bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B028: Label-free Raman signatures of immune cells: A new tool for artificial intelligence in immunotherapy
Authors: Madathil Girish Chundayil , Nagareddy Raveena , Ramkumar Anjana , Krishnan Manu , Harish Vijay , Ashokan Anusha , Nair Shanti Kumar , Koyakutty Manzoor 
Published: February 2019

Abstract
In the emerging era of artificial intelligence mediated immune response analysis, post- imunotherapeutic interventions, monitoring of large pool of data related to different types of immune cells is a critical requirement. Several gold standard methodologies such as flow cytometry, cytoTOF, ELISPOT and other immune-imaging techniques are routinely used for quantifying the phenotypic behavior of immune cells. These techniques involve the use of antibodies for specifically labeling each cell types, which makes the procedure expensive and laborious. Here, we are presenting a novel approach for label free detection of various types of immune cells using their inherent vibrational Raman signatures and a method of using the same data for cluster analysis. Raman spectroscopy is a well-established tool that measures the vibrational fingerprints of the analytes. It has been extensively used in biologic research for differentiating cells and tissues based on their Raman spectral features. Since the basic building block molecules of the cells are the same, variations in the spectral features among cells and tissues are minimal. Mathematical tools such as multivariate statistical analysis and machine learning methods are adopted to identify the significant Raman spectral features that cause the variation among groups (DC, macrophage, NK, T-cell, B cell, neutrophils, etc.). In immunology, no studies have been reported so far in understanding and recording the inherent Raman spectral finger prints of all forms of immune cells, both in the naïve and active stage. In this study, we have created a spectral database of various immune cells such as T-cells, B cells, NK cells, dendritic cells, macrophages, neutrophils and their signature variations in activated and naïve forms. These spectral databases can be used in machine learning algorithms to predict the treatment response in clinical and preclinical settings.
Citation Format: Girish Chundayil Madathil, Raveena Nagareddy, Anjana Ramkumar, Manu Krishnan, Vijay Harish, Anusha Ashokan, Shanti Kumar Nair, Manzoor Koyakutty. Label-free Raman signatures of immune cells: A new tool for artificial intelligence in immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B028.
Abstract B029: A novel media supplementation strategy for improved T-cell culture and preservation of naivety
Authors: Master Alyssa , O'Connor Roddy S. , Ghassemi Saba , Schneider Dina A. , Karimi-Naser Lisa 
Published: February 2019

Abstract
Recent advances in genetic engineering have resulted in exponential growth in cell therapy technologies. As an increasing number of CAR-T therapies are entering clinical trials, there is a scarcity of resources put into optimizing production strategies. This is largely due to the highly competitive timelines for these companies to advance their drug candidate. Yet, due to this pressure, there is a real need for advances in the cell culture media used to recover, sustain and expand these importanT-cells. Here we show that a novel xeno-free media supplement, PhysiologixTM XF serum replacement, results in improved human primary T-cell growth, preservation of naïve and central memory phenotype, and enhanced transduction efficiency when used in place of traditional media supplements. In the presence of this supplement, T-cell proliferation was nearly doubled in comparison to industry-leading serum free media. In a separate study, we compared PhysiologixTM XF to a control media containing the traditional 10% fetal bovine serum for bulk T-cell culture. We observed that T-cells in both control and test media had similar cell size and population doublings following 48 hours of CD3/CD28 activation. However, FACS analysis revealed thaT-cells grown in PhysiologixTM XF showed a 33% increase in beneficial naïve-like and central memory T-cell phenotypes after nine days in culture when compared to control media. Additionally, lentiviral transduction efficiency was increased from 74% to 94% in PhysiologixTM XF supplemented cells compared to control cells. Taken together, these data demonstrate that T-cell culture with PhysiologixTM XF results in improved growth characteristics, desirable cell phenotypes for patient infusion, and improved ease of transduction, all of which may prove beneficial in the CAR-T race from bench to bedside.
Citation Format: Alyssa Master, Roddy S. O'Connor, Saba Ghassemi, Dina A. Schneider, Lisa Karimi-Naser. A novel media supplementation strategy for improved T-cell culture and preservation of naivety [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B029.
Abstract B034: A novel immunomodulatory strategy of targeting glyco-immune checkpoints with EAGLE technology
Authors: Peng Li 
Published: February 2019

Abstract
Cancer therapy has been revolutionized by inhibiting immune checkpoints to harness the power of the immune system in fighting cancer. However, the majority of patients are resistant to the current immuno-oncology drugs. There is a strong need to identify novel mechanisms of cancer immune evasion and explore novel therapeutic modalities. Glyco-immune checkpoint axis plays a critical role in modulating innate and adaptive immune responses against cancer. However, this pathway is underexplored for therapeutic interventions of cancer, because the complexity and heterogeneity of glycan-ligands on tumor cells pose grand challenges for conventional therapeutic modalities. Here we described a novel multifunctional antibody-like therapeutic modality, named EAGLE (Enzyme-Antibody Glyco-Ligand Editing), which can overcome the heterogeneity and complexity problems and specifically edit tumor-specific glycans. We evaluated the efficacy of an EAGLE molecule and studied its mechanism of actions in a breast cancer EMT6 syngeneic tumor model. Systematic delivery of the EAGLE molecule decreased the expression levels of immunosuppressive glycan-ligands on tumor cell surfaces, and increased T-cell infiltration and activation in the syngeneic tumor models. EAGLE treatment led to 50% complete regressions of established tumors as a monotherapy and 100% cures in combination with an anti-PD1 mAb. Furthermore, cured mice from EAGLE treatment completely rejected the rechallenge of tumor cells, suggesting that EAGLE induced anti-tumor immunologic memory. In summary, the novel therapeutic modality, EAGLE, blocked the glyco-immune checkpoint pathway in the tumor microenvironment and potentiated innate and adaptive antitumor immunity, which offers a novel immunomodulatory strategy to treat cancer.
Citation Format: Li Peng. A novel immunomodulatory strategy of targeting glyco-immune checkpoints with EAGLE technology [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B034.
Abstract B071: Validating sequence similarity-driven neoepitope fitness models via immunogenomics on TCGA and multiregional tumor data
Authors: Bubie Adrian , Akers Nicholas , Villanueva Augusto , Losic Bojan 
Published: February 2019

Abstract
Clonal fitness and survival models for checkpoint blockade response prediction have recently been proposed on the basis of ranking neoepitopes via an interaction between a proxy of T-cell recognition, a nonlinear function of neoepitope sequence similarity to known antigens, and neoantigen relative MHC binding affinity. In this work we examine the SKCM (n = 337) and NSCLC (n = 305) TCGA datasets to explicitly test if sequence similarity to known antigens from the IEDB is associated with tumor infiltrating lymphocyte (TIL) burden in patients, as measured by TCR sequencing and CDR reconstruction in RNA-seq data. We find that there is no statistically significant association between either the inferred clonality or magnitude of TIL response and neoepitope sequence similarity to known antigens. We do, however, find significant, moderate associations of TIL response to neoepitope burden. Further, we examined the LIHC (n = 193) and UCEC (n = 245) TCGA cohorts to explicitly derive tumor and virally derived epitopes (HepB, HPV respectively) and ranked their relative predicted MHC binding affinity profiles. We find a greater MHC binding affinity bias exists towards neoepitopes compared to virally derived peptides in a natural setting where both viral and tumor antigens are simultaneously present. Moreover, we find low and significant associations between TIL burden and overall neoepitope burden, but no association with overall viral epitope or expression burden. Finally, we used multiregionally sampled data (12 patients, 72 regions) from HepB-positive HCC liver cancer patients to confirm preferential MHC binding affinity and TIL response bias towards neoepitopes still holds and is significant. Our results suggest that neoepitopes dominate in their recruitment potential of, and association with, TIL burden compared to viral-cofactors. They also suggest that neoepitope sequence similarity to known antigens does not recapitulate patient TIL burden to first approximation.
Citation Format: Adrian Bubie, Nicholas Akers, Augusto Villanueva, Bojan Losic. Validating sequence similarity-driven neoepitope fitness models via immunogenomics on TCGA and multiregional tumor data [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B071.
Abstract B076: Pan-cancer analysis to identify which cancers may benefit most from LAG-3 blockade
Authors: Ganesan Shridar , Panda Anshuman , Bhanot Gyan 
Published: February 2019

Abstract
Immune checkpoint blockade using antibodies that target programmed-cell-death-1 (PD-1) or its ligand programmed-cell-death-ligand 1 (PD-L1), and/or cytotoxic-T-lymphocyte-associated-protein-4 (CTLA-4) have led to dramatic responses, but only in a subset of human cancers. An antibody targeting lymphocyte-activation-gene-3 (LAG-3), relatlimab (BMS-986016), recently showed significant clinical activity in melanoma, and early clinical data showed that LAG-3 expression is a biomarker of response to this agent. We performed a pan-cancer analysis of The Cancer Genome Atlas data to identify genomic and immunologic correlates of LAG-3 expression. Hyper-mutation, and exogenous (Epstein-Barr virus, human papillomavirus) or endogenous (endogenous retrovirus group 3 member 2) viral expression in tumor were associated with increased expression of LAG-3 in multiple cancer types. LAG-3 expression was also correlated with CD8A and PD-L1 expression in most cancer types; however, there were notable exceptions, including head-neck squamous-cell cancer (HNSC), renal cell cancer (RCC) and glioblastoma. In HNSC, LAG-3 expression, but not PD-L1, was significantly increased in HPV+ cancers. In RCC and gliobastoma, LAG-3 was more strongly associated with CD8A expression than PD-L1. These results may have implications on the design of future clinical trials of LAG-3 blockade.
Citation Format: Shridar Ganesan, Anshuman Panda, Gyan Bhanot. Pan-cancer analysis to identify which cancers may benefit most from LAG-3 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B076.
Abstract B077: Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response
Authors: Jiang Peng , Gu Shengqing , Pan Deng , Fu Jingxin , Sahu Avinash , Hu Xihao , Li Ziyi , Traugh Nicole , Bu Xia , Li Bo , Liu Jun , Freeman Gordon J , Brown Myles A , Wucherpfennig Kai W. , Liu Xiaole Shirley 
Published: February 2019

Abstract
Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients responds to treatment. To predict ICB response we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: inducing T-cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and preventing T-cell infiltration in tumors with low CTL level. We identified signatures of T-cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T-cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research. TIDE source code and a web application are available at http://tide.dfci.harvard.edu.
Citation Format: Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J Freeman, Myles A Brown, Kai W. Wucherpfennig, Xiaole Shirley Liu. Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B077.
Abstract B088: Mapping tumoral and immune heterogeneity in PD-1 responsive glioblastoma
Authors: Restrepo Paula , Yong Raymund , Laface Ilaria , Tsankova Nadejda , Gnjatic Sacha , Hormigo Adilia , Losic Bojan 
Published: February 2019

Abstract
Clonal evolution and the immune microenvironment in glioblastoma (GBM) ultimately determine the potential benefit of checkpoint inhibition. In this case study of a patient who benefited from PD-1 blockade therapy, we characterize intratumoral heterogeneity from several primary and recurrent biopsies. We leveraged RNA-seq data from both the primary tumor and three recurrent biopsies to examine major components of the molecular landscape within the context of clonal evolution. Specifically, we surveyed tumor-immune interactions by computing the expressed mutational and neoepitope tumoral burden, along with the magnitude and clonality of infiltrating lymphocytes using VDJ-sequencing. We furthermore derived the regional gene expression landscape, and found significant differences between the primary and recurrent biopsies. We found significant heterogeneity in the predicted neoantigen and infiltrating lymphocyte landscape, with a pronounced shift towards lower predicted immunogenicity and lower immune infiltration in all recurrent biopsies. Notably, we also found evidence suggesting an outlier recurrent biopsy enriched in aberrant expression of the H19-IGF2 locus. Overall, this case study adds to existing knowledge of the molecular landscape and intratumoral heterogeneity within glioblastoma, in turn providing a starting point for future studies aimed at assessing the efficacy of checkpoint inhibition as a suitable treatment for this highly aggressive cancer type.
Citation Format: Paula Restrepo, Raymund Yong, Ilaria Laface, Nadejda Tsankova, Sacha Gnjatic, Adilia Hormigo, Bojan Losic. Mapping tumoral and immune heterogeneity in PD-1 responsive glioblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B088.
Abstract B095: Mapping the genetic features of immune checkpoint responsiveness using AAV-CRISPR mediated in vivo screen
Authors: Wang Guangchuan , Chow Ryan , Bai Zhigang , Ye Lupeng , Chen Sidi 
Published: February 2019

Abstract
Immune checkpoint blockade has achieved tremendous clinical success across many tumor types, but fails to induce clinical responses in many patients. The mechanisms underlying checkpoint resistance remain poorly characterized. Recent studies have applied next generation sequencing techniques to catalog the mutational burden of patient tumors, which provides a wealth of data to determine common mutations. To map the genetic features of response to checkpoint blockade immunotherapy as well as correlating the clinical efficacy with certain mutations, we developed a novel direct in vivo CRISPR screening approach for high-throughput profiling of functional cancer drivers in an autochthonous manner by injecting AAVs carrying an sgRNA library targeting the top 50 TCGA pan-cancer recurrently mutated tumor suppressor genes (mTSG) into the immunocompetent Cas9 transgenic mice. All mice that received the AAV-mTSG library developed liver cancer and died within four months. We then utilized MIP sequencing of sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis as well as identifying specific gene pairs that were co-occurring across mice. Using this approach, we also mapped the mutation landscape changes under the pressures of immune checkpoint inhibitors, anti-PD1 or anti-CTLA4. We monitored liver tumor growth in AAV-mTSG injected LSL-Cas9;LSL-Fluc mice by using intravital bioluminescent imaging system (IVIS) in combination with dissection check before drug administration. Using IVIS data, we grouped them into 3 size-matched cohorts to receive anti-PD1 or anti-CTLA4 treatments or PBS control. According to the survival data, the mice with mTSG-induced liver tumor benefit from anti-PD1 or anti-CLTA4 treatment. By comparing the mutation frequencies of liver tumors in the mice receiving either checkpoint inhibitors or PBS treatment, we mapped the mutation landscape changes associated with anti-PD1 or anti-CTLA4 treatment. We are performing validation studies on top targets such as Arid1a, Stk11, and B2M. Using this approach, we systematically mapped the correlation of these top 50 driver mutations with cancer immune evasion and immunotherapy responsiveness, providing a valuable reference for patient stratification when considering immunotherapy as well as novel targets for synergistic interventions.
Citation Format: Guangchuan Wang, Ryan Chow, Zhigang Bai, Lupeng Ye, Sidi Chen. Mapping the genetic features of immune checkpoint responsiveness using AAV-CRISPR mediated in vivo screen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B095.
Abstract B102: Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy
Authors: Brentville Victoria A. , Symonds Peter , Cook Katherine W. , Daniels Ian , Atabani Suha , Choudhury Ruhul , Vaghela Poonam , Metheringham Rachael L. , Gijon Mohamed , Xue Wei , Durrant Lindy G. 
Published: February 2019

Abstract
Citrullination is the post-translational modification of arginine to citrulline mediated by Peptidylarginine deiminases (PADs), which are a family of calcium dependent enzymes found in a variety of tissues. Citrullinated proteins are known to play a significant role in the pathogenesis of autoimmune diseases and are presented in complex with MHC class II. We have previously shown that citrullinated peptides from vimentin and α-enolase are presented on HLA-DR4 in tumor cells and mediate strong anti-tumor responses (Brentville et al., 2016; Cook et al., 2017). Here we show that responses to these peptides are also restricted through HLA-DP4. These responses can be detected within 2 days of vaccination and can mediate rapid regression of tumors within 4 days in mice suggesting evidence of a pre-existing repertoire of T-cells specific for these citrullinated peptides. Evidence of CD4 T-cells specific to citrullinated antigens have been identified in a number of autoimmune disease patients in particular rheumatoid arthritis patients. These patients show an increase in frequency and change in phenotype of citrulline specific CD4 T-cells compared to healthy individuals (James et al., 2014). In this report we also demonstrate that a repertoire of CD4 T-cell responses to citrullinated peptides exists in healthy individuals and that this can be uncovered/enhanced by removal of CD25+ T-cells thus suggesting the existence of a regulatory mechanism keeping these responses in check. The responding populations appear to be oligoclonal and show an increase in effector memory and Temra phenotype. This suggests that a repertoire of CD4 T-cells exists to citrullinated peptides that could be targeted for cancer therapy.
Citation Format: Victoria A. Brentville, Peter Symonds, Katherine W. Cook, Ian Daniels, Suha Atabani, Ruhul Choudhury, Poonam Vaghela, Rachael L. Metheringham, Mohamed Gijon, Wei Xue, Lindy G. Durrant. Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B102.