bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 331: Characterization of neoepitope (neoE)-specific T cells from peripheral blood for adoptive neoTCR-T cell therapy for patients with breast cancer (bc) or ovarian cancer (oc)
Authors: Cristea Mihaela , Chmielowski Bartosz , Oh David Y. , Funke Roel P. , Bota Daniela A. , Abedi Mehrdad 
Published: July 2021

Abstract
Introduction: Broad application of neoTCR-T cell therapy involves isolation of mutation-targeted CD8 T cells from the blood of patients with different tumor types. An ultra-sensitive process streamlined for high-throughput capture of neoE-specific T cells from blood is leveraged for producing a fully personalized adoptive T cell therapy for trial participants with BC or OC (NCT03970382).
Methods: Expressed mutations were identified by comparative sequencing of blood cells and tumor tissue. HLA typing was performed with OpiType. Proprietary algorithms were used to predict and prioritize tumor-exclusive neoE-HLA candidates. A library of barcoded HLA-mutational neoantigen complexes was used to interrogate PBMCs from each patient using imPACT Isolation Technology® (Dalmas et al., 2020). NeoTCRs cloned from captured antigen-experienced CD8 T cells were precision genome engineered into healthy donor T cells for functional characterization, including secretion of cytokines and effector molecules (Jacoby et al., 2019; Sennino et al., 2019). Based on pre-specified prioritization criteria, up to 3 actionable neoTCRs were selected for manufacturing the products for each individual.
Results: Six patients (2 BC/4 OC) successfully underwent neoTCR product selection. The median age was 59.5 years (range 38-69). Patients received a median of 5.5 prior regimens for metastatic disease (range 4-9). Median tumor mutational burden (TMB) was 2.7 (range 0.9-13.4). HLA-neoantigen libraries contained a median of 91 snares (range 29-262) and represented 6/6 HLA alleles in 4 patients and 5/6 in the remaining 2. A median of 8.5 distinct neoE-specific T cells (range 5-15) were isolated per patient. Following functional characterization 13 neoTCRs met selection criteria: three patients with 3 TCRs, one with 2 TCRs, and two had a single TCR. The median predicted neoE:HLA affinity of the selected TCRs was 77 nM (range 6.3 - 5866) and the median IFN-g EC50 was 4 ng/mL (range 1-431).
Conclusion: Relevant antigen-experienced, tumor mutation-targeted CD8 T cells were isolated from the blood of heavily pre-treated BC and OC patients with low TMB (&lt;10 mutations/Mb). Correlations between TCR characteristics and clinical and biomarker data are planned. This approach holds potential for broad use in women with BC or OC.
Citation Format: Mihaela Cristea, Bartosz Chmielowski, David Y. Oh, Roel P. Funke, Daniela A. Bota, Mehrdad Abedi. Characterization of neoepitope (neoE)-specific T cells from peripheral blood for adoptive neoTCR-T cell therapy for patients with breast cancer (bc) or ovarian cancer (oc) [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 331.
Abstract 344: Correlative biomarker analyses: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in an open-label, single arm phase 2 trial in locally advanced esophageal squamous carcinoma
Authors: He Wenwu , Peng Lin , Bao Yu , Xiao Wenguang , Fang Qiang , Leng Xuefeng , Yan Jiaxin , Mao Tianqin , Shen Xudong , Huang Depei , Zhang Hushan , She Xueke , Han Yongtao 
Published: July 2021

Abstract
Background: NCT04177797 was an open-label, single arm phase 2 trial in locally advanced esophageal squamous carcinoma (ESCC), which adopted toripalimab, plus paclitaxel and carboplatin as neoadjuvant immunotherapy regimen. Here we report correlative biomarker analyses for all 18 included patients.
Methods: After two cycles of neoadjuvant immunotherapy, sixteen patients underwent surgery and seven of them achieved major pathological response (MPR). Two patients did not receive surgery but their imaging evaluation were both clinical complete response (cCR). We defined MPR or cCR as responders, and others as non-responders.  Peripheral blood, gastroscopic tumor and adjacent normal tissues were collected before the first dose of drug and so did surgery samples. Whole exome sequencing (WES) and RNA-seq were conducted for the pretreatment tissues, and surgery samples were performed for multiplex immunohistochemistry (mIHC) with 5 markers.
Results: In pretreatment tumor tissues, there was no significant difference either in the CD8+ (p=0.19) or CD68+HLA-DR- (p=0.57) density between responders and non-responders. However, CD8+ density increased (p=0.0078) and CD68+HLA-DR- density decreased (p=0.039) significantly in responders after neoadjuvant combined immunotherapy, whereas these two markers did not in non-responders (p=0.13 and p=0.36, respectively). Meanwhile, responders were associated with higher baseline gene expression levels of CXCL 5 (p=0.03) and lower baseline CCL 19 (p=0.017) and UMODL1 (p=0.03).
Conclusions: The mechanism of tumor response may be associated reduction of M2 macrophages and CD8 cells recruitment after combined immunotherapy in locally advanced resectable ESCC.
Citation Format: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han. Correlative biomarker analyses: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in an open-label, single arm phase 2 trial in locally advanced esophageal squamous 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 344.
Abstract 355: Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression
Authors: Zeng Xiancheng , Liu Xinyi , Huang Mengli 
Published: July 2021

Abstract
Background: Gastric or GEJ cancer with positive PD-L1 expression have been proved a subgroup who can benefit from first-line and second-line therapy of PD-1 inhibitors. Positive PD-L1 expression promises to be the most effective biomarker in gastric/GEJ cancer patients. The results of CheckMate-649 further revealed that patients with PD-L1 CPS≥5 were more favorable to PD-1 inhibitors. On the other hand, high level of tumor mutational burden, MSI-H and mutations in DDR genes had also been identified as biomarkers in setting of immune checkpoint inhibitors in cancers. The difference of genomic features in subgroups with PD-L1 expression level in gastric/GEJ cancers is a question of interest.
Method: 613 cases of Chinese gastric/GEJ cancer patients were included in our analysis. Immunohistochemistry and 381-gene panel next-generation sequencing (NGS) testing had been performed in their tumor tissue specimen. PD-L1 expression level was evaluated by the combined positive score (CPS). Tumor mutational burden and MSI status were evaluated via NGS testing. Somatic and germline mutations in 30 DDR genes had also been analyzed.
Result: 493 out of 613 patients were CPS&lt;1, 54 cases were CPS&lt;5, 64 cases were CPS &lt;49, 16 cases were CPS≥50. The median TMB score of four subgroups were 5.59, 7.26, 7.26 and 8.06 respectively. The proportion of MSI-H patients in four subgroups were 3.25%, 9.26%, 12.5%, and 12.5% respectively. ARID1A and ARTX genes only were detected somatic mutated. There was a negative correlation trend in germline mutational proportion and PD-L1 expression level in some genes, such as MSH2, POLE, POLD1, PALB2 and PTEN. However, the somatic mutational proportion of MSH6, PMS2, POLE genes had a positive correlation trend with PD-L1 expression level.
Conclusion: In Chinese gastric/GEJ cancer population, the TMB level of CPS≥1 subgroup was significantly higher than CPS&lt;1 subgroup. MSI-H patients were enriched in CPS&gt;5 subgroup. In addition, DDR genes had distinct mutational frequency in subgroups with different levels of PD-L1 expression, indicating they impact the immunogenicity of gastric/GEJ cancer through different mechanisms.
Citation Format: Xiancheng Zeng, Xinyi Liu, Mengli Huang. Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression [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 355.
Abstract 356: Association of LRP1B mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors
Authors: Yang Mengmei , Xie Wenzhuan , Huang Mengli , Wu Peng 
Published: July 2021

Abstract
Background: Bladder cancer is a common genitourinary malignancy worldwide. Immune checkpoint inhibitors(ICIs) including atezolizumab, pembrolizumab, nivolumab have shown durable responses and have been approved by FDA. However ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of LRP1B(The low-density lipoprotein receptor-related protein 1B) are frequently seen in solid tumors and have been reported to be associated with higher tumor mutation burden(TMB) and prolonged survival in NSCLC, melanoma and liver cancer. The association between LRP1B mutation and survival in bladder cancer is unknown.
Methods: The association between LRP1B mutation with TMB was analyzed in bladder cancer patients from the public immunotherapy-treated cohort published by Miao et. al as well as a clinical cohort from 3D Medicines database involving 118 Chinese patients. Wilcoxon test was used for the comparison of TMB. Overall survival(OS) and progression-free survival (PFS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p = 0.05.
Results: 15%(5/33) bladder cancer patients in the public immunotherapy-treated cohort and 18.6% (22/118) patients in the clinical cohort harbored LRP1B mutation. LRP1B mutation is associated with higher TMB in both public cohort(p=0.028) and clinical cohort(p=0.003). Survival analysis in the public cohort demonstrated that LRP1B mutation resulted in significantly longer OS ( 16.8 vs 8.08 months; HR, 0.16; p=0.043) and a increasing trend on PFS without significant difference (15.9 vs 4.1 months; HR, 0.62; P = 0.39) in bladder cancer patients treated with ICIs.
Conclusions: This study shows that LRP1B mutation is relatively common and correlated with higher TMB in bladder cancer. LRP1B mutation may serve as a predictive biomarker of ICI benefit in bladder cancer.
Citation Format: Mengmei Yang, Wenzhuan Xie, Mengli Huang, Peng Wu. Association of LRP1B mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors [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 356.
Abstract 373: Advancing precision oncology by synergizing ddPCR with microdissection
Authors: Johann Donald J. , Shin Ikjae , Peterson Erich , Steliga Mathew , Muesse Jason , Marino Katy , Laun Sarah , Roberge Adam , Weigman Robert , Emmert-Buck Michael , Tangrea Michael 
Published: July 2021

Abstract
Background - The domain of precision oncology includes improving patient treatment outcomes based on the application of advanced molecular profiling methodologies to pathological specimens. To this end, optimal utilization of tumor tissue from diagnostic biopsies is an unmet medical need. This is especially relevant today since precision oncology is a rapidly evolving field where timely tumor genotyping is essential for the indication of many advanced and targeted therapies. National Comprehensive Cancer Network (NCCN) guidelines now mandate molecular testing for clinically actionable targets in certain malignancies. Patients diagnosed with advanced non-small cell lung cancer (NSCLC) are commonly of an older age and have significant co-morbidities. This frequently causes clinical dilemmas regarding the ability to obtain adequate amounts of tissue for tumor genotyping. In these cases, the tumor tissue may have been obtained by an image-guided biopsy, and the diagnosis of NSCLC proper determined via cytology. In certain instances, adequate tissue for tumor genotyping and/or a more advanced mutational analysis to identify oncogenic drivers may not be available.
Methods - Formalin fixed paraffin embedded (FFPE) specimens were examined using advanced immuno-based laser capture microdissection (LCM), following a formal pathology review. In preparation for droplet digital PCR (ddPCR), DNA was extracted from samples and run with a series of positive and negative controls.
Results - Utilizing lung cancer as an example, an improved genotyping approach for NSCLC solid tumors was developed and tested. The strategy involves optimization of the microdissection process and analysis of a large number of identical target cells from FFPE specimens sharing similar characteristics, in other words, single-cell subtype analysis. Immunostaining status, cell phenotype, and spatial location within a histological section are examples of shared characteristics that can guide cell procurement.
Conclusions - Synergy between microdissection and ddPCR enhances molecular analysis. Demonstrated is a methodology that illustrates genotyping of a solid tumor from a small tissue biopsy sample in a time and cost-efficient manner, using immunohistochemistry directed LCM and ddPCR detection.
Citation Format: Donald J. Johann, Ikjae Shin, Erich Peterson, Mathew Steliga, Jason Muesse, Katy Marino, Sarah Laun, Adam Roberge, Robert Weigman, Michael Emmert-Buck, Michael Tangrea. Advancing precision oncology by synergizing ddPCR with microdissection [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 373.
Abstract 374: NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC
Authors: Zhang Linlin , Wang Xin , Song Hui , Meng Fanlu , Yu Guowei , Zhong Diansheng 
Published: July 2021

Abstract
Background: In the era of precision medicine, better response of anti-tumor therapies attribute to detection of specific molecular markers. However, up to the present no validated biomarker for platinum-based chemotherapy could be used in clinic. Next-generation sequencing (NGS) technology has been applied for non-small cell lung cancer (NSCLC) molecular typing for years. Whether analysis of homologous recombination (HR) gene mutations based on NGS results could predict the efficiency of platinum-based therapy in NSCLC is still obscure.
Methods: NGS has been performed for screening homologous recombination (HR) gene mutations, as well as common driver genes in NSCLC, with tumor samples. Advanced or metastatic NSCLC patients receiving platinum-based chemotherapy were included for efficacy analysis.
Results: 129 patients with HR genes information were included for analysis. Among the 129 patients, 55 patients were received platinum-based chemotherapy. The efficiency results showed the objective response rates (ORR) of patients with BRCA1/2 and without BRCA1/2 mutations were 71.4% and 31.3%; and the median progression free survival (PFS) were 7.5 and 5.6 months(p=0.161), respectively. The ORR of patients with and without HR genes mutations were 57.9% and 25.0%; and the median PFS were 8.0 and 5.3 months (p=0.039), respectively.
Conclusions: NGS based profiling of BRCA1/2 and other gene mutations in HR pathways have a promising predictive value for efficacy of platinum-based chemotherapy in advance and metastatic NSCLC.
Citation Format: Linlin Zhang, Xin Wang, Hui Song, Fanlu Meng, Guowei Yu, Diansheng Zhong. NGS based profiling of homologous recombination genes to predict response to platinum-based chemotherapy in NSCLC [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 374.
Abstract 380: WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in NSCLC
Authors: Ren Dian , Zhang Bo , Liu Renwang , Gong Fuyu , Bai Yuezong , Xie Wenzhuan , Huo Huandong , Zhang Hao , Song Zuoqing 
Published: July 2021

Abstract
Background: Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with NSCLC. There are still lots of patients could not reach the clinical benefit, even though with the positive expression of the programmed cell death 1 ligand 1 (PD-L1). Here, we aimed to research the immune resistance mechanism in NSCLC.
Methods: The genomic data and clinical data of the discovery cohort was obtained from The Cancer Genome Atlas (TCGA). The clinical data of validation cohort in NSCLC treated by immunotherapy was retrospective collected. And tissue from patients with NSCLC were performed to whole exome sequencing in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab.
Results: Activation of WNT signaling was inferred that somatic mutations or somatic copy number alterations in WNT signaling elements including APC, WNT16, AXIN2, WNT4, AXIN1, CTNNB1, BCL9L and SMAD4. Two cohort have been enrolled in this study, the discovery cohort from TCGA, and the validation cohort from the Chinese patients with NSCLC. The frequency of WNT pathway alterations from the TCGA cohort was 16%, and which was represented mutually exclusive molecular subsets. In TCGA cohort, activating alteration WNT signaling were associated with shorter median PFS (18.8 vs 3.9 months, p=0.036, HR=0.24 (0.09-0.68)).
Conclusions: Mutations predicted to activate the WNT pathway were associated with innate resistance to immune checkpoint blockade in NSCLC
Citation Format: Dian Ren, Bo Zhang, Renwang Liu, Fuyu Gong, Yuezong Bai, Wenzhuan Xie, Huandong Huo, Hao Zhang, Zuoqing Song. WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in NSCLC [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 380.
Abstract 4: Temporal and spatial topography of cell proliferation in cancer
Authors: Gaglia Giorgio , Kabraji Sheheryar , Argyropoulou Danae , Dai Yang , Bergholz Johann , Coy Shannon , Lin Jia-Ren , Winer Eric P. , Dillon Deborah , Zhao Jean J. , Sorger Peter K. , Santagata Sandro 
Published: July 2021

Abstract
Uncontrolled cell proliferation is a defining feature of malignancy. Current understanding of proliferation, particularly in humans, derives primarily from studying cells growing rapidly in the non-physiological conditions of cell culture. However, tumors are exceedingly complex admixtures of different cell types and subclonal malignant populations comprising proliferative, non-proliferative, and arrested states that are influenced by physical, metabolic, and molecular conditions. Images of single or small sets of protein markers from fixed tissue samples only provide limited and static views into the nature of these complex states. Here we identify proliferation states and develop a quantitative framework to extract cell cycle dynamics from multiplexed, spatially-resolved tissue images of millions of tumor cells from human cancers and genetically engineered tumors in mice. Across spatial scales, tumors display intrinsic regional variability in proliferation patterns and in the coherence of cell cycle markers in high-dimensional space. Cell cycle dynamics and cell cycle coherence are not solely a function of tumor growth and oncogene expression and rapidly adapt following genetic and therapeutic perturbations. Replacing binary metrics with multivariate traits provides a quantitative framework for extracting multidimensional dynamic information from static images that is broadly applicable to the study of temporal processes within the native architecture of human disease tissues.
Citation Format: Giorgio Gaglia, Sheheryar Kabraji, Danae Argyropoulou, Yang Dai, Johann Bergholz, Shannon Coy, Jia-Ren Lin, Eric P. Winer, Deborah Dillon, Jean J. Zhao, Peter K. Sorger, Sandro Santagata. Temporal and spatial topography of cell proliferation in cancer [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 4.
Abstract 408: Quantification of cell surface HLA-A2 and intracellular Survivin protein levels for tumor blasts and non-blast immune cells in multiple myeloma bone marrow aspirates using a rapid sample preservation methodology followed by 10-color FACS assay
Authors: Hardas Tejaswini , Ra Hyun-Jeong , Sheridan James , Kovalenko Maria , Tribouley Catherine 
Published: July 2021

Abstract
Introduction: Multiple myeloma (MM) is a plasma cell disorder characterized by clonal expansion and accumulation of immature undifferentiated neoplastic cells in the bone marrow (BM). Recent advances in fluorochrome chemistries, flow cytometry (FACS) instrumentation and rapid tissue preservation methodologies have created opportunities for broader adoption of FACS in the clinical management of multiple myeloma patients.
Methods: We have developed a 10 color, 2 tube FACS assay based on recommendations made by the European Myeloma Network for phenotyping plasma cell gammopathies to identify abnormal blasts in multiple myeloma patient bone marrow aspirates. The assay includes essential plasma cell markers CD138, CD38, CD56 and CD19 to differentiate abnormal blasts from reactive plasma cells. Use of a multi epitope fluorochrome conjugated anti-CD38 antibody enables CD38 detection in patients on anti-CD38 therapy.
Results: Quantification of cell surface HLA-A2 and intracellular survivin protein was made possible using fluorochrome conjugated antibodies in combination with bead standards. The SmartTube™ proteomic stabilizer system for rapid preservation was used to freeze BM aspirate specimens for later analysis at locations with appropriate FACS equipment and trained staff. Consistent with previously published literature, patient survivin levels were elevated on abnormal MM blasts in comparison to survivin levels on non-blast immune cells.
Conclusion: We have developed a robust FACS methodology that would be easy to implement in the clinical trial and development setting with minimal training. The assay can consistently identify abnormal blasts in BM samples of multiple myeloma patients and quantify intracellular and cell surface biomarkers related to MM disease or disease treatment responses.
Citation Format: Tejaswini Hardas, Hyun-Jeong Ra, James Sheridan, Maria Kovalenko, Catherine Tribouley. Quantification of cell surface HLA-A2 and intracellular Survivin protein levels for tumor blasts and non-blast immune cells in multiple myeloma bone marrow aspirates using a rapid sample preservation methodology followed by 10-color FACS assay [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 408.