bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil-lymphocyte score: A novel prognostic scoring system that utilized the dynamic change of neutrophil, lymphocyte, and albumin and its comparison to other indices.
Authors: Zhao Songzhu , Li Mingjia , Spakowicz Daniel , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall 
Published: May 2020

3048 Background: Indications for immune checkpoint inhibitor (ICI) in cancer care are expanding rapidly. There is increasing need for accurate decision tool to better guide treatment. We have constructed a new prognostic scoring system, neutrophil-lymphocyte score (NRS), based on the nonlinear dynamic change of neutrophil to lymphocyte ratio (NLR) in relation to survival over the first cycle of ICI treatment. We compared this novel system to existing indices such as NLR, lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), Advanced Lung Cancer Inflammation Index (ALI), and Systemic Immune-inflammation Index (SII). Methods: This is a retrospective analysis of 837 patients at Ohio State University from 2011-18. Neutrophil (ANC), lymphocyte (ALC), platelet (plt), monocyte (AMC), albumin (alb), and body mass index (BMI) were collected at baseline. Repeat labs were collected at cycle 2. NLR = ANC/ALC, ALI = BMI x alb / NLR, LMR = ALC/AMC, SII = platelet x NLR, PLR = plt/ALC. NLR Ratio = baseline NLR / repeat NLR. Based on the association between NLR and the overall survival, we assigned 1 point (p) for baseline NLR < 0.7, 6p for 0.7 to < 2, 5p for 2 to < 3, 4 p for 3 to < 4, 3 for 4 to 5, 2p for 5 to < 9, and 1p for ≥9. We also assigned 1p for NLR ratio < 0.6, 2p for 0.6 to < 0.8, 3p for 0.8 to < 1.2, 5p for 1.25 to < 1.4, 3p for 1.4 to < 1.6, and 2p for ≥1.6. NLS = sum of these 2 scores . NLS_A = NLS*alb. Time-dependent receiver operator characteristic (ROC) curves with integrated time-dependent area under the curve (TD AUC) values were used to evaluate the predictive accuracy of each index for survival. Results: For baseline and repeat values, all indices were statistically significant (P < 0.001) in predicting survival. Baseline integrated TD AUC were: ALI 0.704, NLR 0.692, SII 0.663, LMR 0.645, and PLR 0.612. All of the repeat indices at cycle 2 had higher prognostic value than their baseline counterparts. Integrated TD AUC for indices at cycle 2 were: ALI 0.740 (with baseline BMI), NLR 0.729, SII 0.694, LMR 0.671, and PLR 0.652. NLS_A was a composite score based on the dynamic change of NLR from cycle 1 to 2 and the treatment alb with integrated TD-AUC at 0.754. Conclusions: Indices constructed from ANC, ALC, AMC, Plt, alb, and BMI can be obtained inexpensively and provide great prognostic value for pts on ICI. We have constructed a novel scoring system (NLS_A) and demonstrated its improvement over the current prognostic indices. Studies with a larger cohort are needed to further improve and validate this system.
Tumor methylation patterns to measure tumor fraction in cell-free DNA.
Authors: Melton Colin , Singh Pranav , Venn Oliver , Hubbell Earl , Gross Samuel , Saito Yasushi , Newman Joshua , Zhang Lily , Chang Christopher , Cann Gordon , Larson Matthew H. , Stuart Sarah , Demas Vasiliki , Aravanis Alexander , Jamshidi Arash 
Published: May 2020

3052 Background: Cell-free DNA (cfDNA) tumor fraction (TF), the proportion of tumor molecules in a cfDNA sample, is a direct measurement of signal for cfDNA cancer applications. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) is a prospective, multi-center, observational, case-control study designed to support development of a methylation-based, multi-cancer detection test in which a classifier is trained to distinguish cancer from non-cancer. Here we leveraged CCGA data to examine the relationship between cfDNA containing tumor DNA methylation patterns, TF, and cancer classification performance. Methods: The CCGA classifier was trained on whole-genome bisulfite sequencing (WGBS) and targeted methylation (TM) sequencing data to detect cancer versus non-cancer. 822 samples had biopsy WGBS performed; of those, 231 also had cfDNA targeted methylation (TM) and cfDNA whole-genome sequencing (WGS). Biopsy WGBS identified somatic single nucleotide variants (SNV) and methylation variants (MV; defined as methylation patterns in sequenced DNA fragments observed commonly in biopsy but rarely [ < 1/10,000] in the cfDNA of non-cancer controls [n = 898]). Observed tumor fragment counts (SNV in WGS; MV in TM), were modeled as a Poisson process with rate dependent on TF. TF and classifier limits of detection (LOD) were each assessed using Bayesian logistic regression. Results: Across biopsy samples, a median of 2,635 MV was distributed across the genome, with a median of 86.8% shared with ≥1 participant, and a median of 69.3% targeted by the TM assay. TF LOD from MV was 0.00050 (95% credible interval [CI]: 0.00041 - 0.00061); MV and SNV estimates were concordant (Spearman’s Rho: 0.820). MV TF estimates explained classifier performance (Spearman’s Rho: 0.856) and allowed determination of the classifier LOD (0.00082 [95% CI: 0.00057 - 0.00115]). Conclusions: These data demonstrate the existence of methylation patterns in tumor-derived cfDNA fragments that are rarely found in individuals without cancer; their abundance directly measured TF, and was a major factor influencing classification performance. Finally, the low classifier LOD (~0.1%) motivates further clinical development of a methylation-based assay for cancer detection. Clinical trial information: NCT02889978 .
Results of a first-in-human phase I study of SRF231, a fully human, high-affinity anti-CD47 antibody.
Authors: Patnaik Amita , Spreafico Anna , Paterson Alison M. , Peluso Marisa , Chung Jou-Ku , Bowers Beth , Niforos Demi , O'Neill Alison M. , Beeram Muralidhar , Iafolla Marco , Lester Julia , Schram Alison M. 
Published: May 2020

3064 Background: CD47 is a transmembrane protein that acts as a “Don’t Eat Me” signal to evade immune recognition. It is overexpressed in multiple cancer subtypes and is associated with poor prognosis. SRF231 is an investigational, fully human, high-affinity CD47-targeting antibody that delivers an activating signal to myeloid cells and displays favorable preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Methods: In a Phase 1 study, SRF231-101 (NCT03512340), patients with advanced solid and hematologic malignancies who had failed standard therapy were enrolled in dose escalation cohorts (accelerated single-patient followed by standard 3+3) to establish the preliminary safety of SRF231 as a monotherapy and identify a dose and schedule suitable for expansion. In addition to collection of safety data, clinical outcomes were evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and SRF231 pharmacokinetic (PK) and pharmacodynamic (receptor occupancy) analyses were performed. Results: As of January 11, 2020, a total of 46 patients were enrolled, 25 in every-3-week intravenous (IV) dosing schedules and 21 in weekly IV dosing schedules. Weekly dosing schedules also explored the use of a 1.0 mg/kg initiation dose. Other than one patient with recurrent follicular lymphoma, all patients had recurrent/refractory solid tumors. The most common treatment emergent adverse events across dosing schedules were low-grade fatigue (43%), headache (35%), and pyrexia (30%). On every-3-week dosing schedules, 2 dose-limiting toxicities (DLTs) were observed: Grade 3 febrile neutropenia and Grade 3 hemolysis, both at a 12.0 mg/kg dose level. On weekly dosing schedules, 3 DLTs were observed: Grade 4 thrombocytopenia (6.0 mg/kg), Grade 4 amylase and lipase increased (4.0 mg/kg with initiation dose), and Grade 3 fatigue (4.0 mg/kg). The maximum tolerated dose was 9.0 mg/kg on an every-3-week and 4.0 mg/kg on a weekly schedule. Receptor occupancy was maintained at > 90% throughout the dosing period with a 4.0 mg/kg weekly dose schedule. Out of 37 patients who were response evaluable by RECIST, there were no complete or partial responders, although prolonged stable disease has been observed. Conclusions: Preliminary data from a Phase 1 study of SRF231, an anti-CD47 antibody, demonstrate that SRF231 may be administered safely and doses of 4.0 mg/kg weekly maintain > 90% receptor occupancy throughout the dosing period. Updated safety data, clinical outcomes, and PK/pharmacodynamic data will be presented. Clinical trial information: NCT03512340 .
Preliminary dose escalation results from a phase I/II, first-in-human study of MGC018 (anti-B7-H3 antibody-drug conjugate) in patients with advanced solid tumors.
Authors: Powderly John D. , Jang Sekwon , Lohr Joanna , Spira Alexander I. , Bohac Gerry C. , Sharma Manish 
Published: May 2020

3071 Background: Antibody-drug conjugates (ADCs) are cancer agents that have a cytotoxic payload linked to a monoclonal antibody (mAb) that target cancer cells. ADCs offer increased cytotoxic activity while reducing normal tissue exposure. B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 mAb. It is hypothesized that MGC018 has activity against B7-H3 expressing tumors with an acceptable safety profile. Methods: This study evaluates safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of MGC018 in a dose escalation 3+3+3 design. In addition, pharmacokinetics, immunogenicity, and tumor response using RECIST v1.1 are evaluated. Cohort expansion will enroll at the MTD to assess safety and tumor response. Results: The study is enrolling Cohort 3 (6 total cohorts planned) in dose escalation. 20 patients (pts) were enrolled as of Feb 03, 2020. At least 1 treatment related adverse event (TRAE) occurred in 16 pts (80.0%). The most common TRAEs were neutropenia/decreased neutrophil count (35%); fatigue, lymphopenia/decreased lymphocyte count (30.0%); palmar plantar erythrodysaesthesia (PPE), skin hyperpigmentation (25.0%); pruritis, nausea, chills, infusion related reaction (20.0%); and vomiting, pyrexia, maculopapular rash (15.0%). Eleven pts (55.0%) experienced TRAEs ≥ Grade 3; events were decreased lymphocyte count/lymphopenia (n = 6), decreased neutrophil count/neutropenia (n = 3), PPE (n = 2), and maculopapular rash (n = 2). Three related serious adverse events occurred in 3 unique pts: pneumonitis in a pt with concurrent bacterial pneumonia, non-infectious gastroenteritis, and stasis dermatitis in a pt with chronic venous insufficiency. One DLT has occurred (Grade 4 neutropenia). No febrile neutropenia was observed. Target lesion decrease was noted in 1 pt each with small cell lung cancer (-6.3%), non-small cell lung cancer (-23.8%), and metastatic castrate-resistant prostate cancer (mCRPC) (-29.4%) with PSA change from 82.8 ng/ml to 57.1 ng/ml. One mCRPC pt with bone only disease had substantial improvement on bone scan and PSA decrease from 60 ng/ml to 4.7 ng/ml. Conclusions: Results to date demonstrate a manageable safety profile with early evidence of clinical activity. Continued dose escalation and clinical investigation of MGC018 is ongoing. Clinical trial information: NCT03729596 .
A signal-seeking trial of olaparib and durvalumab in homologous repair-deficient tumors: A sub-study of the cancer molecular screening and therapeutics (MoST) program.
Authors: Joshua Anthony M. , Prawira Amy , Thavaneswaran Subotheni , Cosman Rasha , Lee Chee Khoon , Sjoquist Katrin Marie , Simes John , Thomas David Morgan , Espinoza David , Sebastian Lucille , Ballinger Mandy L. , Hague Wendy , Chinchen Sarah , Collignon Emily , Kansara Maya , Palacios Talia , Grady John , Barker Hayley , Thornton Keith 
Published: May 2020

3073 Background: Data on the utility of a PARP inhibitor in combination with a checkpoint inhibitor remain limited, particularly in the histology agnostic setting with homologous recombination deficiency (HRD). This study evaluated the clinical activity of the combination of olaparib and durvalumab with the primary study endpoint of progression-free survival (PFS) at 6 months (PFS6m). Methods: This was a phase II, single-arm, signal-seeking study of the MoST program. Patients were recruited into two cohorts based on HRD genes, agnostic to histology: (1) BRCA 1/2 deficient tumours, excluding breast, prostate, ovarian cancers, and (2) other HRD related genes. Molecular testing was performed using in-house and commercial panels on archival tumour tissue centrally adjudicated by a molecular tumour board. All patients were treated with olaparib 300mg bid for 1 month, followed by combination with durvalumab 1500mg q4 weekly for 13 cycles. Olaparib treatment was then continued until disease progression. Results: Between Nov 2017-Feb 2019, 48 patients were enrolled (16 to BRCA 1/2 cohort 1 and 32 to HRD related genes cohort 2). Most common tumour sites were bone/soft tissue (15%, N=7), pancreas (13%, N=6) and stomach (8%, N=4). Overall best response in cohort 1 was PR (25%, N=4) and SD 4 (25%, N=4), and cohort 2 was PR (6%, N=2) and SD (56%, N=18). Median PFS was 3.65m (Cohort 1) and 3.56m (Cohort 2) respectively. PFS6m was 35% (Cohort 1) and 38% (Cohort 2) respectively. PDL1 status was not predictive of olaparib and durvalumab benefit. The most common grade 3/4 adverse events were anemia (11%%, N=4), abdominal pain (9%, N=3), increased lipase (9%,N=3), increased amylase (9%, N=3), dyspnea (6%, N=2), Hyperglycemia dyspnea (6%, N=2), Pancreatitis dyspnea (6%, N=2) and hematuria (6%, N=2). Conclusions: Olaparib and durvalumab show promising activity in a histology agnostic setting, particularly in BRCA deficient tumours. Further research is needed to identify biomarkers that correlate with treatment benefit. Results from longer clinical follow-up and additional biomarker analyses will be presented. Clinical trial information: ACTRN12617001000392 .
Success and failure of additional immunosuppressants in steroid-refractory pneumonitis related to immune checkpoint blockade.
Authors: Beattie Jason , Fuentes Paige , Rizvi Hira , Luo Jia , Schoenfeld Adam Jacob , Postow Michael A. , Callahan Margaret K. , Warner Allison Betof , Chawla Mohit , Hellmann Matthew David 
Published: May 2020

3078 Background: Severe immune related adverse events (irAEs) with immune checkpoint blockade are uncommon but can be fatal. Steroids are the most common initial treatment for most non-endocrine irAEs, but some patients are or become refractory to steroids. When steroids are not effective, there is limited data to guide management strategies, particularly in the context of pneumonitis. Methods: All patients at MSK treated with immune checkpoint blockade from 2013-2020 were queried for receipt of an immunosuppressant (e.g. TNF antagonists, mycophenolate mofetil, cyclophosphamide) beyond steroids. Patient records were then manually reviewed to identify patients who received such therapy for management of immunotherapy-related pneumonitis. Results: Among 5363 patients treated with immune checkpoint blockade, 364 (6.8%) received an additional immunosuppressant for an irAE, including 28 (0.5% of all patients treated) patients treated for pneumonitis. Most of these pneumonitis events (19/28, 68%) were grade 3 or higher. Agents used included mycophenolate mofetil (7/28; 25%), TNF antagonists (23/28; 82%), and cyclophosphamide (1/28; 3.5%); more than one medication was used in 3 patients (11%). The indications were primary non-response to steroids (n = 16, 57%) and recrudescence after initial response to steroids (n = 12, 43%). At 90 days from initiation of the additional immunosuppressant, 13/28 (46%) patients were alive with improvement or resolution of pneumonitis while 15/28 (54%) had died. Survival with resolution/improvement was more common in patients treated for recrudescence vs primary non-response (67% vs 25%, p = 0.05). Conclusions: Outcomes with additional immunosuppressants in the setting of steroid-refractory immune-related pneumonitis are poor, but resolution can occur in some cases. A deeper understanding of the mechanistic underpinnings of irAEs is needed to more effectively tailor immunosuppressant therapies, particularly in severe pneumonitis events.
Association of a STK11/KEAP1-mutation gene expression signature in lung adenocarcinoma with immune desertion in squamous cell carcinomas and mediation by NFE2L2 deregulation.
Authors: Rieke Damian Tobias , Klinghammer Konrad Friedrich , Obermayer Benedikt , Blanc Eric , Messerschmidt Clemens , Jöhrens Korinna , Klauschen Frederick , Tinhofer Inge , Beule Dieter , Keilholz Ulrich , Ochsenreither Sebastian 
Published: May 2020

3082 Background: KEAP1 and STK11 mutations are associated with resistance to immune checkpoint inhibition (ICI) in non-small cell lung cancer (NSCLC). Mechanisms are currently unknown. Methods: We examined mutation, methylation, copy number and gene expression data from the cancer genome atlas (TCGA) lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma (CESC) data sets as well as public single cell gene expression data from a HNSCC cohort. Pathway annotations were performed using gene set enrichment analysis. A previously published cohort of NSCLC patients treated with ICI was analyzed for the predictive value of NFE2L2 mutations on PFS. Results: Annotation of STK11 and KEAP1 mutant LUAD revealed identical gene set enrichment for mitochondrial metabolism and downregulation of the STING-pathway, immune checkpoints, and interferon signaling. A STK11/KEAP1-mutation derived gene expression signature was established in LUAD and found to be driven by NFE2L2-regulated genes. This gene expression signature was independently predictive of immune desertion in LSCC, CESC and HNSCC and associated with STING-pathway downregulation in single cell sequencing analyses in HNSCC. KEAP1 and STK11 mutations were less frequent in LSCC, CESC and HNSCC but NFE2L2 mutations were identified in 15, 6 and 5%, respectively. NFE2L2 mutant SCC exhibited upregulation of the 15-gene- signature as well as immune desertion. In NSCLC, NFE2L2 mutations were associated with significantly worse PFS with ICI. Conclusions: Alterations of KEAP1, STK11, NFE2L2 and other related genes are linked to NFE2L2 target gene upregulation and immune desertion in LUAD, CESC, LSCC and HNSCC alike. The NFE2L2 pathway should be investigated clinically as a putative negative predictive biomarker for ICI and a potential therapeutic target.
A phase I/II study of GB1275, a first-in-class oral CD11b modulator, alone, and combined with pembrolizumab in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36).
Authors: Rasco Drew W. , Bendell Johanna C. , Wang-Gillam Andrea , Park Wungki , O'Reilly Eileen Mary , Zhou Lei , Galkin Anna , Carter Laura L , Nickle David , Li Jack , Ferguson Beatrice , Chaney Marya F. , Dupont Jakob , Messersmith Wells A. 
Published: May 2020

3085 Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .
Discovery of a novel shared tumor antigen in human lung cancer.
Authors: Tseng Diane , Chiou Shin-Heng , Yang Xinbo , Reuben Alexandre , Wilhelmy Julie , McSween Alana , Conley Stephanie , Sinha Rahul , Nabet Barzin , Wang Chunlin , Shrager Joseph B , Berry Mark F. , Backhus Leah Monique , Lui Natalie , Wakelee Heather A. , Neal Joel W. , Zhang Jianjun , Garcia K. Christopher , Mackall Crystal , Davis Mark 
Published: May 2020

3087 Background: While there has been much attention on mutation-associated neoantigens in tumors, there is less known about non-mutated tumor antigens that are shared across individuals. Understanding tumor-infiltrating T cell recognition of shared tumor antigens is important for understanding cancer immune recognition and escape, and may reveal novel targets for therapy. Methods: We have established a novel approach for discovering shared tumor antigens in human lung cancer. This approach involves identifying candidate T cell receptor (TCR) alpha/beta pairs that are predicted to exhibit specificity for shared tumor antigens in the context of a given human leukocyte antigen (HLA). We then screen the T cell receptor for binding to yeast display libraries of peptide-HLA. The Mark Davis lab at Stanford has previously developed an algorithm that groups T cell receptors into antigen specificity groups based on shared motifs within the TCR complementarity-determining region 3 (CDR3) sequences. Leveraging a dataset of over 700K CDR3 sequences from 178 HLA-typed non-small cell lung cancer (NSCLC) patients, we have found up to 4,300 antigen specificity groups after applying stringent cutoffs. We sequenced TCR alpha/beta pairs from 15 patients with lung adenocarcinoma (n = 4,705). Results: We identified an antigen specificity group enriched in tumor compared to adjacent uninvolved lungs. Antigen screening of the T cell receptor belonging to this specificity group using an A02 yeast display libraries led to the identification of a dominant peptide after four rounds of enrichment. We functionally validated that the peptide derived from the protein TMEM161A stimulated Jurkat cells expressing the TCR alpha/beta receptor of interest. We show that full-length TMEM161A protein is processed and presented into a peptide that stimulates primary T cells expressing the TCR alpha/beta receptor. We observe that a peptide from Epstein-Barr virus (EBV) protein LMP2 also stimulated the same TCR alpha/beta receptor. We have show that TMEM161A RNA and protein are overexpressed in human lung cancer compared to adjacent uninvolved lungs. Conclusions: We have demonstrated a novel approach toward antigen discovery and identified a shared tumor antigen TMEM161A in human lung cancer.