bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 155: A machine learning approach for accurate medulloblastoma subtyping using arm-level SCNAs
Authors: Yan Cheng , Wang Dan , Su Lan , Yang Yufei , Du Hao 
Published: July 2021

Abstract
Background: In 2010, scientific community reached a consensus regarding its subtyping (WNT/β-catenin, Sonic Hedgehog, Group 3, and Group 4). Research demonstrated that different subtype displays distinct genotypic characteristics as well as prognostics. Currently, transcriptomic profiling via NanoString is well-accepted for medulloblastoma subtyping. However, this platform requires high quality RNA sample. An alternative approach is in need for more robust and accurate subtyping. In this study, we explored the feasibility of using machine learning approach for medulloblastoma subtyping based on genome-wide SCNVs.
Method: We retrieved SNP array CEL data of 1097 medulloblastoma (GSE37385) from GEO. 800 samples were remained for further analysis after QC. 32 medulloblastoma samples were collected from Robinson G, et's study as independent validation set. Penncnv was used to calculate log R ratio and B allele frequency. DNAcopy was used for CNV segmentation. GISTIC2 was applied to obtain arm and focal SCNAs. A number of classifiers were trained using SCNAs as well as age and gender. Feature selection was conducted in a model specific manner. Model performance was assessed using AUROC.
Result: Benchmark on validation set showed that accuracy of Naïve Bayes, Random Forest, AdaBoost, Logistic Regression and SVM are 76.25%, 75%, 75%, 77.5% and 80.62% respectively. AUROC is 90.98%, 92.3%, 91.32%, 92.1% and 92.02% in corresponding order. The relatively overfitting and comparable performance across most models implied that SCNAs own moderate predictive power in medulloblastoma subtyping. Generally, SVM with linear kernel demonstrated superior and balanced performance than other models. Feature importance evaluation via Random Forest and AdaBoost showed better predictive power of arm-level SCNAa of 6p, 6q, 7p, 7q, 16q, 17p, 17q, consistently with previous studies. Focal SCNAs on SIRPB1 and age owned high predictive power. Nanostring performs poorly on distinguishing Group 3 and Group 4. Our method showed same tendency, indicating transcriptomic as well as genomic similarity between these two groups. We decided to permit 10% of validation samples as ‘prediction failure' for those with highly similar SCNAs characteristics. Upon this modification, accuracy of most model raised 3% on average.
Conclusion: Our study evaluated the feasibility of using genome-wide SCNAs profile for medulloblastoma subtyping. Benchmark showed moderate predictive power using SCNAs. Among a number of machine learning approaches, SVM with linear kernel demonstrated superior performance.
Citation Format: Cheng Yan, Dan Wang, Lan Su, Yufei Yang, Hao Du. A machine learning approach for accurate medulloblastoma subtyping using arm-level SCNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 155.
Abstract 1558: Radiation therapy and immune checkpoint inhibitor combinations in the E0771 medullary breast adenocarcinoma
Authors: Fadden Patrick , Bui Thi , Davis Kelli , Hurtado David , Sugg Emily , Svancarek Abigail , Belle Ian , Hall Chassidy 
Published: July 2021

Abstract
Greater than 50% of all cancer patients receive radiation therapy at some point during their cancer treatment to control solid tumor growth (Harrington 2011). In addition to the direct action of radiation on tumor cell proliferation, radiation also has the potential to stimulate an anti-tumor immune response (Weichselbaum 2017). The success of immune checkpoint therapies such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitory antibodies has driven large investment into the discovery of novel immune-oncology therapies. While the clinical response to immune checkpoint inhibitors can be profound for those patients that respond, there still exists a large percentage of patients that do not see benefit. In order to expand the number of patients that may respond to immune checkpoint inhibition, combination with radiation therapy needs to be tested and in fact a large number of preclinical and clinical studies are being conducted (for review see Asna 2019). Preclinical syngeneic tumor models are a critical means to assess new immunotherapies and drive preclinical programs. E0771 is a medullary breast adenocarcinoma cell line originally isolated from a spontaneous tumor and can be implanted subcutaneously in C57BL/6 mice (Ewens 2005). In order to characterize the E0771 syngeneic breast tumor model for future studies with radiation and immunotherapy, we assessed the efficacy changes in response to various schedules of radiation doses with and without either anti-PD-1 or anti-CTLA-4 antibody therapies. In addition, we analyzed the tumor infiltrating immune cell populations following radiation therapy. E0771 is sensitive to radiation therapy with a clear dose response. Radiation administered either as a single dose, hypofractionated, or hyperfractionated gave similar tumor responses. Flow cytometry analysis shows a higher infiltration of T regulatory cells compared with CD8+ T cells at baseline, which is exacerbated by irradiation. The CD8/Treg ratio is reversed with the addition of anti-CTLA-4 treatment to radiation and resulted in curative responses for 9 of 10 mice in the combination group.
Citation Format: Patrick Fadden, Thi Bui, Kelli Davis, David Hurtado, Emily Sugg, Abigail Svancarek, Ian Belle, Chassidy Hall. Radiation therapy and immune checkpoint inhibitor combinations in the E0771 medullary breast adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1558.
Abstract 1571: Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1
Authors: Sun Changbo , Nagaoka Koji , Hosoi Akihiro , Kobayashi Yukari , Nakajima Jun , Kakimi Kazuhiro 
Published: July 2021

Abstract
Immune checkpoint inhibitors are now the mainstay for the treatment of lung cancer. However, so-called cold tumors are known to be resistant to checkpoint inhibitors. Neoantigens associated with genetic mutations of the tumor have the potential to stimulate a potent and highly specific immune response. To develop effective immunotherapy for cold lung cancer, we examined whether neoantigen-based immunotherapy can develop immune responses and display anti-tumor effects on the cold lung cancer model, Lewis lung carcinoma cells (LLC1) resistant to anti-CTLA-4 or anti-PD-1 therapy.
LLC1 cells were subjected to whole-exome and RNA sequencing. Mutation-associated neoantigens were predicted and prioritized by their affinity to MHC class I molecules and their expression. Using netMHCpan, sixty mutated peptides with IC50 &lt;200 nM and 68 mutated peptides with IC50&gt;200 nM, but the wild to corresponding mutated peptide ratio of binding affinity&gt;10 were selected as candidate neoantigens. C57BL/6 mice were immunized with dendritic cells pulsed with these neoantigen short peptides (8-10mer). Twenty-five out of 128 short mutated peptides induced peptide-specific CD8+ T cell response to some extent. Next, 25 long peptides (21mer), which incorporated corresponding immunogenic short peptide sequences, were synthesized and used to immunize mice. DC vaccines pulsed with neoantigen in long peptide format (LP) induced both CD4+ and CD8+ T cell response ex vivo. Of them, DC pulsed with LP82 partly delayed the LLC1 growth in vivo.
By RNA-Seq, CD38 was highly expressed in LLC1. Thereby, an anti-CD38 antibody was administered in LLC1-bearing mice immunized with DC pulsed with LP82. The tumor growth was suppressed in the combination treatment. Although CD38 plays an important role in converting nicotinamide adenine dinucleotide (NAD+) to adenosine, adenosine receptor antagonist could not inhibit the tumor growth in mice immunized with LP82. Alternatively, NAD+ accumulation due to CD38 blockade decreased regulatory T cells in the tumor immune microenvironment, consistent with the decreased Foxp3+ transcription and increased IFNg and IL2 production of CD4+ T cells sorted from tumor immune microenvironment.
Our study suggested that the prioritization of neoantigens that can induce anti-tumor response is critical for developing neoantigen-targeting immunotherapy. Combining an effective neoantigen vaccine and precise immune modulator could enhance anti-tumor activities even in cold lung tumors.
Citation Format: Changbo Sun, Koji Nagaoka, Akihiro Hosoi, Yukari Kobayashi, Jun Nakajima, Kazuhiro Kakimi. Neoantigen vaccine plus CD38 blockade suppress the proliferation of murine cold lung cancer LLC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1571.
Abstract 1577: Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma
Authors: Morehead Lauren C. , Koss Brian S. , Wallis Katherine F. , Tackett Alan J. , Miousse Isabelle Racine 
Published: July 2021

Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized melanoma therapy. Still, the 5-year survival for advanced melanoma is only 50%. This leads to two questions: what makes some tumors less responsive to ICIs, and what can be done to increase responsiveness? Prior research suggests that hypoxia in the tumor microenvironment (TME) decreases the efficacy of ICIs, and metformin, an antihyperglycemic and caloric restriction mimetic (CRM), is able to reverse this condition. We hypothesize that other CRMs will also increase responsiveness to ICIs through hypoxia, and potentially other mechanisms. We chose three CRMs to study alongside metformin: hydroxycitrate, resveratrol, and sulforaphane. To identify pathways and understand more about CRMs effect on tumor hypoxia, we performed a proteomics experiment on B16F10 murine melanoma cells treated with all four CRMs. Proteomics analysis was done with a tandem mass tag labeling. To determine effect of caloric restriction mimetics on immunotherapy efficacy, B16F10 cells will be injected subcutaneously in immunocompetent male and female C57BL/6J mice, separated into four groups: 1) no treatment control, 2) ICI therapy only, 3) CRM therapy only, 4) ICI + CRM combination.
Our preliminary data shows that, like metformin, additional CRMs decrease oxidative phosphorylation in cancer cells. This supports the hypothesis that the other CRMs may function similarly to metformin in the TME. We started testing the effect of four CRMs on tumor growth and hypoxia in an animal model. Our ultimate goal is to improve responsiveness to immune checkpoint inhibitors in patients with metastatic melanoma.
Citation Format: Lauren C. Morehead, Brian S. Koss, Katherine F. Wallis, Alan J. Tackett, Isabelle Racine Miousse. Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1577.
Abstract 1579: Oncolytic adenovirus Delta-24-RGDOX collaborates with adoptive cell therapy to sustain anti-tumor immunity
Authors: Jiang Hong , Nguyen Teresa T. , Shin Dong Ho , Sohoni Sagar S. , Gupta Sumit , Yi Yanhua , Fan Xuejun , Gomez-Manzano Candelaria , Fueyo Juan 
Published: July 2021

Abstract
Oncolytic virotherapy and adoptive T cell therapy (ACT) are promising strategies for cancer treatment, but both are underdeveloped into routine clinical interventions for solid tumors. We reported previously that localized treatment with oncolytic adenovirus Delta-24-RGDOX (DNX-2440), which expresses immune co-stimulator OX40 ligand, stimulated tumor-specific T cells proliferation and migration to untreated disseminated tumors. We hypothesize that intratumorally injected Delta-24-RGDOX complements with ACT to overcome antigen escape, leading to more sustainable anti-cancer effect. To test the hypothesis, we used B16-OVA-C57BL/6 subcutaneous (s.c.)/s.c. melanoma model to assess the effect of the combination therapy. Briefly, 10 days after the first tumor implantation, we injected OVA-specific CD8+ T cells from OT-I mice into the first tumor, followed by three injections of Delta-24-RGDOX into the same tumor. We found the combination was more potent to inhibit the injected 1st tumor and untreated disseminated 2nd tumor growth and resulted in improved survival rate than either of the agent alone (p less than 0.05). Interestingly, we observed relapse of the regressed tumors in the group treated by T cells alone, which recapitulated the effect of CAR T therapy in cancer patients. But the relapse was not observed in most of the mice from the combination group, indicating the combination induces more sustainable tumor regression than T cells alone. The survivors from the combination therapy were protected from rechallenging with B16-OVA cells but not lung carcinoma cells, suggesting the development of immune memory against the same tumor cells. Furthermore, profiling the tumor-infiltrating lymphocytes with flow cytometry revealed that the combination promotes the T cell presence within the tumor and increase the population of the T cells targeting other antigens in addition to the original ACT targeted antigen. Collectively, the results demonstrate that Delta-24-RGDOX collaborates with ACT to induce more potent systemic immunity against the tumors, leading to more sustainable tumor regression and improved survival rate. Our study suggests the virus induces antigen spread, resulting in T cell repertoire to target more tumor-associated antigens to overcome cancer relapse due to cancer heterogeneity and limited targets in ACT and CAR T therapy.
Citation Format: Hong Jiang, Teresa T. Nguyen, Dong Ho Shin, Sagar S. Sohoni, Sumit Gupta, Yanhua Yi, Xuejun Fan, Candelaria Gomez-Manzano, Juan Fueyo. Oncolytic adenovirus Delta-24-RGDOX collaborates with adoptive cell therapy to sustain anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1579.
Abstract 1581: Nammisomes: Preclinical validation of a platform for selective and synchronized delivery of novel immunotherapy prodrug combinations to tumors
Authors: Stover David R. , Bharali Dhruba , Safaie Tahmineh , Hay Bruce A. , Sharma Rajesh K. , Ayers Scott 
Published: July 2021

Abstract
The approval of checkpoint inhibitors, CAR-T cell therapies, and other immunotherapies has led to a significant improvement in cancer patient survival rates over the past 7 years. However, the pace of improvement has slowed lately as the field moves beyond the minority of patients with immune primed or accessible cancers. It is generally expected that rationale combinations of immunotherapies that provide mechanisms to both induce as well as maintain the immune responses in the face of tumor-derived immune checkpoint mediators, will be required to effectively treat these patients. Systemic exposure to such combinations often can give rise to severe toxicity profiles that limit their therapeutic efficacy. Nammisomes are an innovative and unique platform designed to deliver novel immune modulating prodrugs more selectively and synchronously to the tumor site. The immune active agents are conjugated to lipids to create prodrugs that self-assemble into a liposomal bilayer. By mixing multiple prodrugs at the desired ratio, co-formulations are produced with the optimum stoichiometry. These Nammisomes are iv injected and selectively enter tumors through the leaky vasculature within tumors, while remaining in circulation in normal tissues with intact blood vessels, The enriched phagocytic activity in tumor environments causes the release of the active agents within tumors relative to normal tissues limiting systemic exposure and toxicities. Preclinical efficacy and safety data of Nammisomes delivering combinations of a TLR agonist and a checkpoint inhibitor showing anti-tumor efficacy and tolerability in syngeneic mouse models will be presented. In summary, Nammisomes will be highlighted as a combination therapeutic modality to demonstrate the potential of this approach in anti-cancer therapy.
Citation Format: David R. Stover, Dhruba Bharali, Tahmineh Safaie, Bruce A. Hay, Rajesh K. Sharma, Scott Ayers. Nammisomes: Preclinical validation of a platform for selective and synchronized delivery of novel immunotherapy prodrug combinations to tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1581.
Abstract 1599: SMARCA4 regulates tumor resistance to anti-tumor immune response
Authors: Chaudhri Apoorvi , Wang Yunfei , Shi Leilei , Rai Kunal , Hwu Patrick 
Published: July 2021

Abstract
Chromatin remodelers regulate chromatin accessibility and translocation of the nucleosome to expose the underlying DNA sequence. SWI/SNF is a conserved chromatin remodeling complex required for transcriptional activation or repression. In fact, SWI/SNF is the most frequently mutated chromatin regulator in cancer. Though the general understanding is that subunits of the SWI/SNF complex mainly act as tumor suppressors, studies have shown that they can have a context-dependent oncogenic role. Moreover, the PBAF subunits of the complex, PBRM1 and ARID2 impart immunoresistance in B16 melanoma tumors. We perform a TCGA analysis of the subunits based on expression and see that high PBRM1 or SMARCA4 expression in SKCM melanoma correlates with lower survival. Interestingly, SMARCA4 is the conserved catalytic subunit of the complex, and is essential to hydrolyze the energy of the ATP to execute the remodeling function of the complex. On performing a knockdown of SMARCA4 in an in vitro model of B16 cells, a co-culture with antigen specific T cells shows an increase in T cell cytotoxicity. Furthermore, RNA sequencing reveals that knockdown of SMARCA4 upregulates the genes associated with interferon response and downregulates MYC targets. We show that SMARCA4 may mediate immunoresistance such that a knockdown of SMARCA4 in the tumor will sensitize it to anti-tumor immunity. We will next take an in vivo approach to examine if SMARCA4 knockdown will enhance the tumor immune response via an interferon related mechanism.
Citation Format: Apoorvi Chaudhri, Yunfei Wang, Leilei Shi, Kunal Rai, Patrick Hwu. SMARCA4 regulates tumor resistance to anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1599.
Abstract 1601: Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma
Authors: Yang Guozhen , Su Xiaodong , Yang Hong , Luo Guangyu , Gao Chan , Zheng Yating , Xie Wenzhuan , Huang Mengli , Bai Yuezong , Wang Zhiqiang , Cai Peiqiang , He Haoqiang , Xiang Jin , Cai Muyuan , Zhang Yijun , Qu Chunhua , Fu Jianhua , Liu Qianwen , Hu Yi , Zhong Jiudi , Huang Yuanheng , Guo Qiyu , Zhang Xu 
Published: July 2021

Abstract
Background: Immunotherapy is effective in treating unresectable esophageal squamous cell carcinoma (ESCC), but little is known about its activities in the preoperative setting. We aimed to evaluate the safety, feasibility and efficacy of neoadjuvant treatment with camrelizumab plus chemotherapy in locally advanced ESCC.
Methods: Patients diagnosed with locally advanced ESCC were retrospectively included if they had received three courses of neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy between November, 2019 and June, 2020 at Sun Yat-sen University Cancer Center. Primary endpoints were safety and feasibility. Pathological response and association between tumor immune microenvironment (TIME)/tumor mutational burden (TMB) and treatment response were also explored.
Results: Twelve patients were included. Neoadjuvant treatment with camrelizumab plus nab-paclitaxel/S1 was well tolerated without any grade 3 or higher toxicities. No surgical delay or perioperative death was reported. Nine patients (75%) responded to the treatment, four with a complete pathological response and five with a major pathological response. Treatment response by radiography was discordant with surgical pathology for five cases while endoscopic ultrasonography was accurate for the entire cohort. Neither programmed death-ligand 1 expression nor TMB was correlated with treatment response. In the TIME, higher abundance of CD56dim natural killer cells was associated with better pathological response in the primary tumor while lower density of M2-tumor-associated macrophages was associated with better pathological response in the lymph nodes.
Conclusions: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective in locally advanced ESCC and is worth further investigation.
Citation Format: Guozhen Yang, Xiaodong Su, Hong Yang, Guangyu Luo, Chan Gao, Yating Zheng, Wenzhuan Xie, Mengli Huang, Yuezong Bai, Zhiqiang Wang, Peiqiang Cai, Haoqiang He, Jin Xiang, Muyuan Cai, Yijun Zhang, Chunhua Qu, Jianhua Fu, Qianwen Liu, Yi Hu, Jiudi Zhong, Yuanheng Huang, Qiyu Guo, Xu Zhang. Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1601.