bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of biomarkers to immune checkpoint blockade therapy across solid tumors.
Authors: Russell Meaghan , Huang Xiu , Vuzman Dana , Lvova Maria , Pantazi Angeliki , Lyle Stephen , Tse Julie Y 
Published: February 2018

26 Background: Immune checkpoint blockade (ICB) therapy has been effective patients with solid tumors. Currently, tumor expression of programmed death-ligand 1 (PD-L1) is clinically used as a biomarker of predicted response to ICBs in non-small cell lung cancer (NSCLC). However, across solid tumors, only a subset of patients benefit from ICBs, so there is need to identify other biomarkers to predict response to ICB. We investigated the use of large panel next generation sequencing (NGS) to characterize biomarkers to ICBs across solid tumors. Methods: NGS and PD-L1 immunohistochemistry (IHC) was performed on a series of solid tumors. NGS analysis included detection of single nucleotide polymorphisms (SNPs), insertions and deletions (indels), copy number variation (CNV), and gene-fusions in 435 cancer-related genes, microsatellite instability (MSI), tumor mutational burden (TMB) based on non-synonymous SNPs, and HPV16/18 and EBV viral status. Genomic alterations in previously reported biomarkers of response to ICBs were assessed. Results: 143 solid tumors were analyzed with NGS and PD-L1 IHC. The samples included 80 NSCLC, 15 colorectal carcinoma, 8 cutaneous melanoma, 6 breast carcinoma, and 34 other solid tumors. The mean TMB varied by tumor type, with the highest in melanoma. The frequency of PD-L1 expression was higher in NSCLC and melanoma compared to colorectal carcinoma. The relationship between PD-L1 expression and the other biomarkers varied by tumor type (Table 1). Positive association (+); Negative association (-): No association (None). Conclusions: We characterized biomarkers to ICBs across a range of solid tumors. We found tumor-specific differences in the mean TMB and frequency of PD-L1 expression. We also found tumor-specific differences in the associations between PD-L1 and other potential biomarkers, including KRAS, NRAs, HRAs, BRAF, and EGFR mutation status. We found no correlation between PD-L1 expression and MSI and viral status. NGS is an efficient platform for analysis of biomarkers in solid tumors.[Table: see text]
Predictive role of peritumoral CD3+ infiltration and neutrophil to lymphocyte ratio on overall survial in pateints affected by colorectal liver metastases treated with chemotherapy and surgery.
Authors: Cimino Matteo , Donadon Matteo , Mavilio Domenico , Di Tommaso Luca , Roncalli Massimo , Hudspeth Kelly , Sacerdote Carlotta , Torzilli Guido 
Published: February 2018

27 Background: Systemic and local inflammation plays an important role in many cancers and colorectal liver metastases (CRLM). While the role of local immune response mediated by CD3+ tumour infiltrating lymphocyte is well established new evidence on systemic inflammation and cancer such as neutrophil–lymphocyte ratio (NLR) are emerging. The aim of the study is to associate these two markers of inflammation to predict overall survival (OS) in patients affected by CRLM. Methods: From January 2006 to January 2013 128 consecutive patients affected by CRLM treated with chemotherapy and surgery were included in the study. CD3+ peritumoral infiltration was defined as the ratio of intra-tumoural\invasive-margin CD3+ infiltration evaluated with immunohistochemistry on CRLM tumor slides. NLR was calculated as neutrophil absolute count divided by the absolute lymphocyte count on blood sample. ROC curves were used to calculate a cut-off for each bio-markers related to OS . Associating the bio-markers two risk groups were determined: low risk (LRG) two protective bio-markers; high risk (HRG) no protective bio-markers. Results: After a median follow-up of 45 months, median OS was 44 months.Twenty-nine patients (22.6%) belong to the LRG whereas 99 patients (77,4) belong to HRG. Adjusted Cox regression analysis showed a worse OS for HRG patients (HR 2.74 p = 0.003 95%CI 1.40-5.37). Median OS was 80.8 vs 42.5 months for LRG vs HRG respectively. Conclusions: High CD3+ peritumoural infiltration associated with low NRL are two protective factor on OS for patients affected by CRLM.
Estimating mutation load at 5% LOD from FFPE samples using a targeted next-generation sequencing assay.
Authors: Chaudhary Ruchi , Cyanam Dinesh , Mittal Vinay Kumar , Tom Warren , Au-Young Janice , Sadis Seth , Hyland Fiona 
Published: February 2018

28 Background: High tumor mutation load is a biomarker which positively correlates with response to immune checkpoint inhibitors. Current methods to estimate tumor mutation load often require large amounts of DNA. Herein, we demonstrate the ability of a targeted panel to estimate mutation load from FFPE samples using low input amount of DNA. Methods: We developed a single-sample analysis workflow to estimate mutation load (somatic mutation count per Megabase (Mb)) from FFPE and fresh frozen tumor research samples. The assay utilizes a PCR-based target enrichment panel that covers ~1.7 Mb. Our workflow requires only 10 ng of input DNA, and enables a 2.5-day turn-around time from sample to the final report. The workflow enables < 60 minutes of hands-on time for automated library preparation and templating on a batch of 8 samples. Sequencing is performed using a high throughput semiconductor sequencing platform to achieve sufficient depth (~500x coverage) and accuracy. Our analysis pipeline calls variants with optimized parameters on the tumor sample only, with no matched normal sample required, and applies filters to remove germ-line. Results: An in-silico analysis using 21,000 exomes from COSMIC demonstrated the panel can achieve high sensitivity (>=93%) and specificity (>99%) necessary to stratify high and low mutation burden samples. Matched tumor-normal analyses on 14 lung and colorectal samples showed that our single tumor analysis workflow detects mutation load with strong correlation (r=0.8699) with tumor-normal analysis. Through dilution experiments on engineered control we learned that the workflow provides accurate estimates of mutation load, predicting ± 7% of expected mutation load on >=20% tumor content. To assess reproducibility, we compared mutation load in library replicates for a cohort of 8 samples (FFPE and fresh frozen tumors, engineered control, and NIST cell-lines) and observed high correlation (r=0.9906) among replicates. Conclusions: We developed a simple workflow on the Ion Torrent sequencing platform to estimate mutation load from FFPE and fresh frozen tumor research samples. This solution will advance research in immuno-oncology.
Use of cancer immunotherapies in the real-world in the setting of microsatellite instability.
Authors: Agarwala Vineeta , Gossai Anala , Singal Gaurav , O'Connell Claire , Li Gerald , Kao Ken , Bourque David , Feuchtbaum Dana , Cobb Garrett Alpha , Nunnally Allen , Frampton Garrett Michael , Ali Siraj Mahamed , Abernethy Amy Pickar , Kramarz Sarah , Trabucco Sally E. 
Published: February 2018

30 Background: In May 2017, the FDA approved for the first time a cancer therapy (pembrolizumab) for use in patients based on the presence of a genomic marker (microsatellite instability, or MSI) rather than anatomical tumor type. Real-world data on the rates and clinical impact of MSI on treatment selection and response are scant, especially outside of colorectal cancer. Methods: We performed a retrospective study of all patients treated in the Flatiron Health network (>265 oncology practices across the U.S.) between January 2011 and June 2017, and who underwent FoundationOne tumor sequencing as part of routine clinical care. Tumor type was determined by pathologist review of specimens submitted to Foundation Medicine. Data on therapy use was sourced from electronic health records (EHRs). Assessment of MSI was performed from DNA sequencing across the coding regions of >300 genes. Results: Our overall cohort included n=16,020 patients. Among patients in whom MSI status could be assessed (n=12,411), 207 patients had MSI-high tumors. The observed rate of MSI-high was 1.7% across all tumor types combined; tumor-specific rates varied significantly, from 4.9% in colorectal adenocarcinoma to 0.3% in breast and non-small cell lung cancer. The rate of MSI-high was 2.4% in patients with an unknown primary based on specimen review. A total of 1,329 patients received common checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab). Among the checkpoint-inhibitor treated patients with known MSI status (n=1,175), 14 (1.2%) had MSI-high tumors, and the majority of these patients (n=8) had colorectal cancer. Conclusions: Evidence of MSI-high is rare in real world cancer care settings. Early identification of patients with this biomarker is important in order to efficiently match them to treatment. Further evaluation of the real-world effectiveness of immune checkpoint inhibitors in the MSI-high population is still needed. Because most patients receiving these therapies today do not have high MSI, exploration of additional biomarkers for immunotherapy response is also critical.
Effect of dual PI3K-δ,γ inhibitor duvelisib on immunosuppressive Tregs and myeloid cells to enhance efficacy of checkpoint and co-stimulatory antibodies in a B cell lymphoma model.
Authors: Pachter Jonathan A , Weaver David T. 
Published: February 2018

33 Background: Duvelisib is a dual inhibitor of PI3K-δ and PI3K-γ which has shown clinical activity as monotherapy in CLL/SLL, FL and T cell lymphoma (O’Brien; Flinn; Horwitz, ASH 2014). Recent publications have demonstrated that PI3K-δ inhibition reduces immunosuppressive Tregs (Ali, Nature, 2014) whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells (Kaneda, Nature, 2016; De Henau, Nature, 2016). Hence, we postulated that duvelisib may augment the efficacy of immune checkpoint or co-stimulatory antibodies. Methods: Mice bearing syngeneic A20 B cell lymphoma tumors (60-90 mm3) were treated with vehicle, duvelisib, anti-PD1, anti-PD1 + duvelisib, anti-OX40, or anti-OX40 + duvelisib. Tumor volumes were measured by caliper. Tregs, macrophages and MDSCs were quantified by flow cytometry from mice bearing A20 tumors after 8 days of treatment. Results: In the A20 model, duvelisib, anti-PD-1 and anti-OX40 treatments each induced tumor growth delay. When duvelisib and anti-PD-1 were combined in mice with pre-existing A20 tumors, strong anti-tumor synergy was observed. When anti-OX40 and duvelisib were combined, tumor regression was observed which correlated with strong reduction of tumor Tregs, M2 macrophages and MDSCs. To assess immune memory, tumor-free mice following anti-OX40 alone or anti-OX40 + duvelisib were injected with A20 cells in the contralateral flank with no further treatment. Whereas mice that had received anti-OX40 alone grew new tumors upon A20 re-challenge, all tumor-free mice that had received anti-OX40 + duvelisib did not grow tumors upon re-challenge and showed elevated memory T cells in blood and spleen. These findings indicate that anti-OX40 + duvelisib treatment established immune memory. Conclusions: The dual inhibition of PI3K-δ and PI3K-γ appears to make duvelisib especially effective in reducing both lymphoid and myeloid immuno-suppressive populations, enhancing the anti-tumor efficacy of immune checkpoint and co-stimulatory antibodies. These data support potential clinical exploration of duvelisib in combination with checkpoint or co-stimulatory antibodies.
Multi-institutional report on toxicities from combined radiation and nivolumab.
Authors: Parker Sean Medard , Zainib Maliha , Mattes Malcolm , Amin Neha 
Published: February 2018

39 Background: Indications for Nivolumab (NIVO), a checkpoint inhibitor immunotherapy drug, in treating a variety of metastatic malignancies has markedly increased. Radiation therapy (RT) is also commonly used in this patient population, however, there are limited data on the safety profile of combined RT-NIVO. We reviewed our experience to assess the acute toxicity profile of concurrent RT-NIVO. Methods: All consecutive patients who received NIVO from 1/2015 to 5/2017 at 4 centers across 2 institutions were retrospectively reviewed. Those patients who completed a course of RT from 1 day prior to initial NIVO infusion through 1 month after last NIVO infusion were considered to have received concurrent therapy and included in the subsequent analysis. Descriptive statistics are reported for patient/tumor/treatment characteristics and observed acute toxicities within 3 months of RT completion. Results: Among 261 patients who received NIVO, 46 (17.6%) received concurrent RT to 67 different sites. The median f/u was 3.3 (.1-19.8) months and 11/46 (24%) were still alive at last analysis. The most common histology, RT prescription, and treatment site included non-small cell lung cancer (23/46, 50%), 30 Gy in 10 fractions (16/67, 24%), and central thorax/abdomen (26/67, 39%), respectively. 79% (53/67) of irradiated sites were treated with 3D-conformal technique and palliative dose-fractionation. Grade 3, 4, and 5 toxicities were experienced by 11, 1, and 2 patients, respectively. However all grade 4 and 5 toxicities were outside of the irradiated area and attributed to the NIVO alone, and only 4/11 (36%) of the grade 3 toxicities were attributed to the RT-NIVO. The irradiated site in these cases included the brain [2/10 (20%)] and central thorax/abdomen [2/19 (10.5%)], including one unexpected grade 3 pancreatitis following stereotactic body RT to the left adrenal gland. Conclusions: Concurrent RT-NIVO is generally well tolerated, though with potentially increased rates of severe toxicity when irradiating the lung, abdomen, or brain. Pending more definitive data, we recommend counseling patients on the potentially increased rates of side effects from combined immunotherapy and radiotherapy to these locations.
Analysis of over 100,000 patients with cancer for CD274 (PD-L1) amplification: Implications for treatment with immune checkpoint blockade.
Authors: Goodman Aaron , Piccioni David Eric , Kato Shumei , Boichard Amelie , Walavalkar Vighnesh , Frampton Garrett Michael , Connelly Caitlin , Fabrizio David , Miller Vincent A. , Sicklick Jason K. , Kurzrock Razelle 
Published: February 2018

47 Background: The majority of patients with Hodgkin lymphoma have copy number alterations in the genes CD274 (PD-L1), PDCD1LG2 ( PD-L2) and JAK2 (chromosome 9p24.1) resulting in high response rates to PD-1/PD-L1 blockade, even in refractory disease. The prevalence and importance of this biomarker as a predictor of response to PD-1 blockade is unknown across all solid tumors. Methods: We analyzed > 100,000 de-identified patient samples from the Foundation Medicine database and 2,039 clinically annotated patients from UCSD. CD274 amplification was called for copy number alterations (CNAs) ≥ 6. PFS was calculated by KM analysis. Results: Altogether, 0.7% of all tumors types had ≥ 6 CNAs in CD274 (Table). CD274 CNAs were identified in 121 tumor histologies. 13 patients at UCSD were found to have CD274 amplification of which nine were treated with PD-1/PD-L1 blockade (either alone or in combination with another immunotherapeutic or targeted therapy) after a median of four prior systemic therapies. The response rate to PD-1/PD-L1 blockade was 67% (6 of 9 patients); median PFS = 15.1 (range, 1.6-21.8+) months (includes 3 objective responses ongoing for 15+ months as well as a glioblastoma with a PR for 4.4+ months). Conclusions: CD274 amplification is rare in most malignancies; however, testing for this alteration is warranted given the frequent and durable responses to PD-1/PD-L1 blockade. [Table: see text]
Phase I study of E7046, a novel PGE2 receptor type 4 inhibitor, in patients with advanced solid tumors: Clinical results and effects on myeloid- and T-lymphoid cell-mediated immunosuppression.
Authors: Hong David S. , Parikh Aparna , Shapiro Geoffrey , Varga Andrea , Naing Aung , Meric-Bernstam Funda , Reyderman Larisa , Bao Xingfeng , Binder Terri A. , Ren Min , Siu Amy , Xu Lu , Liu Mingjie , Dayal Satish , Bhagawati-Prasad Vijay , Tchakov Ilian , Owa Takashi , Ooi Chean Eng , Marabelle Aurelien 
Published: February 2018

49 Background: E7046 is a selective inhibitor of the prostaglandin E2 (PGE2) receptor EP4, which transduces potent immunosuppressive activity of PGE2 in myeloid and T-lymphoid cells. In preclinical studies, E7046 reversed PGE2-mediated activities and facilitated activation of cytotoxic T-cells. Here, we present initial clinical, PK and PD results from a first-in-human study of E7046 in patients (pts) with cancers having high myeloid cell infiltration. Methods: E7046 was given orally, once-daily, in 21-day cycles in sequential dose-escalating cohorts (125, 250, 500 and 750mg). Tumor responses were evaluated by irRECIST and metabolic responses by 18FDG-PET. Immune response modulation was assessed in tumors and peripheral blood. Results: Thirty pts were treated, with no dose-limiting toxicities observed. The most common adverse events were fatigue (37%), diarrhea (33%), and nausea (30%). Grade 3/4 AEs in > 1 pt were abdominal pain (3 pts) and vomiting (2 pts). Grade 3/4 treatment-related AEs occurred in 4 pts (rash in 2 pts, and diarrhea, allergic reaction, anaphylaxis, hypersensitivity, and hyperuricemia, in 1 pt each). Four pts discontinued E7046 due to an AE (bowel obstruction, allergic reaction, abdominal pain, acute renal failure). No objective tumor responses were reported. Treatment duration of ≥20 wks with best response of stable disease (SD) was observed in 5 pts, 3 of whom had partial metabolic responses. E7046 exposure was dose-proportional up to 500 mg. Elimination half-life (12 hr) justified once-daily dosing. E7046 treatment significantly increased tumor CD3+ and CD8+ T-cell infiltration, and blood levels of the T-cell-recruiting chemokine CXCL10. E7046 also modulated blood expression of EP4 signaling genes (IDO1, EOMES, PD-L1). Longer duration of therapy with SD was associated with higher baseline tumor infiltrate of CD8+ T-cells and CD163+ macrophages. Conclusions: E7046 demonstrated favorable tolerability with preliminary evidence of anti-tumor activity and immune modulation in tumor and peripheral blood. MTD was not reached. Further studies of E7046 in combination with other agents are planned. Clinical trial information: NCT02540291.
Capturing the complexity of the immune microenvironment of acute myeloid leukemia with 3D biology technology.
Authors: Rutella Sergio , Vadakekolathu Jayakumar , Altmann Heidi , Patel Tasleema , Reeder Stephen , Liang Yan , Schmitz Marc , Hood Tressa , Danaher Patrick , Warren Sarah , Cesano Alessandra , Beechem Joseph M , Pockley A. Graham , Tasian Sarah K. , Bornhäuser Martin 
Published: February 2018

50 Background: Tumor phenotypes are dictated not only by the neoplastic cell component, but also by the tumor microenvironment (TME), which includes immune and inflammatory cells. We characterized the immune ecosystem of the bone marrow (BM) TME in patients with acute myeloid leukemia (AML) to correlate transcriptomic and proteomic profiles with patient outcome. Methods: We used the nCounter system (NanoString Technologies) to characterize BM specimens from 42 children and 28 adults with AML. Ninety BM samples (63 from de novo AML, 18 from AML in complete remission [CR] and 9 from relapsed AML) were analyzed using the RNA Pan-Cancer Immune Profiling Panel. In situ leukemia-immune system interactions were visualized using Digital Spatial Profiling (DSP). Results: Hierarchical clustering identified subgroups with heightened expression of lymphocyte-associated genes, including NK cell and cytotoxicity genes (“immune-enriched” samples). They also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9, CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4 and PD-L1. Conversely, ‘immune-depleted’ samples over-expressed genes associated with mast cell functions and CD8 T-cell exhaustion and showed low expression of T-cell and B-cell genes. Importantly, relapse-free survival (RFS) and overall survival (OS) were significantly shorter in patients with “immune-enriched” compared with “immune-depleted” AMLs (2.2 vs. 18.3 months, p = 0.0064, and 6.3 vs. 22.4 months, p = 0.017, respectively). DSP of the BM TME showed the co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types, an immune landscape which is consistent with the establishment of adaptive immune resistance mechanisms of immune escape. Conclusions: Our study has identified heterogeneous immune profiles in children and adults with AML. From a clinical standpoint, ‘immune enriched’ AMLs might be amenable to immunotherapy approaches tailored to the BM microenvironment, including blockade of co-inhibitory molecules and/or small-molecule IDO1 inhibitors. Grant support: Roger Counter Foundation, UK; Qatar National Research Fund (#NPRP8-2297-3-494).
Identification of novel liquid biopsy biomarker for monitoring the immune set point in both solid tumor and hematological malignancy patients.
Authors: King David John , Adams Ryan , Nangle Leslie , Mertsching Elisabeth , Ogilvie Kathy , Cubitt Andrea , Mendlein John 
Published: February 2018

52 Background: We identified an extracellular pathway that plays a role in modulating T cell activity in vivo, which we call the Resokine Pathway. The pathway specifically involves a 60 amino acid domain of the tRNA Synthetase for Histidine, which is an essential gene in all cells, including tumor cells, vis-a-vis protein synthesis. Methods: Circulating Resokine levels were measured in 466 plasma samples from patients bearing a number of different tumor types, as well as healthy individuals, using an ECLIA format with sensitivity to 5pM. Serum Resokine levels were also measured in tumor-bearing mice. Results: Low, Circulating Resokine Levels in Cancer Patients are Negligible Compared to Healthy Individuals: Resokine levels in healthy volunteers (n = 148) ranged from 8pM - > 2333pM with 18% of the individuals possessing a level below 30pM. In contrast, levels measured across patients with all tumor types tested ranged from 20pM to > 2333pM (above the upper limit of quantification) with only 4% of the patients possessing low levels, defined as < 30pM; (P < 0.0001). Tumors in Mice Induce Higher Circulating Resokine Levels: Resokine levels in serum from normal C57Bl6 mice ranged from 70 to 250pM (n = 10). Significantly higher levels (450-3000pM) were found in the serum of B16F10 tumor-bearing mice with up to a 10-fold increase in the mean serum level compared to healthy mice (p < 0.001). Resokine levels were correlated with tumor size. Conclusions: Resokine levels correlate with tumor size in mice, and are elevated in human cancer patients. This is consistent with the hypothesis that tumors secrete Resokine, to avoid detection by the immune system. Measurement of levels of the Resokine protein may offer a new liquid biopsy biomarker for tracking immune cell activity in cancer patients. It may also be a target for therapeutic intervention but the pathway may be challenging to inhibit given the presumably higher levels at the tumor and that there are many splice variants of HARS with potential activity (Lo et al. Science 2014, 345:328-32). Acknowledgements: We would like to thank Jedd Wolchok and Phil Wong of MSKCC, New York for access to patient samples.