bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multidisciplinary approach to immune related adverse events as a potential biomarker: Single institution experience in non-small cell lung cancer.
Authors: Martin Sooyoung , Laukamp Kai , Gupta Amit , Ansari-Gilani Kianoush , Kikano Elias , Smith Daniel Arnold , Dowlati Afshin , Ramaiya Nikhil H. 
Published: May 2019

e14124 Background: Immune checkpoint inhibitor (ICI) has emerged as a novel systemic treatment for advanced cancers. As ICI modulates immune signaling pathways by targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) or its ligands (PD-L1), a number of immune related adverse events (IRAE) have been reported. Whether IRAE can be a predictor for treatment response has remained controversial and we evaluated the association between IRAE and outcome. Methods: Retrospective chart and Computed Tomography (CT) review of patients with stage IV NSCLC treated with single agent Nivolumab or Pembrolizumab was performed. Any abnormalities in lab values, imaging finding or clinical signs to suggest pneumonitis, thyroiditis, hepatitis, nephritis, pancreatitis, colitis, pleural/pericardial effusion, arthritis or myositis between the start of the therapy and six months after the end of the therapy were recorded in a binary fashion. Abnormality in the setting of baseline abnormal values or due to clear cause other than IRAE has been excluded. Overall survival as well as best response based on RECIST 1.1 was also recorded. Results: 88 patients treated between January 2012 and March 2017 were identified. 62 patients, 42 patients and 50 patients demonstrated abnormalities in lab values, CT and clinical signs, respectively. When each subcategory was correlated with OS using ANOVA, thyroid function test abnormality (n = 15) and liver function test abnormality (n = 36) were associated with increased OS (p = 0.021, p = 0.038, respectively). Interestingly, elevated C-reactive protein was associated with decreased OS (p = 0.01). Initially, each score was given depending upon the number of abnormal categories (lab, imaging or clinical signs), ranging from score 0 (n = 7), 1 (n = 19), 2 (n = 33) and 3 (n = 17). Increased score was associated with increased OS (p = 0.03). For more detailed analysis, we came up with scoring system which sums up each score given for any abnormality in each subcategory. On Multivariate analysis, there was significant positive correlation between higher score and increased OS (p = 0.001). Conclusions: We have identified several IRAE parameters that were associated with increased OS. Furthermore, scoring system used in the study which encompassed clinical, radiologic and laboratory aspect, showed positive association with increased OS, indicating IRAE’s potential role as a biomarker.
Preclinical functional characterization of AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody for the treatment of patients with early and advanced malignancies.
Authors: Waight Jeremy , Manrique Mariana , Gombos Randi , Costa Matthew , Iyer Priyadarshini , Vincent Sylvia , Ward Rebecca , Paltrinieri Elena , Chand Dhan , Wilson Nicholas , Buell Jennifer , Savitsky David 
Published: May 2019

e14126 Background: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor that modulates T cell priming and CD28-dependent T cell activation. Modulation of this pathway by CTLA-4 antibodies has demonstrated clinical responses in patients with advance disease, however the mechanism of action of these antibodies remains controversial. It is currently understood that anti-CTLA-4 antibodies mediate antitumor effects through receptor-ligand blockade, and, in preclinical models, through depletion of intratumoral regulatory T (Treg) cells via an Fc-dependent mechanism. Recently, we reported a novel Fc-mediated contribution to T cell priming underscored the importance of Fc selection for optimal CTLA-4 antibody activity. AGEN1181 is a clinical stage Fc-engineered IgG1 antibody that leverages this novel mechanism for enhanced functionality. Methods: Fab-mediated biology of AGEN1181 was confirmed by assessing binding affinity, specificity, and blockade of CTLA-4:CD80/86 interactions. Fc-mediated functions of AGEN1181 were evaluated by FcγR binding, reporter-based FcγR signaling, and antibody-mediated Treg cell cytotoxicity assays. In vitro and in vivo pharmacology of AGEN1181 (alone or in combination with anti-PD-1) were evaluated in superantigen (staphylococcal enterotoxin)-mediated T cell stimulation assays and in a non-human primate (NHP) model. Safety and tolerability of AGEN1181 were assessed in cynomolgus monkeys administered 5 once-weekly intravenous bolus infusions at doses of 5, 30, or 100 mg/kg. Results: AGEN1181 bound to CTLA-4 with high affinity and specificity and demonstrated a range of enhanced functional activities relative to first-generation CTLA-4 antibodies. This included superior CD16 (FcγRIIIA) binding, Treg depletion and T cell priming (as measured by ZAP70 phosphorylation and interleukin-2 secretion). In NHP studies, a single dose of AGEN1181, alone or in combination with anti-PD-1 antibody upregulated Ki67 and ICOS expression on peripheral T cells. Finally, AGEN1181 exhibited an acceptable toxicologic profile in multi-dose NHP studies. Conclusions: AGEN1181, an Fc-engineered anti-CTLA-4 antibody exhibits a range of enhanced functional attributes relative to first-generation anti-CTLA-4 antibodies in preclinical studies. Phase 1 clinical studies for AGEN1181 will be initiated imminently.
Characteristics and treatment of rheumatologic adverse events associated with immune checkpoint inhibitors: A multicentric prospective cohort study.
Authors: Mouamnia Amine , Desbarbieux Renaud , Mortier Laurent , Scherpereel Arnaud , Dubucquoi Sylvain , Flipo René-Marc , Philippe Peggy , Cortet Bernard , Vieillard Marie-Helene 
Published: May 2019

e14133 Background: To characterise the specific rheumatologic immune-related adverse events (irAEs) in patients with cancer treated by immune checkpoint inhibitors (ICI), and to propose a treatment flowchart of irAEs. Methods: A multicentric prospective study was performed to characterise the irAEs. Results: From December 2016 to December 2018, 39 patients were referred to the Department of Rheumatology. There were 22 men and 17 women. The middle age was 64,72 years old. The average time to continue ICI treatment after the onset of the irAEs was 3 months. 24 patients were followed for a melanoma, 10 for non-small cell lung cancers and five patients for various other neoplasia (glioblastoma, urothelial carcinoma, Merkel cell carcinoma, esophageal carcinoma, renal cell carcinoma). 43% had inflammatory pain (n = 17), whose 17% had arthritis (n = 7). The diagnosis was polymyalgia rheumatica for 10 patients, eosinophilic fasciitis for one patient, erosive Rheumatoid arthritis for one patient, non-erosive Rheumatoid arthritis for one patient. The other patients (57 %) had mechanical rheumatological involvement. Treatment of irAEs was glucocorticoids for 7 patients with a satisfying response, methotrexate for 1 patient, and sulfasalazine for one patient. The non-inflammatory pain was treated by antalgics and physiotherapy. The ICI was stopped (due to irAEs) for only one patient. Conclusions: In the light of these findings, a logigram of management is proposed and is being validated on a larger prospective cohort. irAEs is a good example of collaboration between oncologist and rheumatologist to improve the patients’ quality of life.
Real-world outcomes with immuno-oncology (IO) therapies: A prospective, observational cohort study in patients (pts) with advanced melanoma (OPTIMIzE).
Authors: Kirkwood John M. , Kottschade Lisa A. , McWilliams Robert R. , Khushalani Nikhil I. , Jang Sekwon , Hallmeyer Sigrun , McDermott David F. , Tawbi Hussein Abdul-Hassan , Wan Yin , Wang Rosa , Ritchings Corey , Rao Sumati , Ramsey Scott 
Published: May 2019

e14144 Background: There is little real-world evidence evaluating treatment patterns and outcomes with IO therapies for pts with advanced melanoma (aMEL). We present results from the OPTIMIzE (NCT02780089) study in pts with aMEL receiving IO therapies. Methods: OPTIMIzE is a US-based multisite (150 sites), community-based study of adult pts with aMEL. Pts receiving first-line (1L) nivolumab (NIVO)+ipilimumab (IPI), anti-PD-1 (NIVO/pembrolizumab), or IPI between 2011-2018 with a minimum 1 y of follow-up were included. Baseline characteristics, objective response rate (ORR), overall survival (OS), treatment-related adverse events (TRAEs), and quality of life (QoL) were analyzed. QoL assessments included the Functional Assessment of Cancer Therapy–Melanoma (FACT-M), EQ-5D index, and visual analog scale (VAS). Results: Cohort size: 81 NIVO+IPI, 147 anti-PD-1, and 16 IPI (IPI arm not included in the analysis). Overall, mean age was 64.5 y; 42% had BRAF mutation. Mean follow-up was 14.1 mo. Pts in the NIVO+IPI group were younger, had better ECOG performance status, and a higher likelihood of M1c disease and elevated LDH vs the anti-PD-1 group. ORR was higher for pts treated with NIVO+IPI vs anti-PD-1 (48% vs 33%, P= 0.08). Unadjusted 1-y OS was 78.4% for NIVO+IPI and 73.1% for anti-PD-1. In multivariate Cox model analysis, the hazard ratio for OS for NIVO+IPI vs anti-PD-1 was 0.78 (95% CI, 0.46–1.33; P= 0.36). Grade 3/4 TRAEs occurred in 53% and 22% of pts in the NIVO+IPI and anti-PD-1 groups, respectively ( P˂0.001). QoL changes from baseline were clinically meaningful for EQ-5D VAS and FACT-M in the NIVO+IPI group at 12 mo (Table). After adjusting for baseline covariates, the difference at 12 mo between NIVO+IPI vs anti-PD-1 was 6.7 ( P= 0.04) for EQ-5D VAS and 8.8 ( P= 0.02) for FACT-M. Conclusions: Safety and efficacy outcomes from this prospective real-world study are consistent with those reported in prior clinical trials in treatment-naive aMEL pts. No clinically meaningful deterioration in QoL measures was observed in either group. Clinical trial information: NCT02780089. [Table: see text]
Endocrinopathies associated with immune checkpoint inhibitors: Standard of care at veterans administration medical centers.
Authors: Johnson Brett , Tuck David P. , Ganas Spyridon , Bayless Nicholas , Kotecha Nikesh , Do Nhan 
Published: May 2019

e14148 Background: Multiple different immune checkpoint inhibitors (ICI) have now received FDA approval for nearly 70 separate indications covering 14 different tumor types. Patients treated with these agents in clinical trials have an observed incidence of immune related adverse events (irAEs), including endocrinopathies, which may increase morbidity and mortality. Limited information describes the incidence and impact of these events outside of clinical trials. Methods: Retrospective data from the Veterans Health Administration (VA) of patients treated with ICI has been aggregated to understand the impact of these events in a standard of care setting, with a goal of improving patient care through predictive models and contributing to the understanding of the mechanisms and response to treatment. Results: Between October 2015 and December 2018, 10,280 patients were prescribed ICI at VA medical centers, with an average age of 70 years (range 20-99). A total of 11098 ICI orders, allowing for combinations or sequential treatments. Overall, nivolumab was prescribed 6024 times (54.3%), pembrolizumab 3976 (35.8%), ipilimumab 565 (5.1%) and atezolizumab 519 (4.6%). Avelumab (13) and durvalumab (1) had limited use. A candidate set of potential endocrine adverse events was estimated based on selected ICD10 codes recorded for the first time after treatment with ICI (Table). Conclusions: The frequency of endocrine immune related adverse events has been reported to be 5-10%. Here we have identified a cohort of ICI treated patients who may have developed endocrine adverse events. This cohort will be used to evaluate phenotyping, potential biomarkers and models of predictive risk.[Table: see text]
Pembrolizumab versus the standard of care for cancer therapy: A meta-analysis of 12 KEYNOTE trials comparing overall survival.
Authors: Parker Nathaniel , Al-Obaidi Ammar , Truong Quoc Van , Badgett Robert 
Published: May 2019

e14159 Background: Pembrolizumab (P) is an antineoplastic agent approved for multiple different tumor origins as well as tumor agnostic based on MSI status. Thus understanding the tumor characteristics most predictive of response is essential. Living meta-analysis provides a method to continuously assimilate emerging trials. In this study, we created a living meta-analysis to compare the effect of P on overall survival (OS). Methods: Meta-analysis was conducted according to the PRISMA guidelines. PubMed and Cochrane databases, and conference abstracts (e.g. ASCO, ESMO), were searched for phase III KEYNOTE RCT’s that reported OS among cancer patients receiving P. Results: 12 phase III trials involving 7,319 patients (3,861 in P arms) treated for 6 different types of cancer were retrieved. Median follow up was 12.9 months [range: 0.1-35.5]. Treatment was P alone, SOC chemo, and P + chemo in 11 (40%), 13 (46%), and 4 (14%) arms, respectively. P significantly improved OS (HR 0.71, 95% CI: 0.59-0.85, p <0.001, I2 = 0%) when used in any cancer type, setting, or therapy for advanced refractory or chemo-naïve cancer patients. The mean median OS was 12.5 vs 11.1 months in the total populations for all P and control arms, respectively (Table). Conclusions: Among all trials, P was associated with improved OS. Additional meta-analysis will be performed with R software (version 3.3.3; R Fdn.). Random-effects models will be used to compare OS. Heterogeneity will be assessed with Cochrane Q -statistic and quantified with I2test via subgroup analyses for cancer type, setting, therapy, and PD-L1%. This meta-analysis is continuously updated at http://openmetaanalysis.github.io/checkpoint-inhibitors. [Table: see text]
Recurrence-free survival (RFS) and objective response rate (ORR) phase 1/2 study of intralesional (IL) neoadjuvant (neo) anti-PD1 agents (aPD1) for stage IIIB-IV melanoma (MEL).
Authors: Samoylenko Igor , Korotkova Olga V. , Shakhray Ekaterina , Zabotina Tatiana , Berdnikov Sergey , Tabakov Dmitry , Zakharova Elena , Petenko Natalia N. , Demidov Lev V. 
Published: May 2019

e14171 Background: We previously reported that aPD1 agents could be safely administered IL in patients (pts) with metastatic MEL with superficial lesions, providing local and bystander tumor response (Samoylenko, I., et al. (ASCO-SITC 2018)). We present results from an interim 6 mos analysis of RFS and ORR for IL neo aPD1 therapy. Methods: Pts with unresectable stage IIIC/D/IVM1a-c MEL (safety cohort, N = 7) and resectable stage IIIC/D/IVM1a (expansion cohort, N = 18), with ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm were allocated to 6 doses/12 of nivolumab or pembrolizumab before surgery (surg). aPD1 was given at scale-based dosing regimen reported previously. Tumor sampling for biomarker analysis and pCR confirmation (or core-needle biopsy, CNB) was performed prior to treatment and at week 13-18. The analysis was conducted on the ITT basis to estimate RFS at 6 mos and ORR. An RFS event was defined as disease progression or death due to any cause after surg and assessed in the expansion cohort. ORR for the both cohorts was evaluated. Results: Since Apr 2016 to Dec 2018 25 pts were enrolled. Baseline characteristics are summarized in Table. ORR was 47,6% (10/21 pts assessed), with 5 (24%) clinical CR and 4 pathological CR (19%). Among 18 pts considered for surg 2 refused from surg when CNB confirmed no residual tumor. 89% of pts (16/18 pts) from the expansion cohort remained recurrence free at 6 mos FU. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 20 of 21 pts assessed. Baseline percent of TILs assessed by flow cytometry (FCT) was higher in responders vs non-responders (7.54±7.51% vs 1.51±2.93, p < .05), whereas CD3-CD16+CD56+ and CD4+CD25+ values were lower in responders vs non-responders (0.94±1.45% vs 7.88±6.84, p < .05, and 6.68±3.46% vs 20.50±16.79, p < 0.05, respectively). PD1, PDL-1 and PDL-2 expression in tumor cells and TILs assessed by FCT did not differ significantly between responders and non-responders. Conclusions: We demonstrated the potential clinical efficacy of IL aPD1 in melanoma pts. Further studies are needed to determine if unsuccessful IL administration could predict failure to adjuvant treatment. Primary analysis of RFS at 1-yr is expected. Clinical trial information: NA. [Table: see text]
Quantitative assessment of immune cell populations and associations with clinical outcomes in African-American (AA) versus Caucasian triple-negative breast cancer (TNBC).
Authors: O'Meara Tess , Yaghoobi Vesal , Blenman Kim , Pelekanou Vasiliki , Silber Andrea , Rimm David L. , Pusztai Lajos 
Published: May 2019

e14180 Background: Tumor infiltrating lymphocytes (TILs) are powerful prognostic and predictive factors in TNBC. We hypothesized that survival differences in TNBC by race may be caused by differences in the tumor immune microenvironment. We assessed racial differences in the extent and composition of immune infiltration in TNBC and correlated these differences with clinical characteristics and disease-free survival (DFS). Methods: Formalin fixed paraffin embedded TNBC samples and clinical information were collected for n = 43 AA and n = 43 Caucasian cases, matched by diagnosis date and stage. Stromal TILs were assessed on H&E-stained slides. Multiplexed immunofluorescence was performed to quantify CD68 (macrophage), CD8 (cytotoxic T cell) and PD-L1 protein expression in the whole-section, tumor and stromal compartments. Average expression for each marker was calculated over all fields of view. Cox proportional hazards were used to assess associations between DFS, staining markers and clinical variables. Results: Characteristics of AA and Caucasian cases were not significantly different. There were 14 and 8 recurrences in the AA and Caucasian cohorts, respectively (median follow-up 8.7 vs 9.4 yrs). TIL counts (p = 0.031) and overall CD68 expression (p = 0.005) were higher in AA compared to Caucasian patients. 21% percent of AA cases had TIL predominant phenotype versus 3% of Caucasians, but CD8 expression was similar by race. PD-L1 expression was higher in stroma compared to tumor across all patients (median 401 vs 267 au, p = 0.002) and did not differ by race. Higher overall and stromal PD-L1 expression were associated with better DFS in the entire population (median 3501 vs 1895 days, p = 0.0009) and in each race separately. Higher CD68 expression was also associated with better DFS (median 3015 vs 2111 days, p = 0.0004). In multivariate analysis of DFS, stage at presentation remained significant (p = 0.002) in addition to PD-L1 and CD68 expression. Conclusions: AA TNBC had higher TIL counts and CD68 expression but similar CD8 and PD-L1 expression compared to Caucasians. High CD68 and PD-L1 expression were associated with better DFS in both race cohorts.
Effect of gastrointestinal microbiome and its diversity on the expression of tumor-infiltrating lymphocytes in breast cancer.
Authors: Shi Jiajie , Geng Cuizhi 
Published: May 2019

e14187 Background: The diversity of gastrointestinal microbiome is closely related to human health. In the present study, we compared gastrointestinal microbiome and tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) patients. Methods: A total of 80 BC patients were divided into three groups based on the expression of TILs as follows: high expression of TILs (TIL-H), medium expression of TILs (TIL-M) and low expression of TILs (TIL-L). DNA of gastrointestinal microbiome was determined by Illumina sequencing and taxonomy of 16S rRNA genes. Kruskal-Wallis test and UniFrac analysis of β-diversity were applied to assess the relationship between patients’ clinical characteristics and diversity of gastrointestinal microbiome. Results: The β-diversity distribution was statistically significant (weighted UniFrac P < 0.01, unweighted UniFac P < 0.01) when comparing between the TIL-L and TIL-H groups or among the three groups (TIL-H vs. TIL-M vs. TIL-L). At the genus level, higher abundances of Mycobacterium, Rhodococcus, Catenibacterium, Bulleidia, Anaerofilum, Sneathia, Devosia and TG5 but lower abundances of Methanosphaera and Anaerobiospirillum ( P < 0.05) were identified in the TIL-L group compared with the TIL-H group . At the species level, the species of stercoris, barnesiae, coprophilus, flavefaciens and C21_c20 displayed a higher abundance in the TIL-L group, while producta and komagatae exhibited a greater abundance in the TIL-H group ( P < 0.05). Conclusions: Collectively, the diversity of gastrointestinal microbiome was related to the expression of TILs in BC patients.
STING-dependent preventive effect by ablative hyperfractioned radiotherapy and delayed delivery of a CSF-1R inhibitor.
Authors: Sun Xiaowen , Deng Lei , Yin Limei , Li Mengqian , Xue Jianxin , Lu You 
Published: May 2019

e14190 Background: It has been reported that hyperfractioned radiotherapy can bring out abscopal effects when combined with checkpoint inhibitors and radiation-induced myeloid-derived suppressor cells (MDSCs) infiltration can lead to radioresistance. Our prior work has shown that ablative hypofractionated radiotherapy (AHFRT) alone can not trigger significant abscopal effects in three mouse tumor models. The goal of this study was to figure out whether the AHFRT play a preventive role in different tumor models and can be enhanced by a CSF-1R inhibitor. Methods: In experiment exploring the preventive effect of AHFRT, on Day 0, B16/ CT26/ MC38 tumor cells or PBS were inoculated s.c. in the left-side thigh of mice, respectively. Then, control mice and mice with established tumors were irradiated by AHFRT (12Gy*3f*3days). When the AHFRT accomplished, mice randomly divided into different groups and the second tumors inoculated s.c. in the right-side thigh, respectively: 1 day/ 3 days/ 7 days after AHFRT accomplished. Besides, “1 day after AHFRT accomplished” mice, both established MC38/CT26 tumors and PBS controls, were divided into 4 groups: control, a-CSF-1R, AHFRT, AHFRT+a-CSF-1R. And MC38 tumor cells were irradiated. The mice and cells followed for tumor growth and further analyses (mainly flow cytometry, western-blotting and qPCR). Results: We found that AHFRT alone could trigger significant preventive effects in” 7 days after AHFRT accomplished” group in B16 tumor model and “ 1 day/ 3 days/ 7 days after AHFRT accomplished” groups in CT26/ MC38 tumor models. In CT26/ MC38 tumor models, all the second tumors were cured which inoculated in “7 days after AHFRT accomplished” groups because of the preventive effects. And these cured mice keep survival without tumors when rechallenged at 180 days after AHFRT accomplished. AHFRT induced CD11b+CD11c+MHC-II+ antigen presenting cells at the 1st day after AHFRT accomplished and effector CD8+ T cells at 3rd day after AHFRT accomplished. AHFRT could active cGAS, STING, CXCL10 and IRF3 in the irradiated MC38 cells. And with a STING inhibitor, the growth of second tumors lost the preventive effect from AHFRT. And a delayed delivery of a small-molecule CSF-1R inhibitor decreased monocyte-MDSC(CD11b+CD11c-Gr1-) and delay the growth of second tumors inoculated 1 day after AHFRT accomplished. Conclusions: We show thatAHFRT triggers in situ vaccination and subsequent prevention effect. The prevention effect is STING-dependent and can be enhanced by a delayed delivery of CSF-1R inhibitor.