bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6587: Proteogenomic characterization of colorectal cancer using the IndivuType multiomics database
Authors: Krawczyk Margarita , Woodsmith Jonathan , Nutsoa Marcel , Corwin Thomas , von der Heyde Silvia , Piras Vincent , Whittaker Mark , Hergovich Alex , Frommolt Peter , Juhl Hartmut 
Published: September 2020

Abstract
Cancer is a highly heterogeneous disease, both intra- and inter-individually consisting of complex phenotypes and systems biology. Although genomic data has contributed greatly towards the identification of cancer-specific mutations and the progress of precision medicine, genomic alterations are only one of several important biological drivers of cancer. Furthermore, single-layer omics represent only a small piece of the cancer biology puzzle and provide only partial clues to connecting genotype with phenotype. A more integrated approach is urgently needed to unravel the underpinnings of molecular signatures and the phenotypic manifestation of cancer hallmarks. We have developed IndivuType, a knowledge and discovery platform that combines genomics, transcriptomics, and proteomics datasets to identify putative therapeutic targets in a colorectal cancer (CRC) cohort of 500 patients. We identified hundreds of proteins dysregulated in CRC that are dependent on the genetic background of the patient. Further, we characterized these proteins using clinical parameters from the IndivuType database to prioritize targets for precision medicine approaches. This project highlights the utility of moving beyond solely genomics approaches to better understand the molecular mechanisms underpinning cancer.
Citation Format: Margarita Krawczyk, Jonathan Woodsmith, Marcel Nutsoa, Thomas Corwin, Silvia von der Heyde, Vincent Piras, Mark Whittaker, Alex Hergovich, Peter Frommolt, Hartmut Juhl. Proteogenomic characterization of colorectal cancer using the IndivuType multiomics database [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 6587.
Abstract 6589: Selecting clinical lead of TCRs targeting alpha-fetoprotein-positive liver cancer on balance of risk and benefit
Authors: Luo Xiaobing , Cui Huijuan , Cai Lun , Zhu Wei , Yang Wei-Chih , Patrick Michael , Zhu Shigui , Huang Jiaqi , Yao Xin , Yao Yihong , He Yukai , Ji Yun 
Published: September 2020

Abstract
Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158-166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit.
Methods: To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs on balance of their potency and specificity by testing their reactivity to normal and transformed cells covering a variety of primary cell types and HLA serotypes, and potential protein candidate in human genome by an extensive alanine scan (X-scan).
Results: We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with protein candidate in human genome identified by X-scan.
Conclusion: Up to date we have selected a AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.
Citation Format: Xiaobing Luo, Huijuan Cui, Lun Cai, Wei Zhu, Wei-Chih Yang, Michael Patrick, Shigui Zhu, Jiaqi Huang, Xin Yao, Yihong Yao, Yukai He, Yun Ji. Selecting clinical lead of TCRs targeting alpha-fetoprotein-positive liver cancer on balance of risk and benefit [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 6589.
Abstract 6599: Screening and characterization of AlloCAR T targeting DLL3 for the treatment of small cell lung cancer
Authors: Zhang Yi , Tacheva-Grigorova Silvia , Melton Zea , Smith Bryan , Sai Tao , Van Blarcom Tom , Amado Rafael , Sasu Barbra , Panowski Siler 
Published: September 2020

Abstract
Small cell lung cancer (SCLC) is an aggressive disease with very limited treatment options. SCLC responsiveness to immuno-oncology agents suggests this indication may be amenable to a T-cell based therapy. Genetically modified T cells that express chimeric antigen receptors (CARs) have shown impressive efficacy in multiple hematological malignancies. To translate this approach for SCLC treatment, we are exploring Delta-like ligand 3 (DLL3) as a therapeutic target. DLL3 is highly expressed in SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary and testis. A large panel of antibodies that bind to DLL3 were generated, formatted into CARs, and tested in in vitro short-term and long-term cytotoxicity assays using target cells that express high, medium or low levels of DLL3. A subset of CAR T cells were highly active and displayed long-term killing potential. These were tested in vivo and robust efficacy was seen in both subcutaneous and systemic SCLC models. To understand the potential for toxicity in pituitary and brain, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and human/mouse cross-reactive DLL3 CAR T cells were injected into the tumor-bearing animals. In both models, T cell infiltration into intermediate and posterior pituitary was detected. However, no tissue damage in brain or pituitary was observed and hormone-secretion function of pituitary was not ablated. We believe toxicity is significantly derisked but as an additional safety assurance, CAR T cells were further engineered to contain an off-switch, by which CAR T cells are eliminated upon administration of Rituximab. Multiple off-switch CAR formats were evaluated, and optimal formats determined independently for each CAR. In summary, DLL3 is a target for SCLC with limited normal tissue expression and toxicity. Multiple DLL3 CAR T cells have been characterized. A subset of these CAR T cells showed robust in vitro and in vivo activity and were chosen for further evaluation as potential clinical candidates.
Citation Format: Yi Zhang, Silvia Tacheva-Grigorova, Zea Melton, Bryan Smith, Tao Sai, Tom Van Blarcom, Rafael Amado, Barbra Sasu, Siler Panowski. Screening and characterization of AlloCAR T targeting DLL3 for the treatment of small cell lung 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 6599.
Abstract 6600: Rapid generation of TCR-engineered T lymphocytes by linking the single cell transcriptome to its corresponding T cell receptor in antigen specific T cells
Authors: Zhu Linnan , Wang Fei , Xu Qumiao , Sun Hai-Xi , Li Ziyi , Liang Yanling , Zhuang Zhenkun , Gu Ying , Chao Cheng-chi 
Published: September 2020

Abstract
Adoptive cell transfer of T-cell receptor (TCR)-engineered T cells has emerged as a powerful and potentially curative therapy for cancers and infectious diseases. However, how to rapidly identify and obtain therapeutic TCRs remains a major challenge in this field. Here, we simultaneously performed deep single-cell RNA and TCR V(D)J sequencing on 879 single T cells from in vitro stimulated CMV pp65NLV-specific CD8+ T cells. The correlation analysis of single-cell transcriptome and TCR V(D)J sequences revealed a differential distribution of T cell transcriptomic profiles among TCR clones. Two distinct cell types were identified in the T cell population. TYPE I T cell subtype, which represents the gene signatures of T cell activation and cytotoxicity, mainly includes TCR clone 1, 2 & 4, while TYPE II subtype, which represents the gene signatures of naïve status, mainly includes TCR clone 3 and other low frequency clones. Based on their temporal phases of T cell activation, the selected TCR sequences from clone 1 (TCRZWX1) and clone 3 (TCRZWX3) were functionally validated by constructing TCR-engineered T cells in vitro. The two clones showed distinct cell stages corresponding to their transcriptome patterns. TCRZWX1 transgenic T cells displayed effector functions including secretion of pro-inflammatory cytokines, IFN-γ and TNF-α, and cytotoxicity in response to CMV pp65NLV peptide. However, TCRZWX3 transgenic T cells displayed non-detectable levels of IFN-γ, which might correlate with a low affinity TCR. Our results provide a novel approach using correlative analysis of the single-cell transcriptome and TCR V(D)J sequences for rapidly identifying potential therapeutic TCRs for T cell therapy.
Citation Format: Linnan Zhu, Fei Wang, Qumiao Xu, Hai-Xi Sun, Ziyi Li, Yanling Liang, Zhenkun Zhuang, Ying Gu, Cheng-chi Chao. Rapid generation of TCR-engineered T lymphocytes by linking the single cell transcriptome to its corresponding T cell receptor in antigen specific 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 6600.
Abstract 6618: A database of potential T cell epitopes for cancer immunotherapy
Authors: Jiang Chongming , Chao Cheng-chi , Cheng Chao 
Published: September 2020

Abstract
Background: Adoptive immunotherapy with tumor-specific T cells is a promising treatment strategy for patients with malignancy. A key of adoptive T cell immunotherapy is to determine suitable immunogenic tumor antigens for targeting. The main challenges of T cell therapy are the relative lack of comprehensive information about proper antigens immunogenic to T cells, and excessive time-consumption to identify which kinds of peptides can be used for vaccine application and cancer immunotherapy. The objective of our work is to build a systematic database for those prospective tumor peptide antigens (dataset A), the documented promising immunogenic epitopes on cell surface having been experimentally validated (dataset B), and the antigens that have been tested in clinical studies (dataset C). The establishment of this database could overcome the prior inconvenience caused by the lack of collection data sets.
Finding: In the dataset A, we predicted a total of 4,999,192 neoantigen from 463 cancer patients across 10 main kinds of cancer types. The dataset B includes 118,564 T cell epitopes that were experimentally proved to exist on various cancer cell surfaces and could be immunogenic. In dataset C, 636 peptides from different stages of 121 clinical trials with 31 cancer types were collected. Finally, a clinical trial by using adoptive immunotherapy with tumor-specific T cells was designed to apply a similar method to identify suitable tumor antigens.
Conclusion: An informative database has been systemically built and tested in both theoretical and practical aspects, which enables a convenient and efficient approach for the selection of tumor antigens in vaccine design and cancer immunotherapy.
Citation Format: Chongming Jiang, Cheng-chi Chao, Chao Cheng. A database of potential T cell epitopes 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 6618.
Abstract 6622: The identification of extranodal NK/T cell lymphoma-associated antigen for helper T cell-based immunotherapy
Authors: Kumai Takumi , Hayashi Ryusuke , Hayashi Tatsuya , Kobayashi Hiroya , Harabuchi Yasuaki 
Published: September 2020

Abstract
Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a fatal destructive tumor that develops around the nasopharyngeal and nasal/paranasal areas. Although this disease was originally considered to be endemic to East Asia, Central and South America and was extremely rare in Europe and the United States, the incidence of NKTL has increased during the last several decades in countries where it was previously not epidemic. The combination of irradiation and chemotherapies such as SMILE and MPVIC-P are effective. However, these therapies cause severe and sometimes fatal adverse effects indicating that a novel strategy to treat NKTL is required. The positive results of clinical trials using immune checkpoint inhibitors in solid tumors proved that immune cells are capable of eliminating tumor. However, autoimmune diseases are inevitable adverse events in this type of therapy, which non-specifically activates T cells. Thus, the identification of epitope peptides in tumor has re-emerged as an attractive concept. I will describe our study to identify NKTL-derived T cell epitopes as a basis of cancer vaccine. The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NKTL remain unclear, we first studied the expression and function of c-Met in NKTL cells. As a result, we found that HGF and c-Met were expressed and contributed to the proliferation of cells in NK/T-cell lymphoma. Next, the helper epitopes were identified from c-Met protein using computer-based algorism. The identified epitope peptides could elicit peptide-specific helper CD4 T cells (HTLs), which showed antitumor responses in vitro. The addition of c-Met inhibitor suppressed TGF-β production from tumor followed by the augmentation of HTL responses. In summary, we identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors.
Citation Format: Takumi Kumai, Ryusuke Hayashi, Tatsuya Hayashi, Hiroya Kobayashi, Yasuaki Harabuchi. The identification of extranodal NK/T cell lymphoma-associated antigen for helper T cell-based 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 6622.
Abstract 6630: Synergistic immuno photothermal nanotherapy (SYMPHONY) for combination cancer therapy
Authors: Liu Yang , Maccarini Paolo , Palmer Gregory M. , Inman Brant A. , Fecci Peter E. , Vo-Dinh Tuan 
Published: September 2020

Abstract
Checkpoint inhibitor immunotherapy has been a revolutionary milestone in cancer treatment because it can counter the tumor immunosuppressive environment to improve patients' overall survival and even result in a durable complete response. However, only a fraction of patients benefit from checkpoint inhibitor immunotherapy. Improving the response rate and maximizing efficacy for immunotherapy are still unmet needs of great clinical significance. We have developed a novel combination cancer therapy referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) by integrating plasmonic gold nanostars (GNS)-mediated photothermal therapy with anti-PD-L1 checkpoint inhibitor immunotherapy to improve the therapeutic efficacy of cancer treatment. GNS nanoparticles are superior photon-to-heat conversion transducers for photothermal therapy because they have tip-enhanced plasmonics from multiple sharp spikes and tunable plasmonic absorption in the near-infrared tissue optical window. Our in vivo experimental results with bladder cancer and brain cancer murine animal models have demonstrated that photothermal therapy with GNS in combination with anti-PD-L1 checkpoint inhibitor immunotherapy not only effectively ablates primary tumor with laser irradiation but also stimulates the immune response to treat distant tumors without laser irradiation. Furthermore, a rechallenge study performed three months later using cancer cells injected into long-term survivors demonstrates that SYMPHONY therapy can generate a long-term memorized immune response and prevent cancer recurrences in cured mice. The SYMPHONY combination therapy results in synergistic treatment surpassing what either single treatment can achieve, and shows the great promise for future translational medicine studies to treat aggressive metastatic cancer diseases.
Citation Format: Yang Liu, Paolo Maccarini, Gregory M. Palmer, Brant A. Inman, Peter E. Fecci, Tuan Vo-Dinh. Synergistic immuno photothermal nanotherapy (SYMPHONY) for combination cancer therapy [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 6630.
Abstract 666: A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry
Authors: MacQueen Amy R. , Viticchie Giuditta , Niewola Karolina , Finotello Francesca , Powley Ian , Shah Pritom , van der Veen Lars , Lahn Michael , Johnson Zoe 
Published: September 2020

Abstract
The inhibition of PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, breaking tumour-induced immune tolerance and restoring anti-tumour immunity. Bioinformatics and protein expression studies have shown that PIK3CD/PI3Kδ is also highly expressed in certain solid malignancies. IOA-244 is a novel, highly selective PI3Kδ inhibitor, with the unique property of being ATP non-competitive. In addition to the effects of PI3Kδ inhibition on the balance of CD8+ T cells and T regulatory cells in the tumour microenvironment, we have recently demonstrated that IOA-244 effectively controls the growth of tumour cells with high levels of PI3Kδ in vivo in T-cell deficient hosts.
Analysis of TCGA datasets shows that certain solid tumours express high levels of PIK3CD transcript, comparable to that of diffuse large B cell lymphoma. Of these indications, cutaneous and uveal melanoma are amongst the highest expressers. To support the clinical development of IOA-244, we demonstrate that patient-derived melanoma cells with a high expression of PIK3CD are susceptible to treatment with IOA-244 in a mouse patient-derived xenograft model. Furthermore, in vitro explant studies using clinical biopsy material demonstrates that PI3Kδ expression can be detected in tumour tissue and that IOA-244 has an anti-proliferative function when added to these samples.
Based on these and other supporting data, IOA-244 has received clinical trial approval in Europe and phase I clinical testing is underway in solid tumours with an anticipated high Treg:CD8 ratio and/or high protein expression of PI3Kδ.
Citation Format: Amy R. MacQueen, Giuditta Viticchie, Karolina Niewola, Francesca Finotello, Ian Powley, Pritom Shah, Lars van der Veen, Michael Lahn, Zoe Johnson. A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry [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 666.
Abstract 6707: Inhibition of proteolytic cleavage of NKG2D ligands increases immune cell-mediated cell killing of tumor cells in vitro
Authors: Yalcin Safak , Cicchini Vanessa , Du Xin , Wu Xin , Kaever Tom , Gibson Neil 
Published: September 2020

Abstract
Natural Killer Group 2, member D (NKG2D) is an activating receptor that is expressed on the key immune cells involved in the cytotoxic arm of the immune system. Ligands of NKG2D, such as MICA and MICB, are not normally expressed but are upregulated in response to stress, such as oxygen or nutrient deprivation, viral infection or oncogenic transformation. One mechanism that tumor cells, that express MICA and MICB, have adopted to evade the cytotoxic potential of NK and T cells, that express the NKG2D receptor, is to cleave MICA/B from the cell surface. Proteolytic cleavage of MICA/B occurs within the α-3 domain of MICA/B. In order to evaluate the therapeutic potential of blocking cleavage of MICA/B we have generated multiple antibodies that bind to the α-3 domain of MICA/B. The lead antibody, PDI-01, was found to bind to multiple recombinant human MICA alleles and human MICB and to recombinant MIC proteins derived from non-human primate sequences with low nM affinity. PDI-01 bound to target antigen on the surface of multiple cancer cell lines including HCT-116 colon carcinoma, HCC1534 lung carcinoma and PLC/PRF/5 liver cancer cell lines. Each of those tumor cell lines were positive for MICA and MICB expression. Low expression of other NKG2D ligands, known as UL-16 binding proteins 1-6 (ULBP 1-6), has been shown in those cell lines. PDI-01 was found to prevent cleavage of MICA from the surface of HCT-116, HCC1534 and PLC/PRF/5 cells via ELISA quantification of soluble MICA levels. Exposure of HCT-116, HCC1534 and PLC/PRF/5 tumor cell lines to PDI-01 increased surface MICA levels as measured by flow cytometry analysis. An increase in immune cell mediated killing of HCT-116, HCC1534 and PLC/PRF/5 cells was observed when tumor cells were incubated with NK-92 cells (NKG2D positive) in the presence of PDI-01. PDI-01 also enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) against these three tumor cell lines. Co-culture of PBMCs, or purified NK cells, with PLC/PRF/5 cells in the presence of PDI-01 led to an increase in TNF-α, IFN-γ, CCL4, CCL5 and IL-6. PDI-01 is being advanced into clinical development and the Phase 1 program is scheduled to be initiated in the 2Q, 2020.
Citation Format: Safak Yalcin, Vanessa Cicchini, Xin Du, Xin Wu, Tom Kaever, Neil Gibson. Inhibition of proteolytic cleavage of NKG2D ligands increases immune cell-mediated cell killing of tumor cells 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 6707.