ALPG/MSLN LG CAR will be tested as a component of AB-1015, a novel therapy for indications including ovarian, fallopian tube, or primary peritoneal cancer.
Citation Format: Jasper Williams, Kevin Martinez, Angela Boroughs, Laura Lim, Marian Sandoval, Cate Sue, Matthew Drever, Anzhi Yao, Joseph Choe, Maxim Sidorov, Sophia Phillips, Dina Polyak, Suchismita Mohanty, Stephen Santoro, Aaron Cooper, W. Nicholas Haining. Logic gates controlled by priming receptors increase specificity and potency of CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2854.
Abstract 286: Patient derived explant culture (PDEC) as a model for treatment resistant ERα positive breast cancers
Authors: Munne Pauliina , Räty Iiris , Peura Aino , Patrikainen Linda , Belitskin Denis , Klefstrom Juha 
Published: June 2022

Abstract
Breast cancer is the most frequent cancer and leading causes of women’s death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα+) phenotype that is initially responsive to antihormonal therapies, but often drug resistance emerges. Three-dimensional ex vivo cultures from patient-derived tumor tissue offer new opportunities for drug development and personalized treatment of cancer. However, one of the main challenges in establishing a tumor type faithful ex vivo tissue culture system is in optimization of biochemical and physical microenvironment to preserve desired phenotypic features. The ERα+ phenotype is not stable in cultured cells for reasons not fully understood. Together with Helsinki University Hospital we examined 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. In our current study we have utilized the PDEC model to identify novel biomarkers that could predict the emergence of tamoxifen resistance in primary breast tumors.
Citation Format: Pauliina Munne, Iiris Räty, Aino Peura, Linda Patrikainen, Denis Belitskin, Juha Klefstrom. Patient derived explant culture (PDEC) as a model for treatment resistant ERα positive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 286.
Abstract 2888: Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy
Authors: Liu Guizhong , Dai Zhengxi , Qu Jiagui , Shi Jianfeng , Zhao Qi , Cai Bin , Nguyen Aaron N. , Zheng Songmao , Xu Jiangchun , Li Yan , Du Felix , Luo Peter 
Published: June 2022

Abstract
Targeting CD28 for systemic T cell activation caused severe cytokine storm and multiorgan failure in an anti-CD28 antibody TGN1412 phase 1 trial. However, tumor specific CD28 targeting in a tumor associated antigen (TAA)×CD28 bispecific format, similar to the clinically validated tumor specific CD3 bispecific T-cell engagers (TCEs), offers an attractive solution to mitigate the serious safety concerns associated with systemic CD28 activation while delivering potent T-cell costimulatory signal. Our goal is to combine tumor specific bispecific TCEs targeting both CD3 and CD28, the two essential pathways in T cell activation for safe and long-lasting T cell-mediated synergistic immunotherapies. Following our success in utilizing the CD3 POWERbody™ TCE platform for tumor targeting with tight safety control, we further applied our suite of antibody technologies to develop tumor specific bispecific CD28 POWERbody TCE programs. Our NEObody™ and SAFEbody® technologies enabled us to discover and engineer species cross-reactive anti-CD28 antibodies targeting a unique and conserved epitope of CD28 as well as precision masking of the antigen binding sites for conditional activation in tumor microenvironment. The engineered tailor-made anti-CD28 arm and the tumor specific antigen targeting arm were then integrated into our proprietary bispecific platform that has robust CMC properties. Toward this end we developed multiple TAA×CD28 bispecific TCEs, including B7-H3×CD28, HER2×CD28, and TROP-2×CD28, etc., which possess fine-tuned specificity and safety profiles to minimize their on-target off-tumor toxicities and to prevent the systemic cytokine release syndrome (CRS). These TAA×CD28 bispecific POWERbodies have no superagonist activities on their own and can be activated for tumor antigen binding by the TAA arm and T cell engagement by the CD28 arm. When combined with TAA×CD3 TCEs and/or checkpoint inhibitors, they show strong synergistic T cell-mediated antitumor responses with robust safety profiles. Taken together, our tumor specific CD28 bispecific POWERbody TCEs exhibit enormous potential to fulfill the promises of safe and durable T cell-mediated immunotherapies when combined with CD3 bispecific POWERbody TCEs and/or checkpoint inhibitors.
Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Bin Cai, Aaron N. Nguyen, Songmao Zheng, Jiangchun Xu, Yan Li, Felix Du, Peter Luo. Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2888.
Abstract 2894: QL401, a dual PD-L1/CD47 blocker effective against both solid and hematological malignancies with improved blood safety
Authors: Tang Irene , Schwimmer Lauren , Gu Shenda , Prior Wei Wei , Tran Hieu V. , Chan Allan , McClain Anna , Chen Shihao , Cao Chuanzeng , Sun Chunyan , Si Meimei , Wang Guijiang 
Published: June 2022

Abstract
Upregulation of CD47, a “Do Not Eat Me” signal, is observed in nearly all solid and hematological malignancies. Engagement of CD47 on tumor cells with SIRPα on macrophages inhibits phagocytosis of tumor cells. Anti-CD47 antibodies block the CD47 - SIRPα engagement and reactivate phagocytosis of tumor cells by macrophages. Yet the ubiquitous expression of CD47 on normal cells, including red blood cells, presents a therapeutic challenge. Systemic targeting of CD47, by either anti-CD47 monoclonal antibodies or SIRPα-Fc fusion proteins, yielded only moderate clinical benefit due to severe adverse side effects, mainly anemia. QL401 is PD-L1 x CD47 bispecific antibody engineered to reduce binding to red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, the “Do Not Eat Me” signal, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic “Eat Me” signal. Therefore, QL401 is multi-functional antibody that re-actives both the innate and adaptive immune response. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse models of solid and hematological tumors showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone and in combination. In vitro safety evaluation of Q401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, Q401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells below normal range. A phase 1 dose escalation and expansion study is expected to start Q1 2022 to evaluate the safety, tolerability, and early efficacy of QL401.
Citation Format: Irene Tang, Lauren Schwimmer, Shenda Gu, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Chunyan Sun, Meimei Si, Guijiang Wang. QL401, a dual PD-L1/CD47 blocker effective against both solid and hematological malignancies with improved blood safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2894.
Abstract 2899: Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors
Authors: Kumar Roshan M. , Prigent Julie , Poullain Hombline , Kok Ayrin , George Carine , Ellouze Sami , Lu Yun-Yueh , Silver Rebecca , Monchecourt Clarisse , Fulton Ross B. , Zhang Qian , Beltraminelli Nicola , Moser Bernhard , Adrian Francisco , Schweizer Liang 
Published: June 2022

Abstract
Regulatory T cells (Tregs) contribute to immunosuppression within the tumor microenvironment and have been associated with poor outcomes in a range of cancers. Targeted depletion of tumor-infiltrating Tregs (TITRs) is an attractive therapeutic strategy with the potential to enhance antitumor immunity in patients who do not respond to current treatments. However, such approaches have been limited to date by a lack of markers that are highly specific for TITRs. CCR8 is a chemokine G protein-coupled receptor (GPCR) that has recently been shown to be specifically expressed on TITRs as compared to Tregs in the periphery or other T cells within tumors. Here, we report the development and characterization of HFB101110, a humanized monoclonal antibody against CCR8 with potent and specific antibody-dependent cellular cytotoxicity (ADCC) activity. HFB101110 specifically recognizes an epitope on the N-terminus extracellular domain of CCR8 and does not recognize the closely related chemokine receptor CCR4. HFB101110 acts through a dual mechanism of action, by both depleting CCR8+ cells via ADCC and blocking binding of the CCL1 chemokine to its receptor CCR8. Blockade by HFB101110 inhibited calcium flux and chemotaxis induced by the interaction between CCL1 and CCR8. Furthermore, HFB101110 showed potent single agent anti-tumor activity associated with depletion of intratumoral Tregs in a human CCR8 knock-in mouse model. HFB101110 mediated specific ex vivo killing of Tregs from primary patient tumor samples both in the presence, and in some cases the absence, of allogeneic NK cells. HFB101110 showed favorable pharmacokinetic properties and a favorable developability profile, and was well-tolerated in both wild-type mice and cynomolgus monkeys. HFB101110 is currently being developed as a novel immunotherapy for the treatment of solid tumors coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform.
Citation Format: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer. Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2899.
Abstract 2921: Probing PRMT5 inhibitors with distinct binding modes using surface plasmon resonance
Authors: Eells Rebecca , Baker Lynn K. , Bray Christopher , Ma Haiching 
Published: June 2022

Abstract
Epigenetic modifications are dynamic and reversible processes that regulate gene expression without altering the underlying sequence of the DNA. Gene expression is instead controlled by modification to the chromatin including DNA methylation, histone modifications, and chromatin remodeling. The proteins that perform these epigenetic modifications can be divided into three classes: writers, which perform the modifications; readers, which recognize the modifications; and erasers, which remove the modifications. While essential for normal cellular function, abnormal expression or alteration of the proteins involved in epigenetic regulation can lead to disease, such as cancer. As a result, epigenetic modifiers present attractive targets for the discovery and development of novel therapeutics. At Reaction Biology we offer a suite of services to enable epigenetic drug including the largest panel for epigenetic screening and profiling in the industry and biochemical and biophysical technologies to evaluate inhibition, potency, target occupancy, and even binding modes. Here we highlight our biophysical platform surface plasmon resonance (SPR) using the epigenetic target PRMT5 as an example. SPR was used to measure the binding kinetics of several small molecule inhibitors of PRMT5 and explore their distinct binding modes.
Citation Format: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma. Probing PRMT5 inhibitors with distinct binding modes using surface plasmon resonance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2921.
Abstract 2936: Multi-omic characterization of transitional cell populations in breast cancer
Authors: Iglesia Michael D. , Jayasinghe Reyka G. , Zhou Daniel Cui , Terekhanova Nadezhda V. , Herndon John , Karpova Alla , Chen Siqi , Deen Nataly Naser Al , Sato Kazuhito , Chen Feng , Veis Deborah J. , Fields Ryan C. , Gillanders William E. , Ding Li 
Published: June 2022

Abstract
Breast cancer is a heterogeneous collection of diseases grouped by hormone receptor status or by expression of key subtype-determining genes. Breast cancer subtypes, in particular basal-like breast cancer and the luminal breast cancer subtypes, differ by hormonal receptor status, proliferation, genomic instability and mutational signatures, treatment response, and prognosis. The highly distinct signatures of basal-like and luminal breast cancer suggest that they may have different cells of origin within the breast duct. As part of the Washington University Human Tumor Atlas Network (WU-HTAN) program, we generated multi-omic data for 53 samples from 37 breast cancer tumors and 4 normal adjacent tissues. Genomic subtyping was applied to both bulk and single-nucleus RNA sequencing. Analysis of single-nucleus gene expression and chromatin accessibility in epithelial cells underscores similarities between basal-like breast cancer and luminal progenitor cells within the breast duct, and between luminal breast cancer and mature luminal ductal cells. This study links distinct breast cancer subtypes to normal breast cell populations and suggests distinct cells of origin for these cancer types.
Citation Format: Michael D. Iglesia, Reyka G. Jayasinghe, Daniel Cui Zhou, Nadezhda V. Terekhanova, John Herndon, Alla Karpova, Siqi Chen, Nataly Naser Al Deen, Kazuhito Sato, Feng Chen, Deborah J. Veis, Ryan C. Fields, William E. Gillanders, Li Ding. Multi-omic characterization of transitional cell populations in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2936.
Abstract 2942: Robust sample recovery post-digital PCR for downstream genomic applications
Authors: Gutierrez Kimberley , Foret Benjamin , Jovelet Cécile , Mallory Allison C. 
Published: June 2022

Abstract
Droplet microfluidics technologies, and particularly, digital PCR have provided highly precise and sensitive detection of genetic targets. There is a strong interest for researchers to reuse sample due to sample scarcity, as well as, to further characterize or validate their experimental findings. Historically, recovery of PCR products for downstream genomic testing applications has been challenging due to the stability of the sample post-reaction. Stilla Technologies has developed Crystal Digital PCR™ and the naica® system, a flexible and highplex droplet and imaging-based digital PCR platform that allows for multi-color detection of genetic targets with the ability to also recover samples after the reaction is performed.
This study shows how the 6-color naica digital PCR system workflow can be combined with a simple protocol for sample recovery. DNA contained in the recovered emulsion is extracted using a standard chloroform protocol that takes approximately 1 hour. DNA recovery rate assessment showed high percentage recovery of droplet sample and on average, 70% of the total DNA present from the initial sample recovered. Recovered DNA from the droplet crystal was sequenced and the results were confirmed by qPCR.
The droplet and sample recovery protocol post-digital PCR has potential applications to support validation of Crystal Digital PCR results, concordance alongside a multitude of genomic platforms, and further characterization of biomarkers and mutations with profiling platforms such as NGS.
Citation Format: Kimberley Gutierrez, Benjamin Foret, Cécile Jovelet, Allison C. Mallory. Robust sample recovery post-digital PCR for downstream genomic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2942.
Abstract 2953: Subtype-specific and structure variation induced 3D genome alteration in acute myeloid leukemia
Authors: Xu Jie , Song Fan , Zhang Baozhen , Lyu Huijue , Kobayashi Mikoto , Zhao Ziyu , Hou Ye , Wang Xiaotao , Luan Yu , Jia Bei , Stasiak Lena , Wang Qixuan , Jin Qi , Jin Qiushi , Fu Yihao , Hardison Ross C. , Dovat Sinisa , Platanias Leonidas C. , Yang Yue , Yamada Tomoko , Viny Aaron D. , Levine Ross L. , Claxton David F. , Broach James R. , Zheng Hong , Yue Feng 
Published: June 2022

Abstract
Acute myeloid leukemia (AML) represents a set of heterogeneous myeloid malignancies hallmarked by mutations in epigenetic modifiers, transcription factors, and kinases that can cause epigenetic reshaping. It is unclear to what extent AML mutations drive chromatin 3D structure alteration and contribute to myeloid transformation. We first performed Hi-C and whole-genome sequencing in 25 AML patient samples and seven healthy donor samples, and identified recurrent alterations of A/B compartments, TADs, and chromatin loops that are unique to different subtypes. To investigate how altered chromatin organization contributes to transcriptional misregulation, we performed RNA-Seq, ATAC-Seq and CUT&ag for CTCF, H3K27ac, and H3K27me3 in the same AML samples. We identified extensive and recurrent AML-specific promoter-enhancer and promoter-repressor loops. We performed both CRISPR deletion and interference experiments and validated two repressor loops that downregulated cancer related genes IKZF2 and RTTN. Furthermore, by using our recently developed algorithm, we identified structural variation-induced enhancer-hijacking and repressor-hijacking events in AML samples. We further demonstrated the role of hijacked enhancers in AML cell growth by CRISPR screening, and the role of hijacked repressors by CRISPR de-repression. We performed whole-genome bisulfite sequencing in 20 AML and normal samples, and showed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Finally, by treating the AML cells with the DNA hypomethylating agent and performing triple knockdown of DNMT1/3A/3B, we demonstrated the impact of altered DNA methylation on gene expression and 3D genome organization. Overall this study provides an invaluable resource for leukemia studies and also highlighted the role of repressor-loops and hijacked cis-elements in gene regulation and human diseases.
Citation Format: Jie Xu, Fan Song, Baozhen Zhang, Huijue Lyu, Mikoto Kobayashi, Ziyu Zhao, Ye Hou, Xiaotao Wang, Yu Luan, Bei Jia, Lena Stasiak, Qixuan Wang, Qi Jin, Qiushi Jin, Yihao Fu, Ross C. Hardison, Sinisa Dovat, Leonidas C. Platanias, Yue Yang, Tomoko Yamada, Aaron D. Viny, Ross L. Levine, David F. Claxton, James R. Broach, Hong Zheng, Feng Yue. Subtype-specific and structure variation induced 3D genome alteration in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2953.