bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic immune signature of inflammation in metastatic melanoma (MM) patients treated with ipilimumab (IPI) and carboplatin/paclitaxel (CP).
Authors: Miller Wilson H. , Jamal Rahima , Cocolakis Eftihia , Thebault Pamela , Friedmann Jennifer Elisabeth , Kazemi Shirin , Dionne Jeanne , Cailhier Jean-Francois , Lepage Stephanie , Belanger Karl , Ayoub Jean-Pierre M. , Le HB , Lambert Caroline , El Hajjar Jida , Van Kempen Leon , Spatz Alan , Lapointe Rejean 
Published: February 2018

185 Background: Only a subset of MM patients benefit from treatment with IPI. In an effort to increase response and identify predictive immune biomarkers, we combined IPI with CP. We here report a significant correlation between overall survival (OS) and biomarkers of a pre-existing inflammatory state. Methods: 30 patients were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and IPI (3mg/kg) every 3 weeks x 4. Blood was collected throughout. OS Kaplan–Meier curves were compared by the log-rank test. Cutoff thresholds defining high or low levels of chemokines, B cell populations and PD-1+CD8+ T cell populations were established from the mean value of a given variable from all patients. Neutrophil to Lymphocyte Ratio (NLR) and Systemic Immune Inflammation Index defined as Platelet x Neutrophil to Lymphocyte Ratio (SII) were calculated at baseline and tested for association with OS. SII ≥ 1375 and NLR ≥ 5 were considered as high risk groups. Results: Median OS was 16.2 months, with a 3-year OS of 36.7% for all patients. High levels of CCL3 (HR = 2.79, p = 0.0159), CCL4 (HR = 8.36, p < 0.0001) and CXCL8 (HR = 3.52, p = 0.0037) were associated with worse OS. Advanced B cell differentiation before treatment was associated with worse patient outcomes. High levels of early differentiated Bm2 ( > 57%) were strongly associated with better OS: HR = 0.26 p = 0.004 whereas high eBm5+Bm5 ( > 14%) levels were strongly associated with worse OS: HR = 2.65, p = 0.029. Patients with higher proportions of PD-1+CD8+ T cells in circulation during treatment had poorer OS (HR = 3.84, p = 0.004) at week 10; (HR = 3.53, p = 0.005) at week 13 and (HR = 2.84, p = 0.040) at week 24. High risk SII (HR = 3.30, p = 0.0192) and NLR (HR = 2.367, p = 0.0486) were associated with worse OS. Conclusions: We have identified a significant correlation between pre-existing systemic inflammatory state and a poor response to IPI and CP. Specifically elevated CCL3, CCL4 and CXCL8, baseline B lymphocyte subset skewing, increased CD8+PD-1+ T lymphocytes, increased NLR and SII were all strongly associated to worse OS. Comprehensive immune monitoring provides evidence for new circulating biomarkers predicting outcome in MM patients treated with IPI and CP. Clinical trial information: NCT01676649.
A clinical insight into therapeutic sequence in advanced melanoma.
Authors: Vera Aguilera Jesus , Paludo Jonas , Tschautscher Marcella , Yu Cecilia , Duma Narjust , Markovic Svetomir 
Published: February 2018

186 Background: The optimal sequence strategy of BRAF/MEK inhibitors, anti-PD- 1/PDL-1 and anti-CTLA-4 in metastatic BRAF-mutated melanoma patients (pts) is unknown and no treatment guidelines exist. Therefore, we report a single-institution experience of different treatment approaches using targeted therapy (TT) and immunotherapy and its impact on outcomes. Methods: BRAF-mutated metastatic melanoma pts treated with TT and immunotherapy from 2012 to2017 were analyzed. Six groups were identified based on treatment strategy. All time-to-event analyses were calculated using the Kaplan-Meier method and Wilcoxon test. Results: Forty-four pts were identified. The median age at diagnosis was 49 years (range 21-73), 54% pts were females and 43% developed brain metastases during disease course. The most common approach strategy was immunotherapy followed by TT, the median duration of treatment was 11 and 19 weeks, respectively. Time-to-next therapy (TTNT) following 1st line treatment was similar in pts treated with TT (median 23 weeks [95% CI: 15-31]) or immunotherapy (median 26 weeks [95% CI: 10-33], p = 0.94). A trend towards better overall survival (OS) was seen in pts who received immunotherapy followed by TT (p = 0.09); patients who received salvage chemotherapy (carboplatin/paclitaxel) had significantly longer OS (median 7 years [95% CI: 3.2-7.08]) ( p = 0.03). Conclusions: No differences in TTNT were seen with immunotherapy, TT or combined (triple therapy) when used as 1st or 2nd line. The significant longer OS benefit with 1st line immunotherapy was only seen in patients who received chemotherapy later in their treatment course. [Table: see text]
Avelumab in patients with previously treated metastatic melanoma: Phase 1b results from the JAVELIN Solid Tumor trial.
Authors: Keilholz Ulrich , Mehnert Janice M. , Bauer Sebastian , Bourgeois Hugues Pierre , Patel Manish R. , Gravenor Donald , Nemunaitis John J. , Taylor Matthew H. , Wyrwicz Lucjan , Lee Keun-Wook , Kasturi Vijay , Chin Kevin M. , von Heydebreck Anja , Gulley James L. 
Published: February 2018

191 Background: Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is approved for the treatment of metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma progressed on platinum therapy (US). Here, we report phase 1b data for avelumab in a cohort of patients (pts) with previously treated metastatic melanoma. Methods: Pts with unresectable stage IIIC or IV melanoma progressed after ≥1 line of therapy for metastatic disease received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs; NCI CTCAE v4.0). Results: As of Dec 31, 2016, 51 pts were treated and followed for a median of 24.2 mo (range 16.1–31.5). Median age was 64 y (range 31–84). Site of primary tumor was cutaneous (n = 28, 54.9%), ocular (n = 16, 31.4%), mucosal (n = 2, 3.9%), or unknown (n = 5, 9.8%). Pts had received a median of 2 prior lines of therapy for advanced disease (range 0–4), including ipilimumab (n = 26, 51.0%). Confirmed ORR was 21.6% (95% CI 11.3–35.3), with complete response in 7.8% and partial response in 13.7%. In pts with cutaneous melanoma, ORR was 28.6% (95% CI 13.2–48.7). There were no objective responses in pts with ocular melanoma; however, 7 pts (43.8%) had stable disease. In pts with ≤1 (n = 25), 2 (n = 17), or ≥3 (n = 9) prior lines, ORR was 36.0% (95% CI 18.0–57.5), 11.8% (95% CI 1.5–36.4), and 0% (95% CI 0–33.6), respectively. Antitumor activity by PD-L1 status will be presented. Median duration of response was not estimable (NE) (95% CI 2.6 mo–NE). Median PFS was 3.1 mo (95% CI 1.4–6.3) and the 6-mo PFS rate was 39.2% (95% CI 25.2–52.9). Median OS was 18.5 mo (95% CI 9.3–NE) and the 12-mo OS rate was 62.3% (95% CI 46.9–74.4). 39 pts (76.5%) had a treatment-related (TR)AE, most commonly infusion-related reaction (25.5%), fatigue (17.6%), and chills (11.8%). 4 pts (7.8%) had a grade ≥3 TRAE. 5 pts (9.8%) had an immune-related AE; all were grade 1/2. No treatment-related deaths occurred. Conclusions: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in pts with previously treated metastatic melanoma. Clinical trial information: NCT01772004.
Association between objective responses (OR) and overall survival (OS) in patients (pts) with metastatic Merkel cell carcinoma (mMCC) treated with avelumab.
Authors: D'Angelo Sandra P. , Hunger Matthias , Schlichting Michael , Hennessy Meliessa G. , Bharmal Murtuza 
Published: February 2018

193 Background: Response rates are key efficacy endpoints in oncology trials, yet correlations with OS are not universal across cancer types. MCC is a rare and aggressive skin carcinoma, although it is chemo sensitive with high response rates, responses are of short duration with no demonstrated benefit to OS. This study explores the association between OR and OS in mMCC pts treated with the anti-PD-L1 avelumab. Methods: Efficacy data with ≥ 18 months of follow-up from Part A of the phase II avelumab trial (NCT02155647) were analyzed. Pts had prior progression on or after chemotherapy and received avelumab 10 mg/kg IV Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed for OR every 6 weeks (RECIST v1.1). Using conditional landmark analyses, OS was compared between pts with and without an independently confirmed OR up to day 47. Only pts alive at the landmark (day 47) are included in this analysis. In a sensitivity analysis, a landmark of 89 days was used. A Cox model including OR as a covariate was fit (unadjusted, controlling for age, visceral disease, and number of previous therapies). Results: 20 pts had an initial OR reported up to day 47, with 7 further pts having an OR between day 48 and day 89, and 2 pts having an OR after day 89, including 10 complete responses (CRs). 5 pts died and 1 withdrew consent before day 47 (all without OR). Survival probabilities 18 months after treatment initiation were 0.900 (95%CI: 0.656; 0.974) for pts with OR up to day 47 vs. 0.262 (95% CI 0.157; 0.378) for pts without OR but alive up to day 47. Similar results were observed for the 89-day landmark. In the unadjusted Cox model, OR was associated with a 94% risk reduction of death (hazard ratio: 0.064 [95% CI: 0.022; 0.181]). The hazard ratio in the adjusted model was 0.052 (95% CI: 0.018; 0.152). Conclusions: Avelumab therapy for previously treated mMCC pts demonstrated a clinically relevant and high survival impact. For avelumab, OR was associated with long-term survival, likely driven by the rapid time to response, substantial tumor reductions including CRs and sustained durable responses not reported in the chemotherapy literature for mMCC. Clinical trial information: NCT02155647.
Validating critical analytical variables of a multiplexed gene expression assay measuring tumor inflammation designed to predict response to anti-PD1 therapy.
Authors: Popa Simina , Church Sarah Elizabeth , Pekker Irena , Dowidar Naeem , Sullivan Amy , Ngouenet Celine , Schaper Carl , Ren Xing , Danaher Patrick , Ferree Sean , Wallden Brett 
Published: February 2018

203 Background: The development and analytical performance of the Tumor Inflammation Signature (TIS) assay has been described previously. The TIS is an investigational use RNA expression assay on the nCounter Dx Analysis System, which is being evaluated as a patient enrichment biomarker for treatment with pembrolizumab single agent across multiple solid tumor types. Here we describe the analytical validation of the RNA input range and analytical precision starting from RNA isolated from formalin fixed paraffin embedded (FFPE) tissue blocks. Methods: Analytical validation of TIS assay performance across an RNA input range was performed using samples from 11 tumor types. The analytical precision between sites, instruments, reagent lots, and users was measured, using RNA samples isolated from FFPE tissue blocks. Results: The assay was validated across the specified RNA input range with ≥ 94% concordance at the minimum specified RNA input (50ng). The total standard deviation of the TIS score was < 0.04 units across three sites with ≥98% concordance between sites. The 6 users across the three sites did not significantly contribute to the assay variability. There was 100% concordance in biomarker high/low categorization between multiple reagent lots and multiple instruments. Conclusions: The analytical performance of the NanoString TIS assay has been validated to give consistent results across the RNA input range and between site, instrument, assay user, and reagent kit lot. The assay is well suited for decentralized clinical testing and is currently under investigation as a biomarker to enrich for response to anti-PD1 therapy across multiple tumor types.
TH1/17 hybrid CD4+ cells in bronchial alveolar lavage fluid from leukemia patients with checkpoint inhibitor-induced pneumonitis.
Authors: Kim Sang , Shannon Vickie , Sheshadri Ajay , Kantarjian Hagop M. , Garcia-Manero Guillermo , Im Jin , Ravandi Farhad , Naing Aung , Futreal Andrew , Daver Naval Guastad 
Published: February 2018

204 Background: Immune checkpoint inhibitor (ICI)-based therapies are showing encouraging results for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 20% of AML or MDS patients receiving an ICI develop lung inflammation (herein, pneumonitis), one of fatal immune related adverse events (irAEs). The mechanisms of pneumonitis, the most important step for risk stratification and early detection, remain elusive. Methods: We analyzed bronchial alveolar lavage (BAL) fluid from 8 AML or MDS patients, who received an ICI, developed respiratory symptoms, and underwent a standard-of-care bronchoscopy. As a control, we analyzed BAL fluid from 5 AML or MDS patients who had never received an ICI or had received last ICI more than 16 weeks prior to the bronchoscopy. We also analyzed matched blood within 72 hours after the bronchoscopy. We stained CD4+ cells with lineage specific markers, including CXCR3, CXCR5, CD25, CD127, CCR4, and CCR6. Proportion of the CD4+ cell subsets within total CD4+ lymphocytes in BAL and blood were compared between the pneumonitis and controls. Results: Th1 (CXCR3hi) CD4+ cells were expanded in controls in BAL (pneumonitis versus control, 4.2 ± 2.5 % versus 17.2 ± 6.3 % within total CD4+ lymphocytes, P= 0.04) and blood (pneumonitis versus control, 0.5 ± 0.3 % versus 4.0 ± 1.3 % within total CD4+ lymphocytes, P= 0.01). In contrast, Th1/17 (CXCR3hi CCR6hi) hybrid CD4+ cells, known to be pathogenic in autoimmune diseases, were expanded in BAL from the pneumonitis group (pneumonitis versus control, 40.3 ± 8.4 % versus 13.7 ± 4.5 % within total CD4+ lymphocytes, P= 0.03). Th1/17 hybrid CD4+ cells were also PD-1hi Ki67hi, suggesting their hyperactive status. Though not reached statistical significance, regulatory T cells were decreased in BAL from pneumonitis group (pneumonitis versus control, 20.8 ± 4.9 % versus 26.2 ± 9.2 % within total CD4+ lymphocytes). Conclusions: These results suggest that Th1/17 hybrid CD4+ cells may play a central role in pneumonitis. Understanding of the Th1/17 hybrid CD4+ cell biology will provide therapeutic targets and reliable biomarkers for pneumonitis.
A novel T-cell bispecific antibody platform for efficient T-cell mediated killing of tumor cells with minimal cytokine release.
Authors: Rangaswamy Udaya , Boudreau Andrew , Buelow Ben , Clarke Starlynn , Dang Kevin , Davison Laura , Force Aldred Shelley , Harris Katherine , Iyer Suhasini , Jorgensen Brett , Ogana Heather , Pham Duy , Pratap Payal , Trinklein Nathan , Schellenberger Ute , Ugamraj Harshad , Vafa Omid , Van Schooten Wim 
Published: February 2018

209 Background: Bispecific antibodies that recruit cytotoxic T cells to kill tumor cells are popular due to their targeted mechanism of action. Despite their attractiveness, there are limitations in the clinic due to undesirable toxicities associated with cytokine release. We describe here a platform for generation of a large collection of human anti-CD3 antibodies obtained from custom transgenic rats. Combining these unique anti-CD3 arms with different tumor targeting arms enables creation of bispecific antibodies of varying tumor cell killing capability. These anti-CD3 arms were combined with tumor antigen binding arms, namely, an anti-BCMA arm for multiple myeloma therapy, or an anti-CD22 arm for B-cell acute lymphoblastic leukemia therapy. Methods: Our platform utilizes a discovery approach involving antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression, generating a highly diverse panel of antibodies with varying affinities. The CD3 antibodies were tested in in vitro T cell assays using human PBMCs to measure activation and cytokine release. Bispecific antibodies were evaluated for their ability to kill target cell lines upon co-culture with primary human PBMCs. The in vivo efficacy of bispecific antibodies was evaluated in a xenograft mouse model. Results: The in vitro T cell activity of these antibodies as measured by interleukin-2, interferon gamma levels and upregulation of the activation marker CD69 covered a broad spectrum of EC50 values. In co-culture systems with human PBMCs, anti-BCMA or anti-CD22 bispecific antibodies potently killed their respective target expressing cells with varying strengths. Additionally, the cytokine release from T cell activation correlated with the affinity of the anti-CD3 arms. The in vivo efficacy of the bispecific antibodies in a xenograft model with human PBMCs transferred into NSG mice showed striking tumor clearance at a wide range of doses. Conclusions: Our platform is highly suitable for creation of an extensive collection of bispecific antibodies for a variety of disease models by selecting the ideal anti-CD3 arm for each unique tumor antigen binding arm.
Phase I trial of the programmed death receptor 1 (PD-1) inhibitor, BI 754091, in patients (pts) with advanced solid tumors.
Authors: Johnson Melissa Lynne , Patel Manish R. , Siu Lillian L. , Kozloff Mark , Aljumaily Raid , Vaishampayan Ulka N. , Elgadi Mabrouk M. , Ge Miaomiao , Duffy Christine , Graeser Ralph , Khedkar Sheetal Vinay , Jones Suzanne Fields , Burris Howard A. 
Published: February 2018

212 Background: Tumors may achieve immune evasion by expressing PD ligand-1 (PDL-1) to bind to PD-1 expressed on activated T cells, initiating immunosuppressive signals within the tumor. Pro-inflammatory anti-tumor activity can be restored when this interaction is blocked by therapeutic PD-1 or PDL-1 inhibition. BI 754091 is a monoclonal IgG4Pro antibody directed against PD-1 that has demonstrated anti-tumor activity in vitro and in vivo. We present the results of the first in human study evaluating BI 754091 in patients with advanced solid tumors. Methods: Patients who had exhausted standard treatment (tx) options, including prior anti-PD-1 tx, were enrolled to receive BI 754091 IV every 3 weeks (Q3W) in one of 3 sequential dose escalation cohorts (80, 240 and 400 mg), 3 patients/cohort, to evaluate the safety and tolerability and establish the maximum-tolerated dose (MTD) or recommended Phase II Dose (RPIID). Additional anti-PD-1 naïve patients with select solid tumors are being enrolled in dose expansion to be treated with the selected RPIID. The objectives of the dose expansion cohort are to evaluate the safety, tolerability, PK and preliminary efficacy of the RPIID of BI 754091, in patients with advanced solid tumors. Results: 17 patients have enrolled to date, 9 patients in the dose escalation and 8 patients in the dose expansion cohorts. Both, safety and PK profile supported a RPIID of 240 mg. The most common all grade Treatment Related Adverse Events (TRAE) were fatigue 35% (6 patients), decreased appetite 18% (3 patients) and arthralgia 12% (2 patients). There were no dose-limiting toxicities, tx-related serious adverse events, or TRAEs ≥Grade 3 reported. To date, one patient (gastric cancer) has had a partial response, 8 had stable disease, and 8 patients continue on treatment. Additional efficacy data among patients in dose-expansion will be reported. Conclusions: BI 754091 is safe and well-tolerated across all dose levels tested for advanced solid tumors, with preliminary evidence of activity. A dose of 240 mg Q3W was selected for dose expansion and RPIID based upon the available safety and PK data. Clinical trial information: NCT02952248.
Effect of body mass index and albumin level on outcomes of patients receiving anti PD-1/PD-L1 therapy.
Authors: Ibrahimi Sami , Mukherjee Sarbajit , Roman Darwin , King Caleb , Machiorlatti Michael , Aljumaily Raid 
Published: February 2018

213 Background: Obesity has been previously investigated for its role in cancer and promoting tumor growth, at least partially by inducing a chronic inflammatory state. However, it’s unclear how this would play out in the era of immunotherapy, where inflammation has been linked to treatment response. Albumin, a marker of nutritional status, is also a negative inflammatory marker. Patients with low albumin levels have been known to have a poor prognosis. In this study, we aim to assess the association of body mass index (BMI) and albumin level with outcomes of patients treated with immunotherapy. Methods: We retrospectively evaluated the outcomes of 198 patients, aged 18 years or older, treated with anti PD-1/PD-L1 at the University of Oklahoma Health Sciences Center from 2014 to 2017. Simple descriptive statistics were created for all covariates. Kaplan Meier and Cox Proportional Hazard regression were performed to assess how categorical and continuous variables were related to overall survival (OS) and progression free survival (PFS). A final multi-variable model was created using all variables associated with OS and PFS. Results: The median age was 62 years and the median follow-up time was 272 days. Melanoma was the most common diagnosis (25.7%) followed by lung cancer (23.5%) and ovarian cancer (11.5%). Higher BMI was associated with better outcomes. BMI (≥30 vs < 30) unadjusted was significantly associated with better OS (236 vs 133 days, p = 0.04) and PFS (316 vs 210 days, p = 0.01). As a continuous variable, a higher BMI was significantly associated with a better OS but not PFS with HR 0.96 (95% CI 0.93-0.99, p = 0.04) and HR 0.98 (95% CI 0.95-1.01, p = 0.09) respectively. BMI was not associated with OS or PFS in a multivariate analysis. Albumin level at initiation of treatment was not associated with OS (p = 0.12) or PFS (p = 0.19). Conclusions: In this single institution cohort, BMI had a significant effect on outcomes of patients receiving anti PD-1/PD-L1 agents. This warrants further investigation of BMI as a prognostic factor.