bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4098: Comparison of frontline therapeutic modalities in stages I/IE extranodal NK/T-cell lymphoma-nasal type (ENKTL-N): A network meta-analysis
Authors: Haddad Philip A. , Gallagher Kevin , Hammoud Dalia 
Published: June 2022

Abstract
Introduction: Despite many studies reporting on the optimal therapies for early stage ENKTL-N in the front-line setting, this area continues to be subject to significant controversy regarding single modalities versus combination or sequential approaches. All these comparative studies were small non-randomized studies that combined stages I & II. The results were often inconclusive and occasionally conflicting. In the absence of direct head-to-head randomized controlled trials in this clinical setting, a network meta-analysis was conducted to compare these therapeutic approaches and their respective impact on 5-year survival in stage I/IE ENKTL-N.
Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of stage I/IE ENKTL-N, treatment with chemotherapy (CT), radiation (RT), sequential CT and RT (SEQ), and chemoradiotherapy (CRT), comparative studies that reported predominantly I/IE 5-year survival and disease-free survival rates. Studies that reported on mixed samples of early and advanced ENKTL were excluded. A frequentist network meta-analysis was conducted using the netmeta package and random-effects model.
Results: Seven studies comprising a total of 377 participants were included. Our network meta-analysis revealed that upfront RT tended to have better 5-year OS and DFS than CRT and SEQ, though it did not reach statistical significance. However, RT demonstrated significant 5-year OS and DFS when compare to CT alone in the frontline setting. Based on the pairwise and network meta-analyses, RT was ranked as the most effective first-line treatment approach followed by CRT, SEQ, and CT in decreasing order. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates.
Conclusions: This is the first network meta-analysis to compare all commonly utilized upfront treatment modalities in stages I/IE ENKTL-N. It indicates that upfront RT alone may be sufficient as there was no signal that chemotherapy added any OS or DFS advantages. Adequately powered randomized trials are warranted.
Citation Format: Philip A. Haddad, Kevin Gallagher, Dalia Hammoud. Comparison of frontline therapeutic modalities in stages I/IE extranodal NK/T-cell lymphoma-nasal type (ENKTL-N): A network meta-analysis [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 4098.
Abstract 4173: Improve anti-PD-1 immunotherapy response in immunologically cold tumors by harnessing RNA-binding protein HuR
Authors: Zhang Qi , Zhe Yang , Wu Xiaoqing , Lan Lan , Wei Lanjing , Xu Liang 
Published: June 2022

Abstract
Cancer immunotherapy, especially those targeting the immune checkpoint PD-1 and PD-L1 has emerged as a revolutionizing treatment modality. Immune checkpoint inhibitors (ICIs)-mediated anti-tumor response depends on T cell capability of recognizing and killing tumor cells. ‘Hot’ tumors, which are characterized by the T cell infiltration, show a better response rate to immune checkpoint blockade (ICB) treatment. In contrast, ‘Cold’ tumors have a particularly low objective response rate (ORR) to ICB. In consideration of the durable and impressive responses observed in ‘hot’ tumors, it will be valuable to make an endeavor to turn immunologically cold tumors into hot tumors. The RNA-binding protein HuR is a member of the embryonic lethal abnormal vision (ELAV) family that is overexpressed in a variety of cancers and promotes tumorigenesis by interacting with a subset of oncogenic mRNAs. In this study, we show the direct binding of HuR protein to PD-L1 mRNA in multiple types of cells by Ribonucleoprotein immunoprecipitation (RNP-IP) and further validated by RNA pulldown assay. We also show that PD-L1 mRNA decay is greatly expedited in HuR-knockout cells, which underlines the stabilization function of HuR on PD-L1 transcripts. Immunoblotting results demonstrate that PD-L1 protein expression level is decreased in HuR-knockout cells while up-regulated in HuR-proficient cells in comparison with control. These data together clarify HuR is engaged in PD-L1 post-transcription regulation. Based on this mechanism, we develop a combination strategy using HuR inhibitors and anti-PD1 antibodies to overcome the limitation by regulating the tumor immune microenvironment. KH-200 is a compound that disrupts the transportation of HuR from nuclear to cytoplasm. To test the combination strategy in vivo, we established the EMT6 syngeneic breast cancer model. After 4-week treatment, the combination group shows great effects in inhibiting tumor growth and prolonging survival. A similar combination effect was further observed in Lewis lung syngeneic lung cancer model. In conclusion, we preliminarily explored the role of HuR in tumor immune evasion. The method using HuR inhibitors as a combination in immunotherapy shows effectiveness in immunologically cold tumor treatment and may have reference significance for clinical cancer therapy.
Citation Format: Qi Zhang, Yang Zhe, Xiaoqing Wu, Lan Lan, Lanjing Wei, Liang Xu. Improve anti-PD-1 immunotherapy response in immunologically cold tumors by harnessing RNA-binding protein HuR [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 4173.
Abstract 4189: Evaluation of implantable cytokine factories in combination with checkpoint inhibitors for eradication of malignant pleural mesothelioma (MPM) tumors in mice with safe and predictable dosing in non-human primates
Authors: Nash Amanda , Aghlara-Fotovat Samira , Hernandez Andrea , Castillo Bertha , Lu Alexander , Pugazenthi Aarthi , Rios Peter , Ghani Sofia , Joshi Ira , Isa Douglas , Xu Chunyu , Sheth Rahul , Peng Weiyi , Oberholzer Jose , Jazaeri Amir , Jang Hee-Jin , Burt Bryan , Lee Hyun-Sung , Ghanta Ravi , Veiseh Omid 
Published: June 2022

Abstract
Pro-inflammatory cytokines have been approved as a cancer immunotherapy for treatment of metastatic melanoma and renal carcinoma for over 30 years. However, widespread use of cytokine therapy in the clinic is limited by its short half-life in circulation and the associated toxicities that emerge as a result of high systemic exposure. To overcome these limitations, we developed a clinically translatable cytokine delivery platform, called cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers. These cells are able to produce a wide range of natural cytokines (IL2, IL7, IL10, or IL12) and allow for controlled and predictable dosing in vivo. In vivo administration of cytokine factories created a high local cytokine concentration (IP space) without substantial leakage into the systemic circulation. Local, or tumor adjacent, administration of pro-inflammatory (IL-2-based) cytokine factories caused reduction of tumor burden by 70% after only 1 week of treatment when delivered as a monotherapy to mice with malignant pleural mesothelioma (MPM). Importantly, when administered in combination with local anti-PD1 injections, these cytokine factories lead to eradication of these highly aggressive tumors in 7/7 treated mice. To validate the translatability of this platform, we evaluated the safety profile in non-human primates. Significantly, this platform produced local and systemic T cell biomarker profiles that predict efficacy without renal, liver, or general toxicity in non-human primates. Our findings demonstrate the safety and efficacy of cytokine factories in preclinical animal models and provide rationale for future clinical testing for the treatment of metastatic peritoneal cancers in humans.
Citation Format: Amanda Nash, Samira Aghlara-Fotovat, Andrea Hernandez, Bertha Castillo, Alexander Lu, Aarthi Pugazenthi, Peter Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Chunyu Xu, Rahul Sheth, Weiyi Peng, Jose Oberholzer, Amir Jazaeri, Hee-Jin Jang, Bryan Burt, Hyun-Sung Lee, Ravi Ghanta, Omid Veiseh. Evaluation of implantable cytokine factories in combination with checkpoint inhibitors for eradication of malignant pleural mesothelioma (MPM) tumors in mice with safe and predictable dosing in non-human primates [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 4189.
Abstract 4208: In situ vaccination of non-small cell lung cancer with CXCL9/10-engineered dendritic cells combined with PD-1 blockade
Authors: Lim Raymond J. , Salehi-rad Ramin , Tran Linh M. , Dumitras Camelia , Abascal Jensen W. , Crosson William P. , Patel Tejas S. , Man Samantha , Li Rui , Krysan Kostyantyn , Liu Bin , Dubinett Steven M. 
Published: June 2022

Abstract
Lung cancer is the most common cause of cancer death worldwide with approximately 85% of patients having non-small cell lung cancer (NSCLC). Checkpoint blockade immunotherapy has evolved the current treatment landscape with robust and durable responses in approximately 20% of patients with progressive, locally advanced or metastatic NSCLC, as well as in treatment-naïve advanced disease. Inefficient tumor antigen presentation, diminished T cell infiltration into tumor and LKB1-inactivating mutations contribute to the mechanisms of resistance to programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) blockade in NSCLC. LKB1 deficiency also facilitates an immunosuppressive environment that promotes tumor growth. One approach to overcome this immunosuppressive tumor microenvironment (TME) is to utilize in situ vaccination with gene-modified functional antigen presenting cells (APCs) to enhance tumor antigen presentation and promote tumor-specific T cell activation. It has been shown that the chemokines CXCL9 and CXCL10 (CXCL9/10) are important signaling molecules secreted by CD103+ dendritic cells (DCs) to orchestrate the anti-tumor immunity. Thus, we hypothesize that intratumoral (IT) injection of CXCL9/10-secreting DCs (CXCL9/10-DCs) can potentiate the response to anti-PD-1 monotherapy in LKB1-deficient NSCLC by promoting antigen presentation and inducing T cell infiltration. Our preliminary data shows that CXCL9/10-DC injection modulates systemic immunity and generates anti-tumor responses that are augmented by the combination treatment with anti-PD1. In an in vivo murine model of Lkb1-null lung cancer bearing high tumor mutational burden (TMB), CXCL9/10-DC facilitates recruitment of effector T cells into the TME and tumor-specific T cell activation. These studies will enhance our understanding of anti-tumor immunity mediated by in situ DC vaccination and facilitate the improvement of novel vaccine therapies.
B. Liu and S. M. Dubinett contributed equally to this work.
Citation Format: Raymond J. Lim, Ramin Salehi-rad, Linh M. Tran, Camelia Dumitras, Jensen W. Abascal, William P. Crosson, Tejas S. Patel, Samantha Man, Rui Li, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. In situ vaccination of non-small cell lung cancer with CXCL9/10-engineered dendritic cells combined with PD-1 blockade [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 4208.
Abstract 4212: In situvaccination with Flt3l gene-modified CD103+type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC)
Authors: Abascal Jensen W. , Lim Raymond J. , Salehi-Rad Ramin , Jing Zhe , Crosson William P. , Kahangi Bitta P. , Reyes Edgar Perez , Reyimjan Diana , Zhu Jessie , Tran Linh M. , Paul Manash , Krysan Kostyantyn , Liu Bin , Dubinett Steven M. 
Published: June 2022

Abstract
A major hurdle in treatment of Non-Small Cell Lung Cancer (NSCLC) with anti-PD-1 immune checkpoint blockade (ICB) therapy is a lack of response (primary resistance) and relapse after an initial response (acquired resistance). Recent studies reveal that responses to PD-1/PD-L1 blockade are associated with high tumor mutational burden (TMB), increased CD8+ T cell infiltration and high baseline PD-L1 expression within the tumor microenvironment (TME), while impaired tumor antigen presentation and the immunosuppressive TME have been associated with resistance to ICB. One approach to overcome anti-PD-1 resistance is to intratumorally vaccinate NSCLC tumors with gene modified conventional dendritic cells (cDC), specifically the type I conventional DC (cDC1) lineage. Recent studies have established that generation of an anti-tumor immune response driven by CD8+ T cells requires the cross presentation of tumor associated antigens and that cDC1s are the primary cross presenting APC subtype in vivo, which can license CD8+ T cells to initiate an adaptive anti-tumor immune response. In addition, previous studies have shown that intratumoral administration of the FMS-like tyrosine kinase 3 ligand (FLT3L) protein can expand endogenous CD103+ cDC1 cells in the TME and augment anti-tumor immune responses to ICB therapy. Here, we engineered murine CD103+ cDC1 cells to constitutively secrete soluble FLT3L (FLT3L_cDC1) and performed in situ vaccination studies on anti-PD1 resistant murine models of NSCLC with LKB1-deficiency and elevated TMB that better represents human disease. The FLT3L_cDC1 cells showed enhanced anti-tumor efficacy compared to non-modified cDC1 cells and synergized with anti-PD-1 ICB to inhibit tumor growth. Our data suggests intratumoral injection of FLT3L_cDC1 cells may represent a promising strategy to potentiate the efficacy of ICB and improve outcomes for patients with primary resistance PD-1/PD-L1 monotherapy.
*B. Liu and S.M Dubinett contributed equally to this work
Citation Format: Jensen W. Abascal, Raymond J. Lim, Ramin Salehi-Rad, Zhe Jing, William P. Crosson, Bitta P. Kahangi, Edgar Perez Reyes, Diana Reyimjan, Jessie Zhu, Linh M. Tran, Manash Paul, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. In situvaccination with Flt3l gene-modified CD103+type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC) [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 4212.
Abstract 5004: Integrative quality control of cancer somatic mutations with CaMutQC
Authors: Wang Xin , Ren Jian , Zhao Qi 
Published: June 2022

Abstract
The quality control of cancer somatic mutations is an essential step for eliminating false positive mutations from technical bias, and selecting key mutation candidates plays a crucial role in both downstream translation research and personal medical decisions. Existing tools, with complicated parameters and changeable filtering standards, may not be suitable specifically for cancer somatic mutations. In addition, previous genomic studies usually adopted different filtering criteria for processing raw sequencing datasets, which greatly restricts the efficiency of integrative exploration for cancer genomics.
In this study, we presented CaMutQC, a heuristic cancer somatic mutations (CAMs) quality control and filtration package for cancer genomic studies. CaMutQC provides two schemes, including filtration of false positive mutations generated by technical issues, and the screening of candidate cancer somatic mutations from single or multiple VEP-annotated files in VCF format. Specifically, for quality control, instead of directly discarding CAMs that failed to meet the thresholds of parameters collected from classic studies, CaMutQC labels them with customized tags to represent the filtering type, enabling portable subsequent analyses. And a vivid and well-structured filter report is generated after filtration or selection. In addition, we proved by applying an updated mutation QC strategy, which takes the union of CaMutQC-filtered cancer variants from multiple variant callers (eg. MuTect, MuSE and VarScan2) on published datasets that, CaMutQC can not only reduce the false positive CAMS, but also greatly rescue the false negative CAMS from each single caller or the overlap of multiple tools.
In summary, in this study, for the first time, we systematically implemented the parameters and criteria of CAMs quality control from published studies into the CaMutQC package, which we believe it would be a valuable tool for cancer genomic research. CaMutQC is implemented in R and is available at https://github.com/likelet/CaMutQC under the GPL-v3 license.
Citation Format: Xin Wang, Jian Ren, Qi Zhao. Integrative quality control of cancer somatic mutations with CaMutQC [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 5004.
Abstract 5040: Genetic predisposition of rectal neuroendocrine tumors
Authors: Saha Subrata , Grunn Adina , Califano Andrea 
Published: June 2022

Abstract
Rectal neuroendocrine tumors (RNETs) represent a clinically and molecularly distinct, yet poorly characterized subtype of gastroenteropancreatic neuroendocrine tumors (GEP-NET), with a virtually uncharted genetic landscape. Given their rare nature, compared with their small intestine (SI-NET) or pancreatic (PNET) counterpart, there have been no systematic efforts to elucidate the genetic landscape of RNETs and understand whether these tumors may present a common genetic etiology and predisposition. We have assembled a discover and a validation cohort comprising blood and tumor samples from 31 and 21 metastatic RNET patients, respectively, which was very challenging given the ultra-rare nature of these tumors. Whole-exome profiles were used to identify both rare and common germline variants that may be predictive of metastatic RNET predisposition, which is suspected to have a strong genetic component, given their frequent multifocal presentation. Among nonsynonymous rare germline variants (MAF &lt; 0.05 in the general population), 314 were significantly over-represented in the discovery cohort (FDR ≤ 0.05), based on ethnicity-matched controls from the 1,000 Genome Project. Of these, 144 were also identified in samples from the validation cohort. Of the 40 that were statistically significant in both cohorts, 11 were deemed pathogenic by CADD Phred-scores analysis (≥ 20.0), including 8 in regulatory regions. This includes pathogenic variants harbored by ALKBH8, LRRC71, PSPH, MUC16, SCRT2, YARS, MICAL3, KDM6B, SYCP2L, and TTN. We validated six statistically significant variants in both cohorts by Sanger sequencing. Critically, a classifier trained on the 314 statistically significant variants in the discovery cohort produced perfect classification (area under the receiver operator curve AUROC = 1) in predicting the tumor bearing vs. healthy individuals in the validation cohort and in an equivalent number of ethnicity matched control samples, shuffled 1,000 times. Moreover, a weighted, graph-based biological pathway analysis method identified co-segregation of genes harboring tumor-predictive variants in cancer related pathways, including genome integrity, DNA replication fidelity, extracellular matrix organization, glycosylation, and the inflammasomes, among others. Taken together, these results support a common, uniquely distinctive genetic etiology for RNETs, suggesting a strong germline predisposition. More critically, the accuracy and sensitivity of the predictor suggests that these rare variants may be effectively used as a biomarker to identify individuals at risk of developing RNETs.
Citation Format: Subrata Saha, Adina Grunn, Andrea Califano. Genetic predisposition of rectal neuroendocrine tumors [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 5040.
Abstract 5070: Prostate-specific membrane antigen (PSMA) targeted multiplexed siRNA-mediated gene silencing of CD46 and PD-L1 in prostate cancer
Authors: Chen Zhihang , Krishnamachary Balaji , Mironchik Yelena , Banerjee Sangeeta R. , Pomper Martin G. , Bhujwalla Zaver M. 
Published: June 2022

Abstract
Small interfering RNA are suitable for gene silencing through a sequence-specific RNA interference process. The redundancy and complexity of molecular pathways in cancer create a need for multiplexed targeting that can be achieved with multiplexed siRNA delivery. Here we delivered multiplexed siRNA with a PSMA-targeted biocompatible dextran nanoparticle (NP) to downregulate CD46 and PD-L1 siRNA in PSMA expressing prostate cancer cells. The multiplexed gene targets selected, PD-L1 and CD46, play important roles in the escape of cancer cells from immune surveillance. PSMA is abundantly expressed by prostate cancer cells allowing prostate cancer specific delivery of the NPs. The NP was decorated with acid cleavable amine functional groups through acetal bonds that undergo degradation under acidic conditions providing rapid release of siRNA. Cell imaging and flow cytometry studies confirmed PSMA-specific delivery of CD46 and PD-L1 siRNA to high PSMA expressing PC-3 PIP cells. Immunoblot, qRT-PCR and flow cytometry confirmed downregulation of CD46 and PD-L1 following treatment with multiplexed siRNA at a concentration of 50 nM. These studies pave the way for delivering multiplexed siRNA to tumors in vivo to unmask tumors to the immune system using PSMA targeted biocompatible NPs.
Citation Format: Zhihang Chen, Balaji Krishnamachary, Yelena Mironchik, Sangeeta R. Banerjee, Martin G. Pomper, Zaver M. Bhujwalla. Prostate-specific membrane antigen (PSMA) targeted multiplexed siRNA-mediated gene silencing of CD46 and PD-L1 in prostate cancer [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 5070.