bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer.
Authors: Devoe Craig E. , Pant Shubham , Wainberg Zev A. , Chung Vincent , George Thomas J. , Kasi Pashtoon Murtaza , VanWyk Haley , Tavares Amy , Perry James , Kheoh Thian , McNeil Lisa , Welkowsky Esther , DeMuth Peter , Haqq Christopher M. , O'Reilly Eileen M. 
Published: June 2024

2636 Background: Diverse KRAS mutations occur in 25% of solid tumors with G12D, V and R most frequent. ELI-002 7P is an expanded spectrum vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D, V, R, C, S, A, and G13D mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Earlier ELI-002 2P showed high rates of T cell and tumor biomarker response (both 21/25, 84%), with median relapse-free survival not reached versus 4.01 months (HR 0.14; p=0.0167) comparing patients (pts) above versus below T cell median (12.75X). Methods: This multicenter phase IA trial assessed safety, immunogenicity and preliminary antitumor activity of ELI-002 7P in pancreatic (PDAC) and colorectal pts with minimal residual disease (MRD) following standard locoregional treatment. Pts with elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), and KRAS mutation were enrolled and treated with subcutaneous fixed dose Amph-CpG-7909 and 1.4 mg or 4.9 mg of Amph-Peptides 7P (Table). Safety, T cell change, and preliminary antitumor activity including biomarker reduction/clearance are reported. Results: No dose-limiting toxicities, no treatment related SAEs or cytokine release syndrome were observed, no maximum tolerated dose was identified, and the recommended phase 2 dose (RP2D) was 10.0 mg Amph-CpG-7909 with 4.9 mg Amph-Peptides 7P. Safety: all grade 1, fatigue (29%), malaise (21%), and injection site reaction (7.1%). At data cutoff Dec 18, 2023, polyfunctional mKRAS-specific T cells were observed in 100% (n=11/11). Both CD8+ and CD4+ responses were induced in 63.6% of pts (7/11), with higher median fold-change from baseline at RP2D and durable responses post-booster immunization in 100% of pts (7/7). Biomarker reductions were observed in 2/5 (40%) at the 1.4 mg Amph-Peptides 7P dose level and in 5/7 (71%) at the RP2D 4.9 mg dose level in pts with all the common G12X (D, V, R) and G13 (D) KRAS mutations; MRD clearance was observed in 1 G12V PDAC pt at 4.9mg. Conclusions: ELI-002 7P was safe with median RP2D T cell responses exceeding the prior formulation (7P median 109.2; 2P 12.75), and early indications of antitumor activity. The randomized phase II is now open in patients with pancreas cancer. Clinical trial information: NCT05726864 . [Table: see text]
Updated safety, efficacy, pharmacokinetics, and biomarkers from the phase 1 study of IMC-002, a novel anti-CD47 monoclonal antibody, in patients with advanced solid tumors.
Authors: Lim Ho Yeong , Ahn Jin Seok , Park Joon Oh , Hong Jung Yong , Lee Sung Young , Jeong Haeun , Yun Hwi-yeol , Shin Seunghwan , Ock Chan-Young , Kim Heung Tae Tae 
Published: June 2024

2642 Background: Preliminary safety and efficacy data from the phase 1a dose escalation study of IMC-002 has been reported, showing no dose limiting toxicity (DLT) across 4 dose levels. Here we present updated insight into safety, efficacy, optimal dose determination through pharmacokinetics (PK) modeling, and CD47 expression. Methods: Eligible pts had metastatic or locally advanced solid tumors that progressed following at least 1 prior systemic therapy and an ECOG PS ≤1. A traditional 3+3 design was employed to evaluate DLT over 21 days, administering 4 doses of IMC-002 (5, 10, 20 and 30 mg/kg) every 2 weeks (Q2W). Tumor assessments were performed Q6W using RECIST 1.1. Optimal dosing was determined through target-mediated drug disposition (TMDD) PK modeling, incorporating FcRn recycling. CD47 immunohistochemistry (IHC) images were analyzed with an AI analyzer (Lunit SCOPE) that can distinguish staining positivity and cell type at the single cell level. Results: A total of 12 refractory patients (hepatocellular carcinoma 9, breast cancer 2, gallbladder cancer 1) were received IMC-002 with a median follow-up of 11 months (max 19 months). All treatment related adverse events (TRAEs) were grade 1-2 (92%) and TRAEs observed with over 20% incidence included skin rash, transient floaters and anemia. After the initial exposure, there was a decrease in hemoglobin levels, but these levels subsequently recovered without the evidence of hemolytic anemia. Among the 12 efficacy evaluable patients, the disease control rate was 50.0% and the clinical benefit rate (CBR, stable disease ≥ 6 months of treatment) was 33.3% with a median treatment duration of 10 months. Based on PK modeling, 20 mg/kg Q3W was selected as optimal RP2D. In the AI analysis of CD47 IHC, the density of CD47 positive macrophages tended to be higher in case with CBR compared to non-CBR cases (mean CD47+ macrophage density: 71.0 vs 44.3/mm2), while the percentage of tumor cells expressing CD47 was similar between the two groups (mean CD47+ tumor cells: 54.5 vs 59.8%). Conclusions: IMC-002 has an excellent safety profile when administered intravenously at a dose of up to 30 mg/kg every 2 weeks intravenously for max 12 months treatment. IMC-002 monotherapy demonstrates meaningful clinical benefits in refractory HCC. The density of CD47+macrophages analyzed by AI is higher in CBR patients. Clinical trial information: NCT05276310 . [Table: see text]
Using cell-free RNA in monitoring immune system and the demonstration of significant systemic deficiency in lymphoid and myeloid biomarkers in patients with cancer.
Authors: Albitar Maher , Zhang Hong , Charifa Ahmad , Ip Andrew , Agersborg Sally , Mohtashamian Arash , Siegel David Samuel DiCapua , Waintraub Stanley E. , Gutierrez Martin , Pecora Andrew L , Goy Andre 
Published: June 2024

3048 Background: Immune system plays a major role in the clinical course of cancer. Evaluating the local interaction between tumor cells and the immune cells (microenvironment) at the cancer site provides important information. However, currently little is known about the immune system as a whole in patients with cancer. Since cell-free circulating RNA (cfRNA) may reflect the entire body, we hypothesized that cfRNA might provide important information on the health and the status of the immune system. To simplify our approach, we evaluated only cellular biomarkers characteristic for lymphoid and myeloid cells using only the expression of 55 genes typically used in flow cytometry evaluation of hematologic cells. We compared findings between patients with cancer, patients with CHIP (clonal hematopoiesis of indeterminate potential), and normal individuals. Methods: cfRNA was extracted from plasma samples of 681 patients with various types of solid tumors, 113 patients with CHIP, and 34 normal individuals. cfRNA was sequenced via a hybrid capture-based panel targeting 55 genes reflecting immune cells including T-cells, B-cells, histiocytes, monocytes, and myeloid cells. The RNA was quantified using TPM (transcript per million). Results: There was significant difference (P<0.0001) between normal individuals and patients with cancers in the levels of circulating biomarkers specific for immune cells. Surprisingly, expression of B-cell, T-cell, monocytic/histiocytic genes were significantly lower in patients with solid tumors when compared to normal individuals. This included CD19, CD20, CD2, CD22, CD3D, CD3E, CD3G, CD4, CD52, CD7, CD79A, CD79B, CD8A, CD8B,CD33, FCER2(CD23), IL2RA(CD25), ITGAM(CD11B), and ITGAX(CD11C). In contrast, there was no significant difference between CHIP and normal for B- or T-cell markers. After adjusting for multiple testing, no deficiency in immune stimulatory markers was present in patients with CHIP. Patients with CHIP showed significantly (P<0.001) lower levels of CD38, CD58, CD16, CD15, CD25, and CD123 mRNA as compared with normal. Furthermore, using 35 immune cell biomarkers in a machine learning algorithm using 2/3 of samples for training and 1/3 for testing predicted the presence of cancer vs no cancer (AUC =0.820), and CHIP from cancer (AUC =0.0830) and CHIP vs normal (AUC =0.871). Conclusions: Immune related biomarkers using cfRNA provide important information on the immune system that can be used to monitor patients and to predict the presence of cancer or CHIP. The demonstration that patients with cancer have deficiency in overall systemic immune elements suggests that further studies are needed in monitoring the immune system and exploring means to boost systemic immunity to prevent the development of overt cancers.
Personalized circulating tumor DNA for minimal residual disease and dynamic assessment in patients undergoing neoadjuvant chemotherapy for breast cancer: Preliminary analysis from MSK-LINC.
Authors: Kim Hong-Kyu , An Julia Ah-Reum , Smith Christopher Gareth , KIM Jisun , Cabel Luc , Moiso Enrico , Ferraro Emanuela , Safonov Anton , Nelson Konner , Szuhany Kathleen , Drago Joshua Z. , Norton Larry , Xu Amy , Scher Howard I. , Chandarlapaty Sarat , Khan Atif J. , Li Bob T. , Robson Mark E. , Plitas George , Razavi Pedram 
Published: June 2024

3049 Background: Identification of minimal residual disease (MRD) with circulating tumor DNA (ctDNA) in pts with early-stage breast cancer holds promise to identify risk of relapse. MSK-LINC is prospective ctDNA plasma analysis of breast cancer pts. This pilot study evaluated the utility of serial ctDNA assessment as a biomarker for monitoring MRD and recurrence prediction in clinical stage II-III breast cancer pts undergoing neoadjuvant chemotherapy (NAC). Methods: 30 pts who underwent NAC across all subtypes were identified from MSK-LINC. The ctDNA analysis was performed at baseline, on-NAC, post-NAC/pre-surgery, within 8 weeks post-surgery, and during follow-up. Personalized ctDNA RaDaR assays were designed using whole exome sequencing data of paired primary tumor and germline samples from each pt. ctDNA levels were quantified as an estimated variant allele fraction (eVAF). Results: ctDNA panels were successfully designed for 29/30 pts (16 Stage II, 13 Stage III), including 6 HR+/HER2-, 12 HER2+, and 11 TNBC, with a median follow up of 4.2 years. The bespoke ctDNA assays targeted a median of 48 variants (21-51), with a median of 43 variants (11-48) passing quality control. A total of 175 plasma samples were analyzed, including 24 baseline and 24 post-surgery. A 100% ctDNA detection rate was observed at baseline in the 24 pts for whom a baseline sample was available (median eVAF 0.33%, range 0.0083% - 8.91%). Pathologic complete response (pCR) was achieved in 11 pts who remained disease free; and of the 18 pts without a pCR, 5 recurred. All patients with a pCR were ctDNA negative post treatment. In 3/5 patients who recurred, MRD detection was achieved, including one patient with persistent ctDNA positivity throughout all timepoints. For the other two pts, ctDNA was first detected in follow-up plasma collected at 4.4 and 9.8 months prior to clinical recurrence. Conclusions: This study demonstrates the potential of ctDNA as a dynamic biomarker for monitoring disease burden in pts with high-risk early-stage breast cancer, highlighting its remarkable sensitivity at baseline and its capability for MRD detection preceding clinical recurrence. These findings suggest the need for further research to fully understand the relationship between ctDNA dynamics during and after NACT with prediction of breast cancer outcomes. ctDNA detection rates in plasma samples across collection timepoints. [Table: see text]
Enhancing cancer detection through AI-driven high content analysis of circulating tumor cells.
Authors: Apurwa Sachin , Shaikh Muqeet , Devhad Sagar , Patel Shoeb , Chougule Rohit , Shejwalkar Pradyumna , Adhav Archana , Dalvi Apurva , Akolkar Dadasaheb , Patil Darshana , Datar Rajan , Vaid Ashok K 
Published: June 2024

3054 Background: The advancements in automated High Content Analysis (HCA) for Circulating Tumor Cells (CTCs) detection necessitate the integration of high-throughput screening (HTS) and Artificial Intelligence (AI) to improve cancer diagnosis efficiency and accuracy. Traditional approaches to cancer detection have faced limitations in speed, cost, and analysis depth, driving the need for innovative solutions in assay development and execution. Methods: We obtained peripheral blood from 150 asymptomatic individuals and 63 newly diagnosed cases of solid organ cancers including Lung, Breast, Head and Neck, Colorectal, Pancreas, Esophagus, Gynecologic cancers. We used differential apoptosis based negative enrichment technique and HCS fluorescent imaging for identification of CTCs and CTC like immune cells from the relevant blood samples. We devised AutoML algorithms which were trained on a cohort of 4,135 cropped region of interest (ROI) images of true CTCs and CTC-mimicking immune cells. These images were annotated with the coordinates of the top-left and bottom-right corners of rectangles to specify ROIs. This method employs a combination of automated sample processing, integration with the Laboratory Information Management System (LIMS) integration, digital filtration, and decision matrix algorithms for sample classification and smooth data flow. The image quality criteria were established prior to dataset analysis. The algorithms underwent training, testing, and validation based on expert recommendations, with dataset splitting of 80% for training, 10% for testing, and 10% for validation phases. Results: The automated deep learning model achieved remarkable performance metrics, presenting an accuracy of 96.66% (95% CI, 96.07%-97.19%), a specificity of 95.34% (95% CI, 94.37%-96.18%), and a sensitivity of 98.14% (95% CI, 97.44%-98.69%) in detecting true CTCs. Additional analysis included the area under the curve and confusion matrix evaluations, indicating the model's robustness in distinguishing between true positive and true negative specimens. This efficiency and precision in data handling, processing, and analysis demonstrate significant advancements in HCA screening, offering enhanced assay development, execution flexibility, and the facilitation of detailed cell-by-cell analysis for cancer detection from a large set of Peripheral Blood Mononuclear Cells (PBMCs) from samples obtained for screening or diagnosis. Conclusions: This study successfully evaluated a deep learning model for the detection of circulating tumor cells (CTCs) in peripheral blood mononuclear cells (PBMCs) using image data from HTS platform. The model achieved superior performance, demonstrating its potential for cancer detection from blood samples.
Discovery of long non-coding RNA biomarkers for prognosis in pediatric acute lymphoblastic leukemia.
Authors: Hsieh Tien-Chan , Li Zixiu , Zhou Peng , Zhou Chan 
Published: June 2024

3055 Background: Acute lymphoblastic leukemia (ALL) ranks among the most prevalent pediatric cancers. Molecular testing, including cytogenetics, has been widely used for prognosticating pediatric ALL. However, cytogenetic testing in pediatric ALL is incapable of detecting submicroscopic genetic changes and suffers from variable sensitivity, which may lead to heterogeneous outcomes within cytogenetic subgroups. In addition to conventional prognostic biomarkers, long non-coding RNAs (lncRNAs) are expressed in both a disease- and tissue-specific manner, emerging as promising biomarkers. However, well-established lncRNA prognostic biomarkers for pediatric ALL have yet to be identified. Therefore, in this study, we discovered three singular lncRNA prognostic biomarkers and a prognostic panel composed of multi-lncRNAs for pediatric ALL using our newly developed BAMBI method. Methods: This study utilized RNA-seq data from 561 distinct individuals, comprising 647 blood or bone marrow biospecimens obtained from pediatric patients with ALL from the dbGaP TARGET dataset. Among these individuals with RNA-seq and survival data, 25.8% deceased during follow-up. The average age at enrollment was 8.1 years. Of this cohort, 36.0% were female, and 61.5% were Caucasian white. Initially, our lncRNA identification tool, Flnc (Li Z., et al., Noncoding RNA. 2022), was employed to identify and quantify both novel and known lncRNAs expressed in pediatric ALL. Subsequently, our machine-learning based method, BAMBI, was utilized to discover lncRNAs as new prognostic biomarkers in pediatric ALL. Results: Three lncRNAs (ZBTB47 and NKTR antisense RNA, AC097359.2’s new isoform, and a novel lncRNA near STXBP5) were identified as individual putative biomarkers for prognosis. Each of these three lncRNA biomarkers exhibited predictive power for survival, with accuracy ranging from 68.2% to 72.8% and AUROC scores ranging from 67.7% to 75%. Furthermore, we established three lncRNA biomarker panels composed of these three lncRNAs along with a few additional lncRNAs, which showed improved prediction power with accuracy ranging from 78.3% to 79.6%, and AUROC scores ranging from 82.1% to 85.2%. Conclusions: We discovered both singular lncRNA and panels of multi-lncRNAs as prognostic biomarkers of pediatric ALL patients. These putative lncRNA biomarkers could be further validated through independent cohorts or prospective clinical study designs.
Correlation of ctDNA and radiographic imaging features derived from 18F-FDG PET/CT for patients with metastatic melanoma treated with immunotherapy.
Authors: Dell'Oro Mikaela R. , Lokre Ojaswita , Gray Elin S. , Francis Roslyn J. , Perk Timothy G. , Ebert Martin A. , Millward Michael 
Published: June 2024

3057 Background: 18F-FDG PET/CT scans are used to assess tumor response for patients undergoing immunotherapy for metastatic melanoma (MM). Evaluating the relationship between features derived from quantitative medical image analysis and markers in blood samples such as circulating tumor DNA (ctDNA) may present an opportunity to discover imaging and blood biomarkers that can influence future patient care. This study evaluates the correlation of ctDNA and radiographic imaging features derived from FDG PET/CT. Methods: Whole-body FDG PET/CT scans from MM patients between 2014-2020 were retrospectively collected under IRB-approved protocol. Patients received pembrolizumab (n=20), ipilimumab (n=4), nivolumab (n=7), or a combination of ipilimumab and nivolumab (n=19). TRAQinform IQ software (AIQ Solutions) identified and quantified regions of interest suspicious of cancer (lesion-ROI), enabling extraction of imaging features including SUVmax, SUVmean, and SUVtotal in baseline (BL) and follow-up (FU) images and change. Plasma ctDNA concentration (copies/ml) and frequency abundance (FA) were evaluated for the first sample (1) after immunotherapy had started (between baseline and first on-treatment scan), and the next available sample (2). Patients were further grouped by ctDNA mutation for analysis. Correlation between imaging features and ctDNA features was assessed using Spearman coefficient (ρ). Results: The patient cohort included 32 males and 19 females with average age of 62 years (range 23-83). For all 51 patients, moderate correlation was observed in SUVmax,BL with ctDNA copies/ml1 (ρ = 0.48, p<< 0.001) and ctDNA FA1 (ρ = 0.49, p << 0.001) and in SUVtotal,BL with ctDNA FA1 (ρ= 0.41, p < 0.001). In BRAF mutation patients (N=32), moderate correlations existed between SUVmax,BL with ctDNA copies/ml1 (ρ = 0.49, p = 0.0041 and ctDNA FA1 (ρ = 0.05, p = 0.0035), and SUVtotal,BL with ctDNA copies/ml2 (ρ = 0.42, p = 0.017), ctDNA FA1 (ρ = 0.40, p = 0.023), and ctDNA FA2 (ρ = 0.43, p = 0.012). All the other combinations displayed weak correlations (ρ < 0.39, p > 0.05). Conclusions: This study shows that in patients with MM receiving immunotherapy, quantitative features from blood biomarkers such as ctDNA correlate with FDG PET/CT imaging features. Combining blood biomarkers with imaging features that are spatially localizable may strengthen prognostication in this patient group. Further analysis is being performed with more types of ctDNA mutations.
Nature and distribution of methyl thioadenosine phosphorylase (MTAP) genomic loss in human tumors.
Authors: Necchi Andrea , Cigliola Antonio , Tateo Valentina , Mercinelli Chiara , Ross Jeffrey S. , Pavlick Dean 
Published: June 2024

3067 Background: MTAP genomic loss, often but not exclusively a bi-allelic homozygous deletion, has recently emerged as important biomarker guiding a novel synthetic lethality mechanism for drugs in the class of PRMT5 and MAT2A inhibitors. In the current study, we assessed the nature and distribution of MTAP complete and partial loss in a variety of tumor samples. Methods: A total of 291,391 tissue samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture method to evaluate all classes of genomic alterations (GA), and determine the microsatellite instability (MSI) status, tumor mutational burden (TMB), homologous recombination deficiency (HRD) score and genomic ancestry. The distribution of both complete and partial loss of MTAP was also determined. Results: MTAP GA were found in 8.6% of total with 9.3% genomic loss and 0.1% each short variant mutations and rearrangements. Important (not rare) tumor types with the most frequent MTAP loss included: 42.6% of glioblastoma (GBM), 13.4% of non-small cell lung cancer (NSCLC), 22.3% of pancreatic ductal and 24.9% of bladder urothelial carcinomas. The most frequently co-altered GA included CDKN2A (99.7%), CDKN2B (95.1%), TP53 (55.4%), KRAS (30.1%), TERT(20.5%) and PIK3CA (12%). In tumor types with frequent known targetable driver GA including short variant mutations in EGFR, ERBB2, BRAF, FGFR2-3and MET and fusions involving ALK, RET, ROS1 and NTRK1-3, MTAP loss was not associated with decreased frequencies of GA in these genes. The frequencies of MSI-high status was 0.3% and of TMB≥10 mut/Mb was 17%. In total, 63.7% of the MTAP loss cases involved deletion of all 8 MTAP exons (complete loss) with partial loss accounting for 36.3% of cases. All partial loss cases involved loss of multiple exons (35.8%) except for loss of only exon 8 (0.5%). There was no impact of MTAP loss status on genomic ancestry, cosmic trinucleotide signature and HRD score. The multiple exon loss frequencies included exons 2-8 loss in 24.7%, exons 5-8 loss in 4.1%, exons 6-8 loss in 3.3%, exons 3-8 loss in 1.6%, exons 7-8 in 1.1%, exon 4-8, 1-5, 2-7,2-5, 1-4, 2-6, 3-7 and 5-7 all at less than 1% frequencies. Conclusions: MTAPloss is a frequent GA of emerging clinical importance as the trials using PRMT5 and MTA-2 inhibitors progress. MTAPloss is frequent in common cancers of the brain, lung, pancreas and bladder and not associated with diminishment of other targetable driver mutations. Although one-third of MTAP loss is a partial loss, the partial loss cases involve near total (exons 2-8) loss and may well also be indicative of PRMT5/MAT2A inhibitor benefit. This study strengthens the opportunity to consider a tumor-agnostic approach to targeted therapies. [Table: see text]