bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor shrinkage and increased overall survival are associated with improved albumin, neutrophil lymphocyte ratio (NLR) and decreased durvalumab clearance in NSCLC and UC patients receiving durvalumab.
Authors: Powles Thomas , Jin Chaoyu , Zheng Yanan , Baverel Paul , Narwal Rajesh , Mukhopadhyay Pralay , Jin Xiaoping , Dennis Phillip A. , Gupta Ashok Kumar , Ben Yong , Ho Tony W. , Roskos Lorin 
Published: September 2018

3035 Background: Progression of cancer is often associated with biomarkers of cancer inflammation, cachexia, and increased protein catabolism. Anti-PD1 and PD-L1 therapy have demonstrated durable responses across a number of tumor types. Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objective of this analysis was to prospectively assess potential correlations of longitudinal changes in ALB and NLR and durvalumab clearance (CL) rate to maximum decrease in tumor size and overall survival (OS) in patients (pts) with NSCLC and UC receiving durvalumab. Methods: Longitudinal target lesion size, serum chemistry, hematology and pharmacokinetic data were obtained from 3L+ NSCLC pts (n = 418) in study ATLANTIC and 2L+ UC pts (n = 182) in study 1108 during durvalumab treatment. Nonparametric correlations (Spearman’s rho) were evaluated between OS, maximum percent change in target lesion size, and the maximum percent change from baseline observed in ALB, NLR, and CL. Results: In NSCLC, maximum decrease in tumor size was correlated with increased ALB (r = 0.46, p < 0.0001), decreased NLR (r = 0.44, p < 0.0001), and decreased CL (r = 0.66, p < 0.0001). OS was similarly correlated with increased ALB (r = 0.47, p < 0.0001), decreased NLR (r = 0.41, p < 0.0001), and decreased CL (r = 0.76, p < 0.0001). In UC, decreased tumor size also correlated with increased ALB (r = 0.43, p < 0.0001), decreased NLR (r = 0.38, p < 0.0001), and decreased CL (r = 0.65, p < 0.0001). OS in UC also correlated with increased ALB (r = 0.50, p < 0.0001), decreased NLR (r = 0.33, p < 0.0001) and decreased CL (r = 0.82, p < 0.0001). Conclusions: In NSCLC and UC pts receiving durvalumab, tumor shrinkage and longer survival are associated with increased ALB, decreased NLR and decreased clearance of durvalumab. These findings support the hypothesis that durvalumab may be associated with a decrease in protein catabolism, inflammation and cachexia among pts who benefited from therapy. Additional biomarkers of cancer, inflammation and cachexia will be evaluated for relationships to clinical outcomes.
High-fidelity genome editing using NextGEN CRISPR (Clo51-dCas9) system for the production of allogeneic CAR-T cells.
Authors: Wang Xinxin , Li Xianghong , Barnett Burton , Martin Christopher , Hermanson David , Smith Jenessa , Rengarajan Srinivas , Tan Yening , Tong Min , Codde Rebecca , Ostertag Eric M. , Shedlock Devon J. 
Published: September 2018

3048 Background: Autologous chimeric antigen receptor (CAR) T therapies are highly efficient at targeting hematological malignancies, but the clinical applications have been limited by individualized manufacturing. Furthermore, there has been little success in treating solid tumors due to immunosuppressive microenvironments. Currently, genome editing technologies are being used to address both issues. However, the CRISPR/Cas9 system has significant safety concerns due to high incidence of off-target mutations and TALEN only works sufficiently in activated cells. A hybrid gene editing system, NextGEN (NG) Clo51-dCas9, can be targeted using gRNA, like CRISPR/Cas9, but exhibits little-to-no off-target cutting like TALEN, thereby overcoming limitations in the genome editing of resting T cells. Methods: We successfully developed a platform for production of allogeneic CAR-T cells with reduced receptivity to inhibitory signaling. Here, T cells were modified by piggyBac-mediated BCMA CAR gene delivery, along with NG reagents to knock out critical genes mediating rejection responses. Gene edited CAR-T cells were assessed by mixed lymphocyte reaction (MLR) and tumor killing. In addition, NG was used to knockout multiple checkpoint inhibitory receptors known to mediate key suppressive signals in T cells. Results: NG demonstrated high gene disruption efficiencies for all targets (84% for TCRα, 91% for TCRβ, 64% for β-2 microglobulin, and 40-60% for the surface inhibitory receptors PD-1, CTLA-4, Tim3, Lag-3, and TGFBRII). In contrast to CRISPR/Cas9, no off-target mutations were detected for multiple targets by deep-sequencing. In MLRs, disruption of TCR eliminated the GvHD response, while disruption of MHCI completely abrogated graft-rejection. Lastly, TCR/MHCI double knockout did not affect the ability to kill BCMA+ multiple myeloma cells in vitro. Conclusions: NG overcomes significant limitations of the CRISPR/Cas9 and TALEN systems with highly efficient genome editing in resting T cells. NG has great potential and flexibility for the manufacture of allogeneic CAR-T cells and for enhancing efficacy against solid tumors.
Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.
Authors: Yeku Oladapo O. , Purdon Terence , Spriggs David R. , Brentjens Renier J. 
Published: September 2018

3050 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies. The presence of an immunosuppressive cytokine and cellular microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, the presence of tumor associated macrophages (TAMs) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC) and NK cells, and has been shown to increase proliferation of T cells and enhance antigen presentation by macrophages. We hypothesized that CAR T cells genetically modified to constitutively secrete IL-12 would overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128-IL12 CAR T cells. We show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Mice treated with 4H1128-IL12 CAR T cells had decreased levels of F4/80+ CD11b+TAM’s. Genetic analysis of recovered TAM’s from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II and downregulation of Arg1. Recovered 4H1128-IL12 CAR T cells showed upregulation of FAS-L and recovered TAMs showed increased expression of FAS suggesting FAS/FAS-L engagement was responsible for decreased TAMs. Blocking the FAS/FAS-L pathway led to recovery of TAM populations in 4H1128-IL12 treated mice. Finally, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128-IL12 CAR T cells.
A randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab, a PD-L1 antibody, to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC).
Authors: Loibl Sibylle , Untch Michael , Burchardi Nicole , Huober Jens Bodo , Blohmer Jens Uwe , Grischke Eva-Maria , Furlanetto Jenny , Tesch Hans , Hanusch Claus , Rezai Mahdi , Jackisch Christian , Schmitt Wolfgang D , Von Minckwitz Gunter , Thomalla Jörg , Kummel Sherko , Rautenberg Beate , Fasching Peter A. , Rhiem Kerstin , Denkert Carsten , Schneeweiss Andreas 
Published: September 2018

3062 Background: Adding an anti-PD-L1 checkpoint inhibitor durvalumab to standard chemotherapy (CT) may increase pathological complete response (pCR) in patients (pts) with TNBC. Methods: GeparNuevo randomizes pts to durvalumab (D) 1.5 g i.v. or placebo (pl) every 4 weeks (wks). D/pl monotherapy (0.75 g i.v.) is given for the first 2 wks (window phase), followed by a biopsy and D/pl plus nab-paclitaxel (nP) 125 mg/m² weekly for 12 wks, followed by D/pl plus epirubicin/cyclophosphamide (EC) q2 wks for 4 cycles. Randomization is stratified by stromal TILs (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). Pts with primary cT1b-cT4a-d disease, centrally confirmed TNBC, and sTILs status can be included. Primary objective compares pCR (ypT0 ypN0) rates. Secondary objectives are pCR rates in stratified subpopulations and according to other pCR definitions; response rates; breast conservation rate; toxicity; compliance and survival. Change in sTILs, Ki67 and other immune biomarkers before CT, after the window phase and after CT will be correlated with outcome. The first 10, 20 and 30 pts will be included in safety interim analyses (SIA). Sample size was planned assuming a pCR rate of 48% for pl (nP treated TNBC cohort in GeparSepto) and of 66% for D (as clinically meaningful benefit), requiring 158 pts to show superiority of D (2-sided α = 0.2, 80% power). Assuming a 10% drop-out rate 174 pts will be randomized. Results: Since 6/2016, 50 pts were recruited within 16 sites; data are presented as available until 01/2017. Median age is 49 years; 86% NST and G3 tumors; sTILs categories 40% low, 40% intermediate and 20% high. Blinded SIA was performed. No pt interrupted D/pl, one nP and one EC. Treatment delay was observed in 9 pts (20.0%) in D/pl, 18 (41.9%) in nP and 2 (13.3%) in EC; dose was reduced in 10 pts (23.3%) in nP and in 4 (26.7%) in EC. 10 pts (20%) had at least one grade 3-4 AE: 4 haematological and 6 non-haematological AEs. 4 SAEs and 5 immune related AEs were reported. 2 pts discontinued study treatment prematurely in the EC phase. Conclusions: The addition of D to standard nP-EC is feasible and does not result in an increased toxicity. Clinical trial information: NCT02685059.
Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids.
Authors: Ziemer Mirjana , Koukoulioti Eleni , Simon Jan-Christoph , Berg Thomas 
Published: September 2018

3073 Background: The CTLA4-antibody ipilimumab, and PD-1-antibodies pembrolizumab as well as nivolumab have revolutionized antineoplastic therapies. Induction of autoimmune-like drug-induced liver injury (DILI) is within the spectrum of adverse reactions of these new drugs and has been observed in about 1-5 % of patients, developing predominantly within the first 6 to 12 weeks after start of treatment. Immediate application of systemic steroids and a permanent discontinuation of immune checkpoint-inhibition therapy are recommended for any alanine aminotransferase increase ≥ WHO grade 3. In severe autoimmune-like DILI the permanent discontinuation of the immune checkpoint inhibitor is recommended, as drug re-exposure might be associated with a significant risk of a fulminant DILI. Methods: We report six patients with severe grade 3 autoimmune-like DILI (according to Common Terminology Criteria for Adverse Events 4.3) treated with long-term application of budesonide, a liver-directed topical steroid. Results: Immune checkpoint inhibitors were stopped and methylprednisolone was applied initially with a dose of 1 mg/kg body weight and tapered thereafter. To reduce systemic steroids and to minimize the exposure time to systemic steroids, the topical steroid budesonide 3 mg three times per day was additionally given in combination with N-acetylcysteine and ursodeoxycholic acid. Under this multimodal approach transaminases normalized and the respective immune-checkpoint inhibitor could be re-started without re-manifestation of DILI under the continuous treatment with budesonide. Conclusions: Budesonide - a liver-directed topical steroid - might be an interesting approach to target liver related autoimmune adverse reactions induced by immune checkpoint inhibitors without compromising their anti-cancer effect. We were able to safely and effectively re-introduce and continue immune checkpoint inhibitors under the continuous application of the topical steroid without showing any further liver toxicity.
Somatic DNA mutations, MSI status, mutational load (ML): Association with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) of CALGB/SWOG 80405 (Alliance).
Authors: Innocenti Federico , Ou Fang-Shu , Zemla Tyler , Niedzwiecki Donna , Qu Xueping , Tam Rachel , Mahajan Shilpi , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Sanoff Hanna Kelly , Hochster Howard S. , Blanke Charles David , Venook Alan P. , Lenz Heinz-Josef , Kabbarah Omar 
Published: September 2018

3504 Background: CALGB 80405 was a randomized phase III trial that found no difference in OS in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet). Primary tumor DNA from 361 pts, including KRAS mutant (mut) pts, has been profiled for somatic gene mutations/ML/MSI to discover molecular markers of OS. Methods: Mutations in 11 genes were determined by PCR, MSI by microsatellite analysis, and ML by next-generation sequencing (FoundationOne). Cox proportional hazard models are used, stratified by prior XRT and +/- adjuvant chemotherapy; adjusted by age, race, gender, synchronous vs. metachronous, liver metastases, sidedness, all RAS. Results: BRAF: Mut pts had shorter OS than wild-type (wt) pts (HR 1.92, 95% CI 1.34,2.75; p<0.001); HR 1.65 (1.09,2.50) after adjusting for sidedness (p 0.022). In mut pts longer OS is observed in Bev arm vs. Cet arm (p 0.041); in wt pts no arm difference is observed (p 0.291, table). MSI: OS does not differ between MSI-H and MSI-S pts (HR 0.78 [0.40, 1.52], p 0.450). In MSI-H pts longer OS is observed in Bev arm vs. Cet arm (p 0.002); in MSI-S pts no difference is observed (p 0.305, table). ML: Hypermutated MSI-H pts are excluded. In a subset of 205 pts, pts with ML>5 (N=93) have longer OS than pts with ML≤5 (N=112) (HR 0.65 [0.42,1.00], p 0.048). In Bev arm higher ML confers longer OS than lower ML (HR 0.85 [0.80,0.96], p 0.004); in Cet arm no difference is observed (HR 0.99 [0.90,1.09], p 0.862). Conclusions: BRAF is a strong negative prognostic factor in mCRC, even when sidedness is taken into account. ML is a novel marker for further evaluation. The effect of Bev and Cet in either BRAF mut or MSI-H pts should be tested in larger datasets. Updated results from more screened samples will be presented. [Table: see text]
Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).
Authors: Kopetz Scott , McDonough Shannon L , Lenz Heinz-Josef , Magliocco Anthony Martin , Atreya Chloe Evelyn , Diaz Luis A. , Allegra Carmen Joseph , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Wang Stephen E. , Lieu Christopher Hanyoung , Guthrie Katherine A , Hochster Howard S. 
Published: September 2018

3505 Background: Metastatic colorectal cancer (mCRC) patients (pts) with BRAFV600 mutations have poor outcomes with standard of care chemotherapy and rarely respond to the BRAF inhibitor vemurafenib. In preclinical models, blockade of BRAFV600 by vemurafenib (V) causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab (C) with anti-tumor activity augmented by irinotecan (I). Methods: Pts with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Eligible pts had ECOG PS ≤1, and had received 1 or 2 prior regimens with no prior anti-EGFR agents. Randomization was stratified for prior irinotecan. Crossover from the control arm (IC) to the experimental arm (VIC) was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 pts were enrolled (99 eligible, 49 in the experimental arm) from 12/2014 to 4/2016, with median age 62 years, 59% female, and 39% with prior irinotecan therapy. PFS was improved with the addition of vemurafenib (HR 0.42, 95% confidence interval [CI] 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI 3.6 – 5.7) mos vs 2.0 (95% CI 1.8 – 2.1) months. Response rate was 16% vs 4% (P = 0.08), with disease control rate of 67% vs 22%. In pts with no prior irinotecan, median PFS was 5.7 (95% CI 3.0-6.1) months in the VIC arm vs 1.9 (95% CI 1.7 – 2.1) months in the IC arm. Grade 3/4 adverse events higher in the VIC arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. 23 pts (46%) in the IC arm crossed over at the time of progression, with median PFS from crossover of 6.0 months (95% CI 3.7 – 7.4). Overall survival (OS) data will be mature for ASCO 2017. Conclusions: These results demonstrate the clinical benefits of the VIC triplet (vemurafenib, cetuximab, and irinotecan) in pts with treatment-refractory BRAFV600 mutated mCRC, and support VIC as a potential new treatment option in this molecular subset. Clinical trial information: NCT02164916.
REsect: Blinded assessment of amenability to potentially curative treatment of previously unresectable colorectal cancer liver metastases (CRC LM) after chemotherapy ± RadioEmbolization (SIRT) in the randomized SIRFLOX trial.
Authors: Garlipp Benjamin , Gibbs Peter , Van Hazel Guy A. , Jeyarajah Rohan , Martin Robert C. G. , Bruns Christiane J. , Lang Hauke , Manas Derek M. , Ettorre Giuseppe Maria , Pardo Fernando , Donckier Vincent , Benckert Christoph , van Gulik Thomas M , Goere Diane , Schoen Michael , Pratschke Johann , Bechstein Wolf O. , Martínez de la Cuesta Antonio , Adeyemi Shola , Seidensticker Max 
Published: September 2018

3532 Background: Secondary resection and radiofrequency ablation (RFA) of primarily unresectable LM from CRC can prolong survival and cure some patients (pts). Effective downsizing treatments are needed but their impact on secondary amenability to surgery/RFA is difficult to evaluate objectively. The added value of SIRT is not well established. Methods: Baseline (BL) and follow-up (FU) imaging at best response for CRC pts treated with FOLFOX chemotherapy±bevacizumab (bev) (CT) vs. CT+SIRT in the phase III SIRFLOX RCT were reviewed by 3−5 expert HPB surgeons (from a panel of 15) for resectability of LM. Reviewers were blinded to each other and to all clinical information incl. time of imaging (BL/FU). Resectability was defined as ≥60% of reviewers assessing a pt as resectable. For non-resectable cases, surgeons indicated whether a combination of surgery and RFA could completely remove all LM. Lesions deemed suitable for RFA by a surgeon needed to be confirmed by an interventional radiologist. Pts were defined as “clearable” if ≥60% of reviewers assessed them as amenable to complete removal of LM by surgery alone or surgery+RFA. Results: 472 pts were evaluable (CT, n = 228; CT+SIRT, n = 244). There was no significant difference in LM resectability at BL (CT, n = 25, 10.96%; CT+SIRT, n = 29, 11.89%; p = 0.77). At FU, significantly more pts in the SIRT arm had resectable LM (CT, n = 66, 28.95%; CT+SIRT, n = 93, 38.11%; p < 0.0001). Of 203 pts in the CT arm and 215 pts in the CT+SIRT arm deemed unresectable at BL, 46 (22.66%) and 67 (31.16%), respectively, were converted to resectability (p < 0.0001). Assessing “clearability” using surgery and RFA, again no difference was noted at BL (CT, n = 31, 13.60%; CT+SIRT, n = 42, 17.21%; p = 0.309). At FU, a trend in favor of CT+SIRT was seen (CT, n = 79, 34.65%; CT+SIRT, n = 102, 41.80%; p = 0.1296). Conclusions: The addition of SIRT to FOLFOX(±bev) based CT significantly increased the gain in resectability of primarily unresectable CRC LM compared with CT alone. For amenability to the combination of surgery+RFA, this effect was still seen, albeit attenuated. Subgroup analyses are ongoing. Clinical trial information: NCT00724503.
Hand-foot skin reaction (HFSR) and outcomes in the phase 3 CORRECT trial of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Grothey Axel , Huang Liping , Wagner Andrea , Van Cutsem Eric 
Published: September 2018

3551 Background: Cutaneous toxicity is a known adverse effect of multikinase inhibitors and has been associated with clinical outcomes (Granito 2016). In the phase 3 CORRECT trial (NCT01103323), the multikinase inhibitor regorafenib significantly improved overall survival (OS) vs placebo in patients with mCRC (hazard ratio [HR] 0.77, 95% CI 0.64, 0.94; 1-sided P = 0.0052). This retrospective analysis explored whether HFSR was associated with outcomes in CORRECT. Methods: Patients randomized to receive regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS and progression-free survival (PFS) (95% CI) were calculated using the Kaplan–Meier method. Patients who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of the 505 randomized patients, 500 received at least one dose of regorafenib. Among the treated patients, 47% (n = 235) had HFSR of any grade and 17% (n = 83) had HFSR grade 3. Of the patients who had HFSR, 69% (n = 162) had their first HFSR event (any grade) during the first treatment cycle. There was some imbalance in baseline characteristics between groups (Table). Survival was improved in patients who had HFSR at any time vs those who did not (Table). The OS benefit was also observed in patients who had the first HFSR event during Cycle 1 vs those who did not (median OS 7.2 vs 5.7 months; HR 0.66, 95% CI 0.51, 0.87). Conclusions: This post-hoc exploratory analysis suggests that patients who had HFSR had a greater treatment benefit from regorafenib. Since HFSR and survival are post-baseline assessments, results may be confounded by baseline factors or other unknown factors. Clinical trial information: NCT01103323. [Table: see text]