tbuckley/cabot-search huggingface dataset:
Tislelizumab plus neoadjuvant chemotherapy and concurrent chemoradiotherapy versus neoadjuvant chemotherapy and concurrent chemoradiotherapy in local advanced nasopharyngeal carcinoma.
Authors: Haiqing Luo, Jiaqi He, Guihua Yi, Haifeng Tang, Donghong Yang, Haiwen Li, Ying Yu, Zihong Chen, Dechao Zhan
Journal: Journal of Clinical Oncology (2024)

6045 Background: Given the recent successes of immunotherapy in local advanced nasopharyngeal carcinoma (LA-NPC), maybe it is promising to achieve better response and improve the survival of LA-NPC if immunotherapy plus neoadjuvant and concurrent chemoradiotherapy (CCRT). Therefore, we retrospectively analysed the safety and efficacy of tislelizumab plus neoadjuvant chemotherapy and CCRT and neoadjuvant chemotherapy followed CCRT in the treatment of LA-NPC. Methods: A total of 90 patients with stage III-IVa NPC were enrolled between January 2020 and March 2021 at Affiliate Hospital of Guangdong Medical University. 43 patients were treated with tislelizumab plus TP (nab-paclitaxel 260mg/m 2 , cisplatin 80mg/m 2 , Q3W, 3 cycles) regimen followed tislelizumab plus CCRT as the combination therapy group (CG) and 47 patients were treated with TP regimen followed CCRT as the observation group (OG). Results: As of January 30th, 2024, the median follow-up time is 37.5 months. The median age was 42 years (range: 16–75 years). A total of 37 patients had stage III cancer and 53 had stage IVa , with 43 and 47 patients in OG and CG, respectively. The male–female ratio in the entire cohort was approximately 2.15:1. All reported parameters were balanced between the two groups with no statistical differences. The complete response rate (CRR) in CG after neoadjuvant therapy improved significantly (37.2% in CG vs 12.8% in OG). The ORR was 88.4% in CG and 70.2% in OG, respectively. The 3-year PFS was 93.75% in CG and 80% in OG. The incidence of acute treatment related adverse events in grades 3 or 4 was 70.2% and 65.6%, respectively. The most common grade 3-4 immune-related adverse events were hypothyroidism (7.0%) and hepatotoxicity (4.7%). No patients in CG had disease progression during treatment. Conclusions: Compared with regular treatment, tislelizumab plus neoadjuvant chemotherapy and concurrent chemoradiotherapy was feasible and well tolerated in LA-NPC patients. This trial is supportive of further prospective trials in LA-NPC.
Validation of HLA presented tumor-exclusive peptides in an independent cohort of head and neck squamous cell carcinoma.
Authors: Simon Laban, Sarah Schröder, Lena Mühlenbruch, Adrian von Witzleben, Tsima Abou Kors, Cornelia Brunner, Yacine Maringer, Annika Nelde, Naomi Hönisch Gravel, Jonas Scheid, Marissa L Dubbelaar, Thorben Gross, Johann M. Kraus, Hans A. Kestler, Paul-Stefan Mauz, Hubert Löwenheim, Jens Greve, Thomas K Hoffmann, Hans-Georg Rammensee, Juliane S. Walz
Journal: Journal of Clinical Oncology (2024)

6047 Background: Response rates to anti-PD1 antibodies in head and neck squamous cell carcinoma (HNSCC) range from 13-20% in recurrent / metastatic disease and up to 50% in locoregionally advanced disease. Vaccines composed of tumor-exclusive antigens may increase response rates to immunotherapy. We have previously identified HLA-presented tumor-exclusive peptides (TEP) in a cohort of 40 oropharyngeal HNSCC (UL dataset) and defined a warehouse of HLA allotype specific TEP (EP2023/071063, patent pending) for semipersonalized vaccine composition for 15 HLA allotypes. Methods: The HLA-bound immunopeptidome of a validation cohort of 40 HNSCC from Tübingen University was analyzed by tandem mass spectrometry (TÜ dataset). Data were processed as previously described to identify TEP. The TÜ dataset was queried for TEP from the previously defined warehouse containing 48 TEP for the respective 15 HLA allotypes in a cohort of 40 oropharyngeal HNSCC (UL dataset) patient samles. Coverage was defined as the fraction of patients presenting at least one of the TEP for a certain HLA allotype. Results: Among all 80 patients, 75 had at least one of the 15 HLA allotypes (36 in the TÜ cohort and 39 in the UL cohort). Of the 48 TEP, 28 TEP for 11/15 HLA allotypes were found in the TÜ validation cohort. The best coverages with the warehouse TEP were found for the following four HLA allotypes: HLA-A*01:01 (TÜ: 91%; UL: 79%), A*02:01 (TÜ: 81%; UL: 52%), B*40:01 (TÜ: 63%; UL: 100%) and A*24:02 (TÜ: 60%; 44%.). Based on a semipersonalized TEP selection by HLA allotype, 27/40 patients in the TÜ cohort presented at least one of the TEP selected (range: 0-10), whereas 28/40 patients in the UL cohort presented at least one of the TEP (range: 0-7). Thus, the total cohort coverage based on a semipersonalized peptide selection was 55/80 patients (68.8%). Conclusions: We validated previously identified TEP from oropharyngeal HNSCC for frequently occurring HLA allotypes in an independent, equally sized cohort of HNSCC patients. A semipersonalized vaccine composition strategy using a warehouse / off-the-shelve approach for immunotherapy trials seems feasible.
A phase II study of nivolumab in patients with recurrent or metastatic carcinosarcomas.
Authors: Miso Kim, Jung Yong Hong, Min Hwan Kim, Minkyu Jung, Gun Min Kim, Kyoo Hyun Kim, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Jiwoo Park, Jeeyun Lee, Hyo Song Kim
Journal: Journal of Clinical Oncology (2024)

6041 Background: We aimed to determine the activity of anti-PD-1 inhibitor, nivolumab in metastatic and/or recurrent carcinosarcoma. Methods: In this phase 2 trial, eligible patients had histologically confirmed metastatic and/or recurrent carcinosarcoma, measurable disease, 1-3 prior chemotherapy, and adequate renal/hepatic/hematologic function. In this single arm phase 2 trial, treatment consisted of nivolumab 3 mg/kg every 2 weeks. Primary outcome was progression free rate (PFR) at 6 months and secondary outcomes included overall response rate, progression-free survival (PFS), overall survival, and safety. Results: Between July 2020 and Nov 2023, 28 patients enrolled and received trial treatment. As of the time of data cut-off (Feb 1, 2024), 4 remains on treatment. Of the 28 patients evaluable, 4 (14.3%) achieved confirmed partial response, and 9 (32.1%) had stable disease, yielding and disease control rate of 46.4%. The median PFS was 2.6 months. The pre-specified primary endpoint was met with 6-months PFR of 30.8%. The common-treatment related adverse events included urticaria (5 [17.9%]), dyspepsia (4 [14.3%]), elevated aspartate aminotransferase (3 [10.7%]), and anemia (3 [10.7%]). The genomic analysis will be available at the meeting. Conclusions: Nivolumab demonstrated promising efficacy with favourable toxicity profile in metastatic/recurrent carcinosarcoma. Clinical trial information: NCT05224999 .
Characterizing the impact of sarcopenia on treatment response and survival in previously treated recurrent or metastatic nasopharyngeal carcinoma: Insights from a secondary analysis of the KL-A167 randomized trial.
Authors: Zheran Liu, Dou Meng, Huilin Li, Dong Li, Zhihui Li, Lei Cai, Jitao Zhou, Xingchen Peng
Journal: Journal of Clinical Oncology (2024)

6046 Background: The relationship between sarcopenia and adverse outcomes among patients with recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) undergoing immunotherapy remains underexplored. This secondary analysis of the KL-A167 clinical trial data aims to elucidate the impact of sarcopenia on treatment efficacy and prognosis in this cohort, while also identifying potential mediating hematological biomarkers. Methods: A cohort of 148 patients enrolled in the KL-A167 clinical trial was analyzed. Logistic and Cox regression models were applied to assess the association between sarcopenia and treatment response, overall survival (OS), and progression-free survival (PFS), with adjustment for clinical prognostic factors. Counterfactual causal mediation analysis was conducted to identify hematological biomarkers potentially mediating the relationship between sarcopenia and prognosis in R/M NPC patients. Results: The presence of sarcopenia was significantly associated with reduced objective response rate (ORR: OR = 0.25, 95% CI = 0.08–0.81, p = 0.020) and disease control rate (DCR: OR = 0.23, 95% CI = 0.07–0.70, p = 0.010). Furthermore, sarcopenia was linked to inferior OS (HR = 2.07, 95% CI = 1.12–3.81, p = 0.020) and PFS (HR = 2.59, 95% CI = 1.48–4.54, p = 0.001). Notably, sarcopenia was characterized by elevated levels of neutrophil count, fibrinogen, and white blood cell count, alongside decreased creatine kinase levels. Fibrinogen emerged as the sole elevated biomarker significantly associated with both OS and PFS. Causal mediation analysis indicated that fibrinogen accounted for 23.5% of the association between sarcopenia and OS and 15.7% of PFS. Conclusions: Sarcopenia significantly correlates with poor treatment response and survival outcomes in patients with R/M NPC receiving immunotherapy. Targeting fibrinogen may offer a novel strategy to mitigate the negative impact of sarcopenia on patient survival.
The combination of patient-specific tumor and HPV sequencing to enable high-sensitivity detection of ctDNA in patients with HPV-associated oropharyngeal carcinoma.
Authors: Bill Diplas, David N Brown, Xin Pei, Linda Chen, Chiharu Graybill, W. Michael Korn, Emily Westheimer, Ardijana Novaj, John Humm, Amita Shukla-Dave, Heiko Schöder, Nora Katabi, Eric Jeffrey Sherman, Jorge Reis-Filho, Britta Weigelt, NANCY Y. LEE, Nadeem Riaz
Journal: Journal of Clinical Oncology (2024)

6058 Background: Detection of Human papillomavirus (HPV) in plasma has been used to monitor treatment response in HPV-associated oropharyngeal carcinoma (OPC) but was found to have limited sensitivity in patients with low disease burden. We hypothesized that the combined detection of personalized tumor-specific alterations and HPV could provide a more sensitive approach for detecting circulating tumor DNA (ctDNA) and for disease monitoring in early-stage HPV-associated OPC patients. Methods: Patients with HPV-associated OPC (T0-2/N1-N2c) enrolled in a phase II chemoradiation (CRT) de-escalation trial (NCT03323563) were chosen for this study. The patients underwent resection of the primary tumor prior to CRT and a baseline plasma was drawn at this time. Additional plasma samples were collected weekly throughout CRT. Whole-exome and targeted HPV sequencing was performed on the primary resection to build a dictionary of somatic variants and for HPV typing, respectively. A dual PCM-HPV assay was developed based on the Invitae Personalized Cancer MonitoringTM (PCM) platform and used to evaluate the plasma samples. Tumor volume was measured by T2 MRI using a region of interest outlining the largest lymph node in the undissected neck. Results: 158 patients with T0-2/N1-N2c HPV-OPC were enrolled on the trial and the dual PCM-HPV assay was successfully designed for 111 patients targeting a median of 50 patient-specific mutations (range: 26-50). Preliminary analyses were performed on 71/111 patients (64.0%) with HPV16-associated tumors and available baseline plasma. 64/71 (90.1%) and 61/71 (85.9%) were ctDNA positive by PCM testing and HPV testing alone, respectively. Combining HPV plasma testing with PCM (PCM-HPV) improved the sensitivity to 68/71 (95.7%). This increased sensitivity was maintained when analyzing plasma samples collected weekly following CRT. The 3 patients with double negative HPV and PCM results at baseline had a lower tumor volume (p=0.05) and lower levels of genome instability (p=0.02) than those with ctDNA or PCM positive baseline plasma. HPV cfDNA levels are weakly correlated with tumor HPV genome copy number (r=0.16; p=0.001). Conclusions: The combined detection of personalized tumor-specific alterations and HPV provides a highly sensitive approach for detecting low disease burden in early stage HPV-associated OPC patients before and during treatment. [Table: see text]
Features of HPV+ OPSCC predictive of recurrence identified by transcriptional profiling of a case-control cohort.
Authors: Devraj Basu, Malay Kumar Sannigrahi, Lovely Raghav, Lova Sun, Roger B. Cohen, Phyllis A. Gimotty, Jalal Jalaly, Alexander T. Pearson
Journal: Journal of Clinical Oncology (2024)

6055 Background: De-escalating therapy for HPV+ oropharyngeal cancers (OPSCCs) is hampered by poor ability to predict recurrence, and limited insight into the biologic traits predisposing to recurrence impedes personalizing therapy. We aimed to (1) define biologic features underlying therapy resistance by transcriptional profiling and (2) evaluate the features for prognostic utility. Methods: A single institution cohort of 851 HPV+ OPSCC patients undergoing transoral robotic surgery during 2007-2020 was used to identify 50 cases that recurred locoregionally in the adjuvant RT field (n=14) and/or at distant sites (n=43). As controls, we used 49 recurrence-free patients with long-term follow up and similar stage, smoking history, and adjuvant therapy. RNAseq of pretreatment tumors was used to compare individual gene expression and Hallmark/Kegg pathway activity between cases and controls using unpaired t-test (p&lt;.05) and Gene Set Enrichment Analysis (p-adj&lt;.05), respectively. Activity of the significant pathways was quantified in individual tumors using Gene Set Variation Analysis (GSVA), and a regression-based composite of GSVA scores was developed to distinguish cases from controls by ROC analysis. The composite score was used to test for stratification of recurrence free survival (RFS) in external cohorts using Youden Index and logrank test. Results: The21 Hallmark/Kegg pathways downregulated in cases indicated suppression of anti-tumor immunity, and the 20 upregulated ones revealed increased biosynthetic function and tumor cell proliferation. The 1472 upregulated mRNAs contained several components of the ATR-chk1 DNA repair pathway and trans-lesion synthesis polymerases, suggesting that mitigation of DNA replication stress enhanced tumor growth. The 958 downregulated mRNAs suggested reductions in the cytoplasmic dsDNA sensing and downstream NF-kB signals that lead to replication stress-driven anti-tumor immunity. Two GSVA scores were created to quantify the key tumor-intrinsic and immune suppressive features separately in each tumor. The scores correlated with each other (R=0.6, p&lt;.001), and a regression-based combination of them distinguished cases from controls (AUC=.76, p&lt;.001). This composite score also stratified RFS in three external cohorts: TCGA (n=52, p&lt;0.001) and two single institution cohorts containing both surgical and nonsurgical cases (n=46, p=.002; n=81, p&lt;0.001). Conclusions: HPV+ OPSCCs failing primary surgical therapy show evidence of reduced replication stress mediating tumor progression and low anti-tumor immunity. These features appear generalizable to heterogeneously treated external cohorts, where they predicted recurrence. Our results provide a new basis for creating transcriptomic predictors of treatment response and suggest targetable molecular mechanisms to overcome therapy resistance.
High-throughput transcriptome profiling indicates ribosomal RNAs to be associated with resistance to immunotherapy in non-small cell lung cancer (NSCLC)
Authors: Myrto K Moutafi, Katherine M Bates, Thazin Nwe Aung, Rolando Garcia Milian, Vasiliki Xirou, Ioannis A Vathiotis, Niki Gavrielatou, Athanasios Angelakis, Kurt A Schalper, Leonidas Salichos, David L Rimm
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Despite the impressive outcomes with immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC), only a minority of the patients show long-term benefits from ICI. In this study, we used retrospective cohorts of ICI treated patients with NSCLC to discover and validate spatially resolved protein markers associated with resistance to programmed cell death protein-1 (PD-1) axis inhibition. Methods Pretreatment samples from 56 patients with NSCLC treated with ICI were collected and analyzed in a tissue microarray (TMA) format in including four different tumor regions per patient using the GeoMx platform for spatially informed transcriptomics. 34 patients had assessable tissue with tumor compartment in all 4 TMA spots, 22 with leukocyte compartment and 12 with CD68 compartment. The patients’ tissue that was not assessable in fourfold redundancy in each compartment was designated as the validation cohort; cytokeratin (CK) (N=22), leukocytes CD45 (N=31), macrophages, CD68 (N=43). The human whole transcriptome, represented by~18,000 individual genes assessed by oligonucleotide-tagged in situ hybridization, was sequenced on the NovaSeq platform to quantify the RNAs present in each region of interest. Results 54,000 gene variables were generated per case, from them 25,740 were analyzed after removing targets with expression lower than a prespecified frequency. Cox proportional-hazards model analysis was performed for overall and progression-free survival (OS, PFS, respectively). After identifying genes significantly associated with limited survival benefit (HR&gt;1)/progression per spot per patient, we used the intersection of them across the four TMA spots per patient. This resulted in a list of 12 genes in the tumor-cell compartment ( RPL13A, GNL3, FAM83A, CYBA, ACSL4, SLC25A6, EPAS1, RPL5, APOL1, HSPD1, RPS4Y1, ADI1). RPL13A, GNL3 in tumor-cell compartment were also significantly associated with OS and PFS, respectively, in the validation cohort (CK: HR, 2.48; p=0.02 and HR, 5.33; p=0.04). In CD45 compartment, secreted frizzled-related protein 2, was associated with OS in the discovery cohort but not in the validation cohort. Similarly, in the CD68 compartment ARHGAP and PNN interacting serine and arginine rich protein were significantly associated with PFS and OS, respectively, in the majority but not all four spots per patient. Conclusion This work highlights RPL13A and GNL3 as potential indicative biomarkers of resistance to PD-1 axis blockade that might help to improve precision immunotherapy strategies for lung cancer.
Single-cell analysis reveals cellular and molecular factors counteracting HPV-positive oropharyngeal cancer immunotherapy outcomes
Authors: Junha Cha, Da Hee Kim, Gamin Kim, Jae-Won Cho, Euijeong Sung, Seungbyn Baek, Min Hee Hong, Chang Gon Kim, Nam Suk Sim, Hyun Jun Hong, Jung Eun Lee, Martin Hemberg, Seyeon Park, Sun Ock Yoon, Sang-Jun Ha, Yoon Woo Koh, Hye Ryun Kim, Insuk Lee
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear. Methods To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets. Results We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4 + follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8 + resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161 + Trm and changes in tumor size. Conclusions We found that CD161 + Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers. Trial registration number NCT03737968 .
METTL3-Mediated N6-Methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis
Authors: Yu-Cheng Tsai, Tsung-Han Hsieh, Yuan-Ru Liao, Ming-Tsun Tsai, Tzu-Ping Lin, Der-Yen Lee, Jihwan Park, Donggun Kim, Katalin Susztak, Shang-Feng Yang, Chih-Ching Lin, Szu-Yuan Li
Journal: Journal of the American Society of Nephrology (2024)

Chemical modifications on RNA profoundly affect RNA function and regulation. m6A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human CKD samples regarding its influence on pathological mechanisms.
Use of an Artificial Intelligence-Generated Vascular Severity Score Improved Plus Disease Diagnosis in Retinopathy of Prematurity
Authors: Aaron S. Coyner, Benjamin K. Young, Susan R. Ostmo, Florin Grigorian, Anna Ells, Baker Hubbard, Sarah H. Rodriguez, Pukhraj Rishi, Aaron M. Miller, Amit R. Bhatt, Swati Agarwal-Sinha, Jonathan Sears, R. V. Paul Chan, Michael F. Chiang, Jayashree Kalpathy-Cramer, Gil Binenbaum, J. Peter Campbell
Journal: Ophthalmology (2024)
Chenodeoxycholic Acid‐Modified Polyethyleneimine Nano‐Composites Deliver Low‐Density Lipoprotein Receptor Genes for Lipid‐Lowering Therapy by Targeting the Liver
Authors: Xiaotang Guo, Jiming Xu, Xiyuan Lu, Xiaoyan Zheng, Xi Chen, Zhenning Sun, Beilei Shen, Hao Tang, Yiman Duan, Zhengwei Zhou, Xu Feng, Yang Chen, Junjie Wang, Jing Pang, Qin Jiang, Bin Huang, Ning Gu, Juxue Li
Journal: Advanced Healthcare Materials (2024)

Abstract Lipid‐lowering drugs, especially statins, are extensively utilized in clinical settings for the prevention of hyperlipidemia. Nevertheless, prolonged usage of current lipid‐lowering medications is associated with significant adverse reactions. Therefore, it is imperative to develop novel therapeutic agents for lipid‐lowering therapy. In this study, a chenodeoxycholic acid and lactobionic acid double‐modified polyethyleneimine (PDL) nanocomposite as a gene delivery vehicle for lipid‐lowering therapy by targeting the liver, are synthesized. Results from the in vitro experiments demonstrate that PDL exhibits superior transfection efficiency compared to polyethyleneimine in alpha mouse liver 12 (AML12) cells and effectively carries plasmids. Moreover, PDL can be internalized by AML12 cells and rapidly escape lysosomal entrapment. Intravenous administration of cyanine5.5 (Cy5.5)‐conjugated PDL nanocomposites reveals their preferential accumulation in the liver compared to polyethyleneimine counterparts. Systemic delivery of low‐density lipoprotein receptor plasmid‐loaded PDL nanocomposites into mice leads to reduced levels of low‐density lipoprotein cholesterol (LDL‐C) and triglycerides (TC) in the bloodstream without any observed adverse effects on mouse health or well‐being. Collectively, these findings suggest that low‐density lipoprotein receptor plasmid‐loaded PDL nanocomposites hold promise as potential therapeutics for lipid‐lowering therapy.