bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1875: Novel cell-based bioassays for monoclonal antibody and bispecific molecules in PD-1 blockade monotherapy and combination therapy
Authors: Grailer Jamison , Gilden Julia , Wang Jun , Garvin Denise , Stecha Pete , Hartnett Jim , Edenson Steven , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: June 2022

Abstract
Programmed death 1 (PD-1) is an immune checkpoint (IC) receptor that negatively regulates T-cell immune function. Blocking the interaction of PD-1 with its ligand PD-L1 unleashes the immune system and enhances anti-tumor responses. Immunotherapy using PD-1 blockade has led to a paradigm shift in cancer drug discovery, due to its durable effect against a wide variety of cancers. However, despite its tremendous clinical success in cancer treatment, a significant fraction of patients and tumor types remain unresponsive to this therapy. This has led to the development of combination therapies combining PD-1 checkpoint inhibitors with a broad range of clinically active treatments including those targeting other IC receptors. A major challenge in immunotherapy drug development is the lack of quantitative and reproducible functional assays as existing methods rely heavily on primary immune cells and are highly variable. Here, we report the development of a suite of cell line-based reporter bioassays for monoclonal antibody targeting human PD-1/PD-L1, or bispecific molecules target PD-1/PD-L1 and a co-stimulatory receptor (e.g., 4-1BB, OX40, ICOS) or an immune inhibitory receptor (e.g., CTLA-4, LAG-3, TIGIT). A mouse PD-1/PD-L1 assay and a human PD-1/PD-L2 assay are also developed and can be used in parallel with human PD-1/PD-L1 assay to address preclinical study and assay specificity. Each of these assays consist of two engineered cell lines: a T effector cell line that express a luciferase reporter driven by specific promoter/response elements responding to the intracellular signals mediated by the T cell receptor (TCR), PD-1 and the second IC receptor, and an artificial antigen presenting cells (aAPCs). Particularly, the combination bioassays are able to measure the synergetic effect of PD-1 blockade with a second IC inhibitor receptor blockade or a costimulatory receptor activation. These reporter-based assays reflect the mechanisms of action for the therapeutic drugs of interest and are sensitive and quantitative. They are prequalified according to ICH guideline and demonstrated the performance characteristics (specificity, precision, accuracy, and linearity) to be used as potency assay for product release and stability studies during immunotherapy drug development and manufacture.
Citation Format: Jamison Grailer, Julia Gilden, Jun Wang, Denise Garvin, Pete Stecha, Jim Hartnett, Steven Edenson, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Novel cell-based bioassays for monoclonal antibody and bispecific molecules in PD-1 blockade monotherapy and combination therapy [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 1875.
Abstract 1885: Semi and fully automated immunostaining sample preparation platforms improve live leukocyte recovery, reproducibility, and cytometry data quality
Authors: Lye Melvin , Eberle Christoph , Wang Ann , Feld Geoffrey K. , Kim Namyong 
Published: June 2022

Abstract
Limited innovation in automated cell and organelle sample preparation methodology limits the effectiveness of modern analytical methods, such as single-cell ‘omics, flow and mass cytometry. These techniques traditionally rely on manual centrifugation-based protocols for cell washing and suspension preparation, hampering researchers’ access to the reproducibility and scalability benefits of automation. We have developed a suite of cell suspension preparation systems that enable semi and full automation of cell washing protocols. These Laminar Wash࣪ technologies robustly, gently, and efficiently remove debris, dead cells, and unbound reagent using laminar flow and liquid handling robotics, rather than turbulent and harsh pelleting-plus-pipetting methods. Adaptation of standard protocols to Laminar Wash automation typically improves repetitive immunostaining processes and workflows, in terms of reduced hands-on time and inter- and intra-operator variability. We demonstrate the superior live cell retention and reproducibility of Laminar Wash over centrifugation in processing murine and humanized mouse peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) for flow cytometry. Furthermore, we show how Laminar Wash improves flow cytometry data quality, in terms of debris removal and separation of immune cell subsets for both PBMCs and TILs. Overall, these results show how Laminar Wash methodology assists in standardizing sample preparation for cytometric analysis, an important and unmet need in cancer immunotherapy discovery and manufacturing workflows.
Citation Format: Melvin Lye, Christoph Eberle, Ann Wang, Geoffrey K. Feld, Namyong Kim. Semi and fully automated immunostaining sample preparation platforms improve live leukocyte recovery, reproducibility, and cytometry data quality [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 1885.
Abstract 1886: Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug
Authors: Lee Won Yong , Ponthan Frida , Sonis Stephen T. 
Published: June 2022

Abstract
Squamous cell carcinomas (SCCs) are the dominant form of cancers of the upper aerodigestive tract. Main risk factors are smoking and human papilloma virus (HPV) infection. Despite the HPV vaccination efforts, the number of oropharyngeal cancers (OSCCs) has been steadily increasing especially in males. Standard of care primarily focuses on the surgical removal of cancerous tissues followed by chemoradiation therapy. However, the recurrence rate of OSCCs remains fairly high as the tumor frequently develops therapy resistance and more effective therapeutic regimens are needed. The chronic inflammatory state yet paradoxical immunosuppressive tumor microenvironment has been regarded as a cause of therapy resistance and suggested as a potential therapeutic target. Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) contribute to pro-inflammatory tissue responses. TLR2 present in the OSCC tumor appears to play important roles in regulating immune responses and promoting pro-inflammatory tumor microenvironment. GM-1111 is a synthetic glycosaminoglycan-based anti-inflammatory molecule that potently inhibits PRRs such as TLR2 and NLRP3 inflammasome. In addition, GM-1111 inhibits multiple angiogenic molecules - CXCL12, VEGF, and FGF2. We hypothesized that GM-1111 might be able to reduce OSCC tumor growth by simultaneously disrupting pro-inflammatory as well as angiogenic signaling. To test this hypothesis, male CD1 nude mice bearing FaDu cell tumor in the back were treated with either (1) vehicle, (2) GM-1111 (30 mg/kg, q.d., s.c.), (3) vehicle with irradiation (2 Gy/day x 5 days), or (4) GM-1111 with irradiation 17 days. Established tumors grew in two phases from slow for the initial 7 days to fast growths during the remaining days. Irradiation- or drug-induced tumor regression was observable about 5 days after the last radiation therapy (day 10). Compared to the vehicle only (1) treatment group, GM-1111 treated animals (groups 1 vs. 2: p = 0.0032; groups 1 vs. 3: p &lt; 0.0001; groups 1 vs. 4: p &lt; 0.0001) demonstrated significantly reduced tumor growth. These results suggest that GM-1111 has a potential to reduce OSCC and further confirm our previous orthotopic human tongue SCC-25 cell xenograft study data.
Citation Format: Won Yong Lee, Frida Ponthan, Stephen T. Sonis. Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug [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 1886.
Abstract 1932: Pollock: Fishing for cell states
Authors: Storrs Erik , Zhou Daniel Cui , Wendl Michael C. , Wyczalkowski Matthew A. , Karpova Alla , Wang Liang-Bo , Li Yize , Southard-Smith Austin , Jayasinghe Reyka G. , Yao Lijun , Liu Ruiyang , Wu Yige , Terekhanova Nadezhda V. , Zhu Houxiang , Herndon John M. , Chen Feng , Gillanders William E. , Fields Ryan C. , Ding Li 
Published: June 2022

Abstract
The use of single-cell methods is expanding at an ever-increasing rate. While multiple algorithms address the task of cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a reference dataset, and classification interpretability. Here, we introduce Pollock, a suite of algorithms for cell type identification that is compatible with popular single cell methods and analysis platforms, provides a series of pretrained human cancer reference models, and reports interpretability scores that identify the genes that drive cell type classifications. Our model combines two important approaches, one each from machine learning and deep learning: a variational autoencoder (VAE) and random forest classifier, to make cell type predictions. Pollock is highly versatile, being available as a command line tool, Python library (with scanpy integration), or R library (with Seurat integration), and can be installed as a conda package, or in containerized form via Docker. To allow for easier pan-disease and pan-tissue analyses, Pollock also ships with a library of pretrained cancer type specific and agnostic modules that were trained on expertly-curated single cell data that are ready to “plug and play” with no additional annotation or training required. Conversely, Pollock also allows for the training of custom classification modules, if an annotated reference single cell dataset is available. These pretrained models were fitted on manually curated and annotated single cell data from eight different cancer types spanning three single cell technologies (scRNA-seq, snRNA-seq, and snATAC-seq). Pollock also provides feature importance scores that allow for cell type classifications to be traced back to the genes influencing a particular cell type classification, further promoting biological interpretability. These scores could allow for new, technology-specific biomarker discovery. We also demonstrate the utility of Pollock by applying it in a pan-cancer single cell immune analysis.
Citation Format: Erik Storrs, Daniel Cui Zhou, Michael C. Wendl, Matthew A. Wyczalkowski, Alla Karpova, Liang-Bo Wang, Yize Li, Austin Southard-Smith, Reyka G. Jayasinghe, Lijun Yao, Ruiyang Liu, Yige Wu, Nadezhda V. Terekhanova, Houxiang Zhu, John M. Herndon, Feng Chen, William E. Gillanders, Ryan C. Fields, Li Ding. Pollock: Fishing for cell states [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 1932.
Abstract 1943: Elucidating early tumor microenvironmental changes due to immunotherapy with label-free Raman spectroscopy and machine learning
Authors: Paidi Santosh K. , Troncoso Joel R. , Rajaram Narasimhan , Barman Ishan 
Published: June 2022

Abstract
Clinical benefit is observed in only a limited fraction of patients that undergo immunotherapy for a variety of cancer types. Therefore, the determination of robust biomarkers for accurate prediction of response to immunotherapeutic agents remains one of the grand challenges of 21st century. Our primary goal was to investigate if phenotypic differences due to treatment with ICI can be recognized with minimally perturbative molecular tools and guide personalization of immunotherapy. In this work, we provide first-in-class evidence that Raman spectroscopy (an optical method) and machine learning allows sensitive detection of early changes in biomolecular composition of tumors in response to immunotherapy with immune checkpoint inhibitors (ICI). By studying the widely investigated CT26 murine model of colorectal cancer treated with anti-CTLA-4 (n = 8) and anti-PD-L1 (n = 7) ICIs and controls (n = 10), we revealed new biological insights into the nature and degree of microenvironmental modifications induced by exposure to clinically relevant doses of ICI. Multivariate curve resolution-alternating least squares (MCR-ALS) decomposition of Raman spectral datasets revealed early changes in lipid, nucleic acid, and collagen content of the tumors following therapy. We trained supervised classification models - support vector machines and random forests on the spectral datasets and showed that the models provided excellent prediction accuracies for response to both ICIs and delineated spectral markers specific to each therapy, consistent with their differential mechanisms of action. On the basis of these findings, we sought to determine if the tumor microenvironment changes delineated by Raman spectroscopy correspond to proteomic alterations via quantitative mass spectrometry. Of the more than 6600 proteins identified, about 136 proteins were found to be significantly different in treated tumors relative to controls (p &lt; 0.05 and log2 fold change of &gt; 2). A subset of these differentially expressed proteins is known to regulate lipid metabolism and extracellular matrix composition, while others are known to control transcriptome dynamics or are associated with response to ICI therapy, thereby corroborating our Raman spectroscopic measurements. Our observation of biomolecular changes in the TME should catalyze detailed investigations for translating such markers and label-free Raman spectroscopy for clinical monitoring of immunotherapy response in cancer patients.
Citation Format: Santosh K. Paidi, Joel R. Troncoso, Narasimhan Rajaram, Ishan Barman. Elucidating early tumor microenvironmental changes due to immunotherapy with label-free Raman spectroscopy and machine learning [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 1943.
Abstract 1958: CTC surge
Authors: Xue Chengsen , Amukele Timothy K. 
Published: June 2022

Abstract
Circulating Tumor Cells (CTC) are a prognostic biomarker for some types of malignant epithelial cancers and have been correlated with poor clinical outcomes. However, the routine measurement of CTC in clinical practice is still very uncommon and some key features of CTC in clinical samples are only being discovered. One of these features that we have identified by supporting CTC clinical research for over 10 years, is the presence of two distinct patient populations: one with high levels of CTC &gt;220/7.5mL blood and one with levels of CTC &lt;160/7.5mL. The clinical significance of this observation is still unknown, but based on this report, we propose a new oncology phenomenon: CTC Surge. Methods: In the past ten years we worked on more than half dozen clinical study projects by using CellSearch Systems by Menarini Silicon Biosystems (formerly Veridex), the only CTC technology platform approved by FDA. The Cell Search system detects CTCs by staining with surface markers coated on nanoparticle beads. The detection of CTC is linear over the reportable range of 0 to 1238 tumor cells. The FDA-approved clinical significant cut-off lines are 5 CTCs for prostate and breast cancers, and 3 for colorectal cancer. Results: All CTC results are sorted by count from low to high. There are two distinct groups roughly above 220 and below 160 per 7.5 mL of peripheral blood. The significance of a CTC enumeration &gt; 220 is that there are as many as 150,000 tumor cells in circulation at the moment of sample collection. This may be the reason why some patients’ condition suddenly worsens when there is an overwhelming presence of CTCs in the bloodstream. The CTC test is a great tool for clinicians and scientists to monitor cancer diseases progression. Unlike a low number of CTCs that may actively engage in intravasation through a set of genes, the mechanism of CTC Surge likely has a completely different set of driving forces, such as internal wound, tumor necrosis and open access to blood vessels inside or surround the tumor mass. Although we do not yet know the clinical significance of our observation, the CTC test offers a simple tool to monitor the rapidly changing tumor dynamics seen in CTC Surge.
Citation Format: Chengsen Xue, Timothy K. Amukele. CTC surge [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 1958.
Abstract 1975: Potential novel Immuno-oncology mechanism revealed during translational phase I Immuno-blood profiling of experimental ADC medicine OBT076 in a gastric cancer patient
Authors: Rohlff Christian , Sahebjam Solmaz , Mita Alain , Lee Rosen , Peddaboina Chander Sekhar , Bisht Arnima , Hudson Lindsey , Fridman Wolf , Fandi Abderrahim , Rixe Olivier 
Published: June 2022

Abstract
CD205 is a type I transmembrane glycoprotein, with unique characteristics that make it an ideal target for Antibody Drug Conjugate (ADC) therapy. Here we report on a potential novel immuno-oncology mechanism revealed during the Translational Phase I (NCT04064359) immuno-blood profiling of a chemo-refractory patient treated with OBT076, an experimental CD205-directed ADC.
A chemo-refractory advanced gastric cancer patient with 60% CD205 expression in the primary tumor via IHC and having previously undergone 2 lines of chemotherapy treatment (Docetaxel/cisplatin/5FU and Ramucirumab/Paclitaxel), received five 21-day cycles of OBT076 (one at 2.5mg/kg and four cycles at 2.0 mg/kg) followed by 1 cycle of Pembrolizumab (PZ; 200mg) ~4 weeks later. Clinical response was evaluated and immunological markers (CD45, CD205, CD4, CD8, and PD1) in peripheral blood cells were quantified using flow cytometry.
After 2 OBT076 cycles at 2.0 mg/kg, there was an ~40% shrinkage in the primary gastric tumor size and resolution of ascites and lymph node metastases were observed. Following 2 further cycles and PZ, complete response was achieved for the primary tumor. Flow cytometry showed (1) an initial decrease in the absolute numbers of dendritic cells by day 8, followed by a 2-fold increase in numbers by day 21 after treatment; (2) a near total decrease in the population of CD8+ CD205+ cells by day 8, no recovery in levels were observed; (3) a 3-fold increase in CD4+ and CD8+ T-cell numbers between days 8 and 21 and (4) an initial decrease in CD4+ PD1+ and CD8+ PD1+ T-cell numbers followed by an ~4-fold increase between days 8 and 21.
In summary our results show that increases in PD1+ T-cells, T-cell induction, and decreases in immuno-suppressive CD4+ CD205+ and CD8+ CD205+ cells occur simultaneously; coinciding with rapid resolution of the primary tumor, lymph node metastases and ascites. These findings suggest that OBT076 activates the patient’s immune response against the tumor through a potentially novel mechanism: drug-induced depletion of CD8+ CD205+ immuno-suppressive cells and subsequent T-cell activation. Additionally, our data support the use of immune checkpoint inhibitors in conjunction with OBT076 to achieve favorable clinical outcomes.
Citation Format: Christian Rohlff, Solmaz Sahebjam, Alain Mita, Rosen Lee, Chander Sekhar Peddaboina, Arnima Bisht, Lindsey Hudson, Wolf Fridman, Abderrahim Fandi, Olivier Rixe. Potential novel Immuno-oncology mechanism revealed during translational phase I Immuno-blood profiling of experimental ADC medicine OBT076 in a gastric cancer patient [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 1975.
Abstract 2003: Poor diet quality is associated with immune aging in survivors of pediatric acute lymphoblastic leukemia
Authors: Benmoussa Abderrahim , Kientega Tibila , Morel Sophia , Cardin Guillaume , Bérard Sophie , wajnberg Mickael , Valtchev Petko , Blondin-Masse Alexandre , Curnier Daniel , Krajinovic Maja , Laverdière Caroline , Sinnett Daniel , Levy Emile , Marcoux Sophie , Rodier Francis , Marcil Valérie 
Published: June 2022

Abstract
Rationale and objectives: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Despite a 90% five-year survival rate, survivors of childhood ALL often suffer from late effects, including cardiometabolic disorders. Contributing factors such as inflammation and oxidative stress, combined with drug treatments, can induce premature aging and cellular senescence with a significant impact on cardiometabolic disorders. Premature aging can lead to decreased thymic T-cell production, resulting in decreased circulation of T-cell receptor excision circles (TRECs). Because diet has been associated with cardiometabolic disorders, we hypothesized that the quality of diet in children who had survived ALL was related to the immune aging biomarker TREC, in concert with inflammatory status.
Methods: Adolescent and young adult survivors of pediatric ALL of the PETALE cohort (n=241, 22.1 ± 6.3 years at diagnosis, 49.4% male) were examined in their profile for TREC levels (by qPCR) and for adherence to 6 diet quality indices.
Results: Adjusted linear regressions revealed that the Healthy Diet Indicator (HDI) was associated with TREC levels (β=50.0, p=0.005, adjusted p=0.03). After performing a conceptual relational analysis (CAR) for data mining of various biomarkers of inflammation, oxidative stress, endotoxemia, and endothelial or adipose dysfunction; interleukin-6 (IL-6) and C-reactive protein (CRP) were found to be negatively associated with TREC levels (β= -80 and -80.1, p=0.017 and 0.026, respectively) but not with HDI. Further analysis revealed that IL-6 and CRP levels were moderators, but not mediators, of the association between HDI and TREC.
Conclusion: This study supports the positive impact of a healthy diet on premature immune aging and the moderating role of inflammation in this association.
Citation Format: Abderrahim Benmoussa, Tibila Kientega, Sophia Morel, Guillaume Cardin, Sophie Bérard, Mickael wajnberg, Petko Valtchev, Alexandre Blondin-Masse, Daniel Curnier, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Emile Levy, Sophie Marcoux, Francis Rodier, Valérie Marcil. Poor diet quality is associated with immune aging in survivors of pediatric acute lymphoblastic 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 2003.