bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 871: Development of a smartphone-based electrochemiluminescence biosensor for dopamine detection in advanced breast cancer
Authors: Kwon Hyun J. , Uppala Padma P. Tadi , Rivera Elmer C. , Neto Mabio R. , Marsh Daniel , Swerdlow Jonathan J. , Summerscales Rodney L. 
Published: September 2020

Abstract
Introduction: Studies conducted in our laboratory on proteomic profiling of breast cancer serum among women by shotgun LC-MS methodology have identified several biomarkers for early detection of breast cancer. However, not all of the identified biomarkers have been validated due to costs involved with validation tests. The development of a reliable, cost-effective highly sensitive portable system, the Electrochemiluminescence (ECL) biosensor will enable us to validate identified biomarkers that have valuable diagnostic applications.
The purpose of this study was to detect dopamine, which has been identified as a biomarker in advanced breast cancer. Dopamine and its receptors act as novel therapeutic agents in advanced breast cancer. Dopamine significantly enhances the efficacy of commonly used anticancer drugs through its antiangiogenic action.
Methods: In this work, a compact, mobile phone-based ECL sensor apparatus was developed using the phone cameras, screen-printed electrodes (SPE), and mobile app for dopamine detection. Methods of DC voltage application for ECL reaction were comprehensively studied from the mobile phone itself or external power. Under optimized sensing conditions, with disposable carbon SPE and 20 mM coreactant tri-n-propylamine (TPrA), acceptable repeatability and reproducibility were achieved in terms of relative standard deviation (RSD) of intra- and interassays, which were 6.7 and 5.5 %, respectively. The biochemical compound dopamine was measured due to its ECL quenching characteristics and its clinical significance in breast cancer detection and therapeutic properties. The quenching mechanism of Ru(bpy)32+/TPrA by dopamine was investigated based on the estimation of the constants of the Stern-Volmer equations.
Results: The linear range for detectable dopamine concentration was from 1.0 to 50 µM (R2 = 0.982). As the developed mobile phone-based ECL sensor is simple, small and assembled from low-cost components, it offers new opportunities for the development of inexpensive analytical methods and compact sensors.
Conclusion: The ECL sensor demonstrated that a new instrumentation with mobile technology in the point-of-care diagnostics of breast cancer could provide reliability and sensitivity of a high-end equipment. This project is funded by the NSF CBET division.
Citation Format: Hyun J. Kwon, Padma P. Tadi Uppala, Elmer C. Rivera, Mabio R. Neto, Daniel Marsh, Jonathan J. Swerdlow, Rodney L. Summerscales. Development of a smartphone-based electrochemiluminescence biosensor for dopamine detection in advanced breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 871.
Abstract 879: Functional and single-cell assessment of CRISPR-modified CAR-T cells from NSCLC patients and healthy donors
Authors: Padalia Zinkal , Dunn Andrew , Karagiannis Konstantinos , McEwan Brigid , Kuppuraju Meghna , Sagert Jason , Karnik Sushant , Dequeant Mary-Lee , Terrett Jonathan , Kalaitzidis Demetrios 
Published: September 2020

Abstract
Cancer patients that have undergone multiple lines of treatment can have dysfunctional immune systems. In both solid tumors and hematological malignancies, T cells have been reported to be in various states of dysfunction including senescence or exhaustion. In order to assess the potency of CAR-T cells derived from cancer patients, we created CAR-T cells targeting CD70 from non-small cell lung cancer (NSCLC) patients as well as healthy donors. Anti-CD70 CAR-T cells were created by using CRISPR/Cas9 to insert the CAR cassette into a knocked-out TRAC locus. The TRAC knock-out eliminates any TCR-mediated effector functions. CAR-T preparations from either NSCLC patients or healthy donors were assessed in vitro for T cell effector functions including cell killing, cytokine secretion and expansion in the presence of lung tumor cells expressing antigen. CAR-T cells from NSCLC patients and healthy donors were also assessed for their ability to control human lung cancer-derived tumors in immunocompromised mice. Following these functional assessments, the heterogeneity of CAR-T preparations derived from different sources was characterized further by performing single-cell RNA sequencing analysis and single-cell protein analysis (CITE-Seq and single cell cytokine secretion). A superior understanding of CAR-T cell heterogeneity and donor variability could aid in producing more efficacious drug products for cancer.
Citation Format: Zinkal Padalia, Andrew Dunn, Konstantinos Karagiannis, Brigid McEwan, Meghna Kuppuraju, Jason Sagert, Sushant Karnik, Mary-Lee Dequeant, Jonathan Terrett, Demetrios Kalaitzidis. Functional and single-cell assessment of CRISPR-modified CAR-T cells from NSCLC patients and healthy donors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 879.
Abstract 880: Allogeneic CAR-T cell products containing 10 gene edits using CRISPR/Cas9 can retain full functionality in vivo and in vitro
Authors: McEwan Brigid , Kuppuraju Meghna , Padalia Zinkal , Terrett Jonathan , Kalaitzidis Demetrios 
Published: September 2020

Abstract
Hematologic malignancies have proven most responsive to CAR-T therapies. However, there is significant variability in the depth and duration of response to autologous CAR-T cells. Furthermore, CAR-T responses in solid malignancies have been minimal. T cells from cancer patients can be compromised by the disease and prior treatments, and the use of allogeneic CAR-T products could potentially provide a more robust therapy. However, even CAR-T cells from healthy donors may benefit from additional gene edits that could enhance effector function, increase durability, evade immune mechanisms and/or combat the tumor microenvironment. These types of additional CAR-T features are readily enabled by CRISPR/Cas9 technology. While recent clinical data has demonstrated the persistence of therapeutic T cells that had been edited with CRISPR, the extent of gene editing that therapeutic T cells can tolerate has not been fully described. Herein, we have generated CAR-T cells with 10 gene edits. Loss of function alleles were produced in 9 genes and a CAR cassette was knocked into the TRAC locus via homology-directed repair. CD19-directed CAR-T cells with these 10 gene edits were fully functional in vitro, as shown by their ability to expand and kill target cells and secrete cytokines while remaining non-transformed. These cells were also highly efficacious in an in vivo model of CD19+ malignancy. Importantly, these edits, which produced insertions and deletions in target genes, could be detected in the blood of mice several months post injection. These data demonstrate that CRISPR/Cas9 can be used to create highly edited allogeneic CAR-T cells, unlocking the potential to enhance many functions relevant to CAR-T health and anti-tumor activity.
Citation Format: Brigid McEwan, Meghna Kuppuraju, Zinkal Padalia, Jonathan Terrett, Demetrios Kalaitzidis. Allogeneic CAR-T cell products containing 10 gene edits using CRISPR/Cas9 can retain full functionality in vivo and in vitro [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 880.
Abstract 89: Role of CDK8 and CDK19 in STAT1 phosphorylation at serine 727
Authors: Li Jing , Liang Jiaxin , Wang Lili , Broude Eugenia , Roninson Igor , Chen Mengqian 
Published: September 2020

Abstract
Transcription factor STAT1 is part of the JAK/STAT signaling cascade; it plays an essential role in mediating responses to interferons (IFN). STAT1 modulates many cellular processes and has been implicated in both tumor-suppressing and tumor-promoting activities. IFNγ treatment induces STAT1 phosphorylation at tyrosine 701, enabling the translocation of STAT1 from cytoplasm to the nucleus. STAT1 is also phosphorylated at serine 727; S727 phosphorylation modulates the transcriptional activity of STAT1. Transcription-regulating kinase CDK8 was shown to be primarily responsible for IFNγ-induced STAT1 S727 phosphorylation, and serine-phosphorylated form of STAT1 was proposed as a potential pharmacodynamic (PD) marker for the activity of CDK8, an emerging cancer drug target. However, the role of CDK8 in STAT1 S727 phosphorylation in the absence of IFNγ treatment is controversial, as is the role of CDK19, a closely related paralog of CDK8, as well as the relative contributions of kinase-dependent and kinase-independent activities of CDK8 and CDK19. We have found that Senexin B, a selective CDK8/19 inhibitor, decreased both IFNγ-induced and basal STAT1 S727 phosphorylation in all the tested types of tumor cells but some phosphorylation was maintained even at the highest concentrations of Senexin B. We then generated a series of derivatives of human 293 cells with CRISPR-mediated knockout of CDK8, CDK19 and both CDK8 and CDK19 (double knockout, dKO), with subsequent reconstitution of dKO with wild-type (WT) CDK8 or CDK19 or with kinase-dead (KD) mutants of these proteins. The knockout of CDK8 or CDK19 individually had only a moderate effect on IFNγ-induced and basal STAT1 S727 phosphorylation, which remained susceptible to Senexin B. In contrast, such phosphorylation was strongly decreased in dKO cells, where it was unaffected by Senexin B. Senexin B-sensitive STAT1 S727 phosphorylation was restored by re-introduction of WT CDK8 or CDK19 but not of their KD mutants. Hence, both CDK8 and CDK19 mediate STAT1 S727 phosphorylation in kinase-dependent manner. We also tested different cytokines and stress-inducing agents for the ability to induce STAT1 S727 phosphorylation in WT and dKO cells. Several treatments, including serum stimulation, EGF, TNFα, etoposide and taxol, increased this phosphorylation in dKO cells, indicating that STAT1 serine phosphorylation induced by many treatments was CDK8/19-independent. Hence, great caution needs to be utilized in using STAT1 S727 phosphorylation as a PD marker for CDK8 activity.
Citation Format: Jing Li, Jiaxin Liang, Lili Wang, Eugenia Broude, Igor Roninson, Mengqian Chen. Role of CDK8 and CDK19 in STAT1 phosphorylation at serine 727 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 89.
Abstract 893: A chimeric PD1-CD28 switch receptor enhances the activity of TRuC-T cells
Authors: McCarthy Derrick P. , Guyette Sarah , Lofgren Michael , Sethuraman Jyothi , DeSilva Thamara , Aziz Ahmar , Patterson Troy , Datari Shruti , Chan Tiffany , Kieffer-Kwon Philippe , Rold Christopher J. , Singh Reshma , Ding Jian , Horton Holly , Barnitz R. Anthony , Cornforth Andrew , Tighe Robert , Hofmeister Robert J. , Gutierrez Dario A. 
Published: September 2020

Abstract
Cluster of differentiation 28 (CD28) and programmed death receptor 1 (PD-1) are members of the CD28 superfamily of co-receptors that have critical roles in the regulation of T cell-mediated immunity and inflammation. Ligation of CD28 synergizes with T cell receptor (TCR) signaling to enhance T cell activation through the PI3K-Akt pathway, while PD-1 ligation by its ligands (PD-L1/L2) sequesters critical mediators of signaling from the TCR complex, thereby shunting T cell activation and effector function. Thus, the expression of PD-L1/L2 in solid tumors may pose a significant barrier to anti-tumor immunity and the efficacy of adoptive T cell therapies (ACT). We have recently described a novel class of engineered T cells that integrate a T cell receptor fusion construct (TRuC®) into the natural TCR complex, thereby reprogramming the specificity of the T cell to recognize tumor surface antigen in a human leukocyte antigen (HLA)-independent fashion. TC-210 T cells expressing mesothelin (MSLN) specific TRuCs demonstrate robust anti-tumor immunity in preclinical models of mesothelioma, protecting mice from tumor re-challenge while inducing lower levels of inflammatory cytokine release when compared to a 2nd generation MSLN-targeted CAR T. Here, we show that co-expression of a PD-1:CD28 switch receptor comprising the PD-1 extracellular domain fused to the CD28 intracellular domain, enhances the activity of TC-210 T cells. When compared to TC-210 expressing only the TRuC, co-expression of PD1:CD28 was able to restore PD-L1 mediated inhibition of cytokine production and proliferation in co-culture with tumor cells. In vivo and molecular mechanistic studies are currently underway.
Citation Format: Derrick P. McCarthy, Sarah Guyette, Michael Lofgren, Jyothi Sethuraman, Thamara DeSilva, Ahmar Aziz, Troy Patterson, Shruti Datari, Tiffany Chan, Philippe Kieffer-Kwon, Christopher J. Rold, Reshma Singh, Jian Ding, Holly Horton, R. Anthony Barnitz, Andrew Cornforth, Robert Tighe, Robert J. Hofmeister, Dario A. Gutierrez. A chimeric PD1-CD28 switch receptor enhances the activity of TRuC-T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 893.
Abstract 899: Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1
Authors: Rachid Madani , Tijeras-Raballand Annemilaï , Serdjebi Cindy , Brun Sonia , Ansaldi Christelle , Raymond Eric , Halfon Philippe 
Published: September 2020

Abstract
Introduction:Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, leading to 75,000 deaths annually. Immunotherapeutic intervention has emerged as a novel effective treatment to delay the progression of aggressive tumors and suppress tumor recurrence and metastasis. However, few clinical immunotherapy trials have been conducted in HCC patients and there is an unmet need for novel therapeutic strategies. Combinations of conventional and novel treatments with immune-oncologic agents are now regarded as a therapy that can dramatically improve the outcome of patients with HCC.GNS561 is a lysosomotropic small molecule that was investigated in the context of antitumor activity alone or in combination with a PD-1 inhibitor using a transgenic immunocompetent mouse model (ASV-B).
Materials and Methods: 40 ASV-B mice were treated with either the vehicle (p.o. water pH= 4, 5 days per week), GNS561 (p.o. 50 mg/kg/5 days per week), mouse anti-PD1 antibody (i.p. 10 mg/kg/twice a week [BIW]) or a combination of GNS561 and mouse anti-PD1 (p.o. 50 mg/kg/5 days per week and i.p. 10 mg/kg/BIW respectively) for 8 weeks. Tumor burden was evaluated by measuring the liver volume and blood flow velocity in the coeliac trunk by US/doppler 4 and 8 weeks (W8) after treatment start, the macronodules count and liver weight at sacrifice (W8). Intra and peritumoral CD8+ cells were counted.
Results: All treatments were well tolerated. No significant response was observed with the anti-PD1 monotherapy compared with the vehicle. At W8, GNS561 alone or in combination with an anti-PD-1 showed a significant rapid and durable tumor response based on the macronodule count, decreased liver blood flow in the coeliac trunk, liver volume and weight (-59% and -77%; -18% and -31%; -36% and -37%; -37% and -52%, respectively). Based on preliminary mechanistic data, GNS561 alone or in combination showed an increase in the count of CD8+ cells penetrating the tumor site compared to the vehicle and the anti-PD1 alone, suggesting GNS561 may reinstore the anti-PD1 activity by facilitating CD8+ cells to reach the tumor site to exert their antitumoral activity.
Conclusion: GNS561 alone or in combination with an anti-PD1 showed a significant antitumoral response. A combination of GNS561 with an anti-PD1 could then be of clinical interest in the treatment of hepatocelullar carcinoma.
Citation Format: Madani Rachid, Annemilaï Tijeras-Raballand, Cindy Serdjebi, Sonia Brun, Christelle Ansaldi, Eric Raymond, Philippe Halfon. Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 899.
Abstract 901: Ferritin nanocages to deliver CD47 antagonist, SIRPγ, for cancer immunotherapy
Authors: Choi Yoonjeong , Kim Insan 
Published: September 2020

Abstract
Eliciting effective tumor antigen-specific immunity requires targeting the initial stages of the anticancer immunity cycle, including activation of antigen presenting cells (APCs) for tumor antigen uptake and presentation, and T cell priming. Here, the research aimed to explore the novel immunotherapeutic strategy using protein nanocage platform that enhances the phagocytic activity of phagocytes in combination with treatment of immunogenic cell death inducing agents, which could boost processing of antigens by APCs, thereby trigger efficient antitumor immunity. The recombinant ferritin protein nanocages expressing SIRPγ peptides, named FHSirpγ, was designed to interact with CD47 of cancer cells, which could effectively blocking ‘don't eat me signal', CD47. The binding affinity of FHSirpγ to cancer cells was reinforced by adapting several mutations on protein sequence, which showed up to 10 folds of improvement. Therefore, FHSirpγ was able to successfully stimulate phagocytosis of phagocytes toward various cancer cells, e.g. HT29, B16F10, CT26.CL25 and J558, up to approximately 2 folds in vitro. In the aspect of improvement in antigen release, Carfilzomib(CFZ), the FDA approved 2nd generation proteasome inhibitor on multiple myeloma, was treated to cancer cells, which showed tolerable level of cell cytotoxicities and enhanced release of danger associated molecular patterns(DAMPs), such as HSP70 and HMGB1, which were detected from cell culture medium after 24hrs of incubation on above mentioned cell lines. The antitumorigenic efficacy was preliminary verified in the case of B16F10 and J558 implanted murine tumor model, which showed approximately 75% of tumor growth regression when FHSirpγ and CFZ were treated intravenously. Overall, treatment of FHSirpγ showed antitumor efficacy via enhancement of phagocytosis in vivo and in vitro, especially when combined with immunogenic cell death inducer.
Citation Format: Yoonjeong Choi, Insan Kim. Ferritin nanocages to deliver CD47 antagonist, SIRPγ, for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 901.
Abstract 904: Stimulation and expansion of oncogene-reactive tumor infiltrating T cells through combined Ad-HER2Δ16 vaccination and anti-PD1 enable anti-tumor responses against established HER2 BC
Authors: Crosby Erika J. , Acharya Chaitanya , Rabiola Christopher , Muller William J. , Chodosh Lewis A. , Broadwater Gloria , Shepherd Jonathan , Hollern Daniel , He Xiaping , Perou Charles M. , Ashby Benjamin K. , Vincent Benjamin G. , Morse Michael A. , Lyerly Herbert K. , Hartman Zachary C. 
Published: September 2020

Abstract
Despite promising advances, overcoming immune suppression and driving productive immune responses in the tumor microenvironment remains a significant challenge. Using a spontaneous breast cancer model, we found that vaccination targeting HER2d16, a highly expressed driver of oncogenicity and HER2-therapeutic resistance, elicited significant anti-tumor responses. In contrast, vaccines targeting a non-driver tumor-specific antigen (GFP) or unique non-driver tumor neoepitopes had no impact on tumor occurrence or progression. While vaccine-induced HER2-specific CD8+ T cells were essential for responses, tumors treated therapeutically with a vaccine alone ultimately progressed. However, long-term tumor control and complete tumor regression was only achieved when vaccine was combined with immune-checkpoint blockade (anti-PD1). Single cell RNAsequencing of tumor-infiltrating T cells (TILs) revealed that while vaccination expanded CD8 T cells within the tumor, only the combination of vaccine with anti-PD1 therapy induced a tumor rejection activation signature that was identified in the expanded T cell clones. We go on to use the single cell data to clone and reexpress the TCRs from expanded TILs from vaccinated mice and show that they are HER2-reactive. This data conclusively demonstrates the efficacy of this vaccination strategy in expanding tumor rejection T cells and supports its further evaluation in an ongoing Phase II trial (NCT03632941). The workflow used to identify and clone expanded, tumor specific T cells has broad potential applications across tumor types and treatment platforms.
Citation Format: Erika J. Crosby, Chaitanya Acharya, Christopher Rabiola, William J. Muller, Lewis A. Chodosh, Gloria Broadwater, Jonathan Shepherd, Daniel Hollern, Xiaping He, Charles M. Perou, Benjamin K. Ashby, Benjamin G. Vincent, Michael A. Morse, Herbert K. Lyerly, Zachary C. Hartman. Stimulation and expansion of oncogene-reactive tumor infiltrating T cells through combined Ad-HER2Δ16 vaccination and anti-PD1 enable anti-tumor responses against established HER2 BC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 904.