bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantification of immune cell-mediated destruction of tumor cells in vitro using the RNA disruption assay.
Authors: Pascheto Isabella , Pritzker Laura B , Kumar Aseem , Parissenti Amadeo Mark 
Published: May 2020

e15017 Background: Immune checkpoint inhibitors (ICIs) are increasingly being used in the treatment of human cancers, often in combination with cytotoxic chemotherapy drugs. However, current ICIs are costly and are only effective against a fraction of patient tumours. Thus, a tool that could reliably quantify tumour response to ICIs and predict outcome post-treatment would be highly valuable. Patients with non-responding tumours could be spared the costs and toxic side-effects of the ineffective drugs and moved promptly to alternate treatments. We have observed that a variety of structurally and mechanistically distinct chemotherapy agents induce the degradation of ribosomal RNA (rRNA) into a large number of high molecular weight fragments (between the 28S and 18S rRNAs)---a phenomenon we have termed “RNA disruption”. High tumour RNA disruption during treatment, as quantified using the RNA disruption assay (RDA), has been shown to predict pathologic complete response and improved disease-free survival in breast cancer patients. Methods: To assess whether RDA could be used to monitor immune cell killing of tumour cells, we collected peripheral blood mononuclear cells (PBMCs) from consenting healthy human donors and enriched the cell population for natural killer (NK) cells to 90% using a negative selection approach. The cells, with or without IL-2 pre-treatment, were incubated with K562 cells, after which K562 cell killing was quantified over time using a standard immunocytotoxicity assay and K562 cell RNA disruption was measured using RDA. Results: Freshly isolated human NK cells when incubated with K562 chronic myeloid leukemia cells induced cell destruction and RNA disruption in K562 cells in a dose-dependent manner. Pre-incubation with IL-2 augmented both NK cell-mediated RNA disruption and NK-mediated cytotoxicity in K562 cells. Interestingly, the pattern of K562 RNA disruption fragments generated by NK cells was similar to that generated by chemotherapy drugs. Conclusions: RDA was successfully used to quantify immune cell-mediated destruction of tumour cells, raising the prospect of its possible use to monitor tumour destruction by immune cells in vivo and to predict response to ICIs (alone or in concert with cytotoxic chemotherapy drugs).
Platelets impact the responsiveness of immune checkpoint blockade therapy in solid tumors.
Authors: Riesenberg Brian P , Li Mingjia , Spakowicz Daniel , Hoyd Rebecca , Beane Joal , Yang Yuanquan , Oezkan Filiz , He Kai , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , Bertino Erin Marie , Otterson Gregory Alan , Kendra Kari Lynn , Presley Carolyn J , Carbone David Paul , Li Zihai , Owen Dwight Hall 
Published: May 2020

e15023 Background: A growing body of evidence has linked platelets (plts) with immune suppression in the tumor microenvironment (TME). Our group has demonstrated, plts are the dominant source for TGF-β in TME and pharmacologic inhibition of plt function enhances multiple forms of immunotherapy (Sc Immunol 2017 PMID 28763790; J Immunol 2019 PMID 31358658; Sci Transl Med 2020 PMID 31915300). To further delineate this relationship, we examined the roles of plts on T cell exhaustion in a preclinical model and on response to immune checkpoint inhibitors (ICI) in a large cohort of patients (pts) with stage 4 cancers. Methods: The mouse MC-38 colon adenocarcinoma model was used in age-matched female C57Bl/6J mice. Antiplatelet therapy (APT) consisting of aspirin and clopidogrel (both at 30 mg/kg daily) was delivered p.o. and anti-PD-1 antibody (100 mg/mouse every 3 days) was administered i.p. starting on days 5 and 9 respectively. TME analysis via multispectral histology or flow cytometry was performed. Retrospective analysis was carried out on 826 pts who received ICI from 2011-2017 at the Ohio State University. Baseline plt count was collected within 7 days before initiating ICI. Repeat plt count was obtained prior to initiation of cycle 2. Normal plt counts were defined as 150,000 – 450,000/µl blood, and thrombocytosis as plt ≥450,000/µl blood. Kaplan Meier and log-rank analysis were performed to estimate median survival and determine the association with plt count. Results: In pre-clinical models, pretreatment with APT (1) synergized with PD-1 blockade to enhance T cell infiltration into MC-38 tumors resulting in immediate tumor reduction, and (2) decreased tumor infiltrating CD8+ T cell TOX expression, a transcription factor associated with T cell exhaustion (Nat Immunol 2019 PMID: 31427776). Among pts receiving ICIs, 46 (5.6%) pts with thrombocytosis had a significantly reduced median OS vs pts with normal plt counts: 6.0 (95 CI: 1.5—10.6) months (mos) vs 11.6 (95 CI: 9.7—13.4) mos (p = 0.002). Fluctuations ≥50,000 plt/mL in either direction between cycle 1 and 2 were associated with a significant reduction in median OS: 8.3 (95 CI: 6.4—10.1) mos vs 13.6 (95 CI: 11.2-16.1) mos (p < 0.001). Conclusions: There is a strong association between plts and failure of ICI in both the preclinical and clinical settings, likely via modifying the amount of active CD8+ T cells infiltrating into tumors. These findings merit further study to delineate the underlying mechanism for plt-mediated immune suppression and strategies to overcome it.
hPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
Authors: Chauhan Aman , Prieur Alexandre , Kolesar Jill , Arnold Susanne M. , Payen Léa , Lescuyer Gaelle , Liaud Pierre , Cousin Thierry , Sands Madison , Napier Dana , Evers Mark B , Joubert Dominique , Anthony Lowell Brian 
Published: May 2020

e15038 Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Additional 69 samples are currently undergoing analysis. Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Current data are for 31 patients. Data on total 100 patients will be presented at ASCO 2020. Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.
Plasma cell free PD-L1 RNA expression correlated with tissue PD-L1 immunohistochemical staining and tumor mutation burden in non-small cell lung cancer.
Authors: Walker Paul R. , Bowling Mark , Sharma Nitika , Namireddy Praveen , Parent Teresa , Cherry Cynthia R. , Yeh Chen-Hsiung 
Published: May 2020

e15049 Background: Programmed death ligand-1 (PD-L1) protein expression by immunohistochemical staining (IHC) correlates with response to immune checkpoint inhibitor (ICI) therapies in non-small cell lung cancer (NSCLC). Tumor mutational burden (TMB) is another immune biomarker of ICI response in NSCLC. Clinical studies indicate tissue PD-L1 protein expression and TMB are independent yet complementary. Both are limited by tissue acquisition and potential heterogeneity. Plasma cell free PD-L1 RNA (cfRNA) levels and tissue protein PD-L1 expression and TMB was analyzed and correlated in patients with advanced NSCLC. Methods: Patients with advanced NSCLC underwent complementary plasma and tissue next generation sequencing (NGS) with immune biomarkers prior to treatment. Plasma PD-L1 cfRNA was assessed by the Circulogene proprietary direct-on-specimen enrichment technology NGS platform. Correlating tissue testing was performed by the Caris Molecular Intelligence platform with the anti-PD-L1 22C3 IHC antibody and TMB measuring the total number of non-synonymous somatic mutations per megabase. Results: 107 patients with advanced NSCLC were evaluated with simultaneous plasma and tissue NGS testing. 17% (95% confidence interval [CI] 10-24%) patients plasma PD-L1 positive. 48.5% (CI 38-57%) tissue IHC PD-L1 positive. 7 of 18 plasma PD-L1 positive patients were tissue PD-L1 negative. 48% (CI 39-58%) total patients TMB ≥ 10 mutations per megabase (TMB high). Correlating TMB high in 72% (CI 50-94%) of plasma PD-L1 positive and 56% (CI 42-69%) of tissue PD-L1 positive patients. TMB high in 49% (CI 37-59%) plasma PD-L1 negative and 50% (CI 35-65%) tissue PD-L1 negative patients. Conclusions: Although less frequent than tissue PD-L1 protein expression, plasma PD-L1 cfRNA expression correlated with a higher association of tissue TMB high findings than tissue PD-L1 positive patients. There was not any TMB high difference between plasma PD-L1 negative and tissue PD-L1 negative patients. Over one-third of plasma PD-L1 positive patients were tissue PD-L1 negative. Clinical correlation with immune checkpoint inhibitor therapies is ongoing.
Monitoring early clearance of circulating tumor DNA as an effective tool to predict clinical benefits of immune checkpoint inhibitors in lung cancer patients: The preliminary results from clinical trial NCT04203095.
Authors: Zheng Di , Ni Jian , Zhong Yi , Ziliang Qian , Wang Baiyun 
Published: May 2020

e15056 Background: Immuno-checkpoint inhibitors (ICI)is the stand-of-care of lung cancer treatment nowadays. But it’s still challenging to find an effective biomarker to predict clinical benefits from ICIs. Early data suggested that monitoring early clearance of circulating tumor DNA (ctDNA) as a tool to predict clinical benefits. Here we started a clinical trial (NCT04203095) to further validate it. Methods: 19 advanced non-small cell lung cancer patients who were planned to be treated with ICIs with or without chemotherapy were recruited consecutively since April 2019 ( NCT04203095 ). Clinical response was evaluated by RECIST 1.1 assessments at 12 weeks of treatments and afterward during 3-month interval visiting in the first year. Fresh plasma samples were collected -1 (before),+3 weeks and +12 weeks after the first dose. Plasma cell-free DNA(cfDNA) was send to low-coverage whole genome sequencing, followed by chromosomal instability (CIN) analyses by a customized workflow (UCAD). CIN scores were calculated by summarizing the copy number variations genome wide. Results: Early clearance of ctDNA was defined as Pearson correlations co-efficiency of copy number variations of cf DNA was below 0.65 between the baseline and 3 weeks after ICIs were administered. These 19 patients included 11 squamous cell carcinoma (SCC) and 8 adenocarcinomas. 8 of 11 respoonding patients showed early clearance of ctDNA, and 7 of 8 patients with SD or PD didn’t obtain early clearance of ctDNA. Meanwhile, clinical stage, histology, treatments (PD1 single or PD1+chemo combinations), sequence of treatment (first line, second line or multiple lines) did not predict clinical response, and baseline CIN score was not significantly correlated with clinical responses. In summary, only ctDNA early clearance was statistically significantly associated with clinical response (P = 0.020). Conclusions: Early clearance of plasma circulating tumor DNA at 3 weeks after treatments might be used a predictive biomarker of immune-checkpoint inhibition response. Clinical trial information: NCT04203095 .
Analysis of the management of immunotherapy-derived toxicity in the Stockholm region.
Authors: Villabona Lisa Elena Esther , Huopaniemi Oona 
Published: May 2020

e15069 Background: The debut of immune-checkpoint inhibitors (ICPis) has changed the prognosis of many cancer patients. The immune-related adverse events (irAEs) caused by these monoclonal antibodies are common and can affect nearly any organ system. International guidelines on management of irAEs have been published in recent years. The aim was to investigate the identification and management of irAEs in the Stockholm region, as well as how the patients respond to the management they received. Methods: All adult patients who had received ICPis at the Karolinska University Hospital in 2018 were included. Patients who had enrolled in another study on ICPis were excluded. 62 eligible patients enrolled. Data was collected from the patients’ medical records. In addition to the irAEs documented by clinicians, irAEs were also identified retrospectively. Variables recorded were grade of irAE, management, date of first documentation and date of re-challenge, among others. Management was compared to the guidelines. Descriptive statistics as well as linear correlation analysis and Kaplan-Meier analysis were then performed. Results: 62 patients proved eligible. 121 irAEs were recorded. Nurses at Advanced Home Health Care (AHHC) were first to document grade 3-4 irAEs in 58% of the cases. Kaplan-Meier analysis (p-value 0.043) showed that patients whose irAEs were managed according to the guidelines reached re-challenge sooner. A negative correlation (p-value 0.003) was observed between management according to guidelines and identification by a clinician. Conclusions: Increased knowledge at AHHC and at oncological clinic is necessary to improve the identification and management of irAEs.
A multidisciplinary immune-related toxicity (IR-Tox) program for immune-related adverse events: A two-year experience.
Authors: Balaji Aanika , Zhang Jiajia , Suresh Karthik , Mammen Jenna , Melia Joanna , Kim Amy K. , Berkenstock Meghan , Sander Inbal , Monroy-Trujillo Jose Manuel , Ostrow Lyle Wilfred , Riemer Joanne , Lipson Evan J. , Forde Patrick M. , Sharfman William Howard , Brahmer Julie R. , Cappelli Laura , Naidoo Jarushka 
Published: May 2020

e15074 Background: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) that may require multidisciplinary input. We developed an IR-Tox program consisting of an electronic irAE referral platform +/- in-person consultation, and a monthly irAE tumor board, run by an IR-Tox team comprising 38 organ-specialists and oncologists. Herein, we present our 2-year experience. Methods: Electronic referrals for patients (pts) treated with ICIs at an academic center were sent to the IR-Tox team between 08/2017-12/2019. Demographic, treatment, and irAE data, including in-person consultations and hospitalizations, were collected in an IRB-approved database. Results: The IR-Tox Team received 270 referrals from 227 discrete pts (outpt: 64% inpt: 36%). Median age was 63 years (range: 3-91), 52% were male, 23% had a prior autoimmune condition, and 28% had a prior irAE. Pts had thoracic (30%), gastrointestinal (18%) or melanoma/skin cancers (17%). The majority of pts received ICI monotherapy (56%) vs. combination (44%). Referrals were for suspected irAE (92%, 209/227) or pre-ICI assessment for known autoimmune disease (8%, 18/227). Referrals for confirmed irAEs (147/209) were mainly for high-grade toxicity (G1 = 8%, 2 = 37%, 3 = 54%), 49% were hospitalized (72/147), and 86% (127/147) improved/resolved. In those who did not have a confirmed irAE (n = 62), an alternative medical condition was the most frequent diagnosis (27%, 17/62). The most common irAEs were pneumonitis (51%), dermatitis (11%), arthritis (7%), hepatitis (6%), and colitis (5%). In the entire cohort, organ-specialists were consulted electronically in 92% of pts (209/227), and 73% were subsequently seen in-person (166/227), with the majority (90/166; 54%) undergoing an invasive diagnostic procedure to confirm the irAE. Of outpatients referred, 64% (94/146) required subsequent in-person consults from organ-specialists and only 12% (18/146) were hospitalized. After all irAE-hospitalizations, continued irAE management was delivered in conjunction with organ-specialists in 51% of cases (32/72). Conclusions: A multidisciplinary IR-Tox program is a utilized service that has assisted in irAE identification and management over 2+ years. Use of an electronic referral platform may impact subsequent need for in-person specialist consultations and/or hospitalizations for irAEs. Ongoing management of complex irAEs is now commonly delivered in a multidisciplinary fashion.
Personalized treatment of immune checkpoint inhibitor-related severe hemophagocytic lymphohistiocytosis (HLH).
Authors: Obeid Michel , Özdemir Berna C. , Latifyan Sofiya , Michielin Olivier 
Published: May 2020

e15079 Background: HLH is a rare but potentially lethal immune related adverse event (irAE) with an incidence of 0.03-0.4 % in cancer patients undergoing immune checkpoint inhibition (ICI). Given the rarity of HLH there are currently no diagnostic or therapeutic guidelines and the majority of the reported cases have been treated with corticosteroids alone with very variable response rates. There is currently no established therapy for corticosteroid resistant HLH occurring in the context of immunotherapies. We investigated the treatment possibility of severe HLH according to the cytokine profile. Methods: We report the clinical presentation, the cytokine profile and the outcome of three melanoma patients with ICI-related HLH not responding to high dose corticosteroid therapy alone who were treated with additional anti-IL-6R at the Centre Hospitalier Universitaire Vaudoise. We collected the following data: treatment setting, ICIs received, duration of each treatment, HLH criteria, bone marrow biopsy, cytokine profile, response to corticosteroid and to anti-IL-6R therapy. Results: We identified a severe HLH in three metastatic melanoma patients treated with ipilimumab and nivolumab for 2 of them and 1 with pembrolizumab. HLH occurred in a median of 10 weeks after initiation of immunotherapy. The patients met at least five of the HLH-2004 criteria including high ferritin levels ( > 100.000 ng/ml). High levels of interferon-gamma (IFNγ), IFNγ-induced chemokines, particularly CXCL9, CXCL10, CXCL13, IL-18 and IL-6 were found in all patients. For 2 of them we identified a highly infiltrated bone marrow by activated CD8+ T and NK cells. Median duration of corticosteroids therapy was 6.5 weeks. The evolution of the three patients was rapidly favorable in a median of 2.5 weeks after the addition of an anti-IL-6R therapy targeting the IFNγ/Th1 axis. Conclusions: HLH is a potentially life-threatening irAE necessitating emergency therapy. CXCL9 and Th1 cytokines are markedly elevated in patients with ICI-related HLH due to the activation of the IFNγ pathway. High CXCL9 and Th1 cytokines levels appear to be potential specific biomarkers for ICI-related HLH diagnosis. Blocking this axis by anti-IL-6 therapy seems a very promising strategy for severe ICI-related HLH allowing rapid resolution of symptoms and normalization of the abnormal laboratory results.
Molecular alterations with hyperprogression in lung cancer patients treated with immune checkpoint inhibitors in a large health system.
Authors: Tadesse Eyob ale , Heslin Kayla , Hendawi Mohamed , Hirsch Jonathan , Idyro Christopher , Thompson Michael A. 
Published: May 2020

e15082 Background: Immune checkpoint inhibitor (ICI) therapy has become a mainstay of lung cancer treatment. However, not all NSCLC patients (pts) benefit, a subset paradoxically experience accelerated tumor growth while on immunotherapy. Hyperprogression (HP) refers to accelerated tumor growth on ICI with worsening clinical status. Various molecular alterations may be associated with HP including MDM2/MDM4 amplifications, EGFR aberrations, and STK11/LKB1 mutations. Kato et al. ( http://ow.ly/2n8a30nQpZv ) showed HP in 6/6 pts with MDM2/MDM4 amplification and in 2/10 pts with EGFR alterations. Methods: Lung cancer pts treated with ICI from Jan 2017 to Jan 2019 at Aurora Health Care were reviewed after IRB approved. Pts with NSCLC histology (ICD diagnosis codes and / or manual chart review), ICI treatment, and molecular testing were identified via the real world data (RWD) integrated in the Syapse platform. Additional chart review to ascertain HP was performed, and molecular results obtained via Syapse molecular lab integrations were analyzed. Pts had various forms of real world biomarker testing including oligo NGS panels. HP is defined as: 1) time-to-treatment failure (TTF) < 2 months (time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death), 2) > 50% increase in tumor burden by RECIST, 3) spread of the disease to a new organ between baseline and first radiologic evaluation or clinical deterioration, and 4) ECOG PS ≥2 during the first 2 months of treatment. HP > = 3, Progression 1-2, non-progressor 0 criteria fulfilled.Pts with and without HP were compared using Chi-squared and Fisher Exact tests. T-tests were performed for continuous variables. Results: Out of 1536 lung cancer patients 350 (22.8%) were treated with ICI including: atezolizumab (35), durvalumab (6), nivolumab (177), pembrolizumab (145). Some pts were treated with more than one ICI. 64/350 (18.2%) pts had HP. 79/350 (22.5%) pts had progressive disease without meeting the definition of HP. Biomarker associations with HP are shown in the table. Conclusions: Only the STK11/LKB1 mutation was associated with HP (P = < 0.0001) with 5 of 6 STK11 pts treated with ICI showing HP. Other potential HP biomarkers will be assessed prospectively as larger panels are utilized. [Table: see text]