bluuebunny/crossref_metadata_2025_split huggingface dataset:
Up-regulation of stromal cell-derived factor by il-17 and il-18 via PI3K dependent pathway.
Authors: Ahn Inhye , Ju Ji Hyeon 
Published: March 2020

3046 Background: Stromal cell-derived factor-1 (SDF-1) is a versatile chemotactic cytokine and a sole ligand of CXCR4. SDF-1-CXCR4 axis is the most commonly expressed pathway in cancer cells, and is also responsible for metastasis, homing of stem cell, HIV infection, and autoimmune diseases. Interleukin (IL)-17 plays a key role in the pathogenesis of inflammation by inducing SDF-1 to propagate inflammation and vascular endothelial growth factor to provoke angiogenesis. Recent studies revealed that IL-17 pathway is interwoven with multiple cytokines and downstream pathways. Members of the IL-1β family, including IL-18, have recently gained attention. By measuring SDF-1 production regulated by individual and simultaneous cytokine stimulations, two cytokines were explored to define their effects, their downstream signal transduction pathways, and the impact of their antibodies. Methods: Synovial tissue was obtained from patients with rheumatoid arthritis and their age- and sex-matched controls with osteoarthritis. Fibroblast-like synoviocytes (FLS) were isolated and stimulated with a combination of IL-17 and IL-18 and quantified SDF-1 production with ELISA and their transcripts with RT-PCR. Another subset of FLS were preconditioned with PI3K inhibitor, 100 nM wortmannin, and stimulated with either 5 ng/mL of IL-17, 10 ng/mL of IL-18, or combination of both cytokines. Mann-Whitney test was adopted for statistical analysis. Results: Both IL-17 and IL-18 increased SDF-1 level and its mRNA transcript, not only individually but also synergistically (p <0.05). In the group where PI3K inihibitor was applied, the individual and synergistic promotion of SDF-1 production by IL-17 and IL-18 were inhibited (p<0.05). Concomitant application of anti-IL-17 and anti-IL-18 led to further decline of SDF-1 production (p<0.01). Conclusions: This is the first report of PI3K-dependent synergism between IL-18 and IL-17, and adds a novel perspective of the role of IL-18 in immune regulation. The individual effects of these two cytokines, and their interaction through PI3K, suggest an interrelationship between the IL-1 family and IL-17.
An Fc-optimized NKG2D-Ig fusion protein for induction of NK cell reactivity against breast cancer.
Authors: Steinbacher Julia , Raab Stefanie , Grosse-Hovest Ludger , Schmiedel Benjamin Joachim , Steinle Alexander , Kanz Lothar , Salih Helmut Rainer 
Published: March 2020

3054 Background: The anti-tumor activity and clinical success of the monoclonal antibody trastuzumab, approved for treatment of HER2/neu-overexpressing breast cancer, is at least partially mediated by induction of antibody dependent cellular cytotoxicity (ADCC). However, only about 20% of patients show HER2/neu overexpression, and trastuzumab treatment is associated with side effects. The ligands of the activating immunoreceptor NKG2D (NKG2DL) are widely expressed on malignant cells, but generally absent on healthy tissue. We aimed to take advantage of this tumor-restricted expression by using NKG2DL as target-antigens on breast cancer cells. To this end we generated NKG2D-Ig fusion proteins with modified Fc moieties and studied their ability to induce NK cell anti-tumor reactivity. Methods: The Fc parts within the constructs were modified by amino acid exchange as previously described (Lazar 2006; Armour 1999). Direct effects on tumor cell viability as well as induction of NK cell activation, degranulation, cytotoxicity and IFN-γ release in cultures with breast cancer cell lines expressing different HER2/neu levels were determined. Results: Compared to NKG2D-Fc containing a wildtype Fc part (NKG2D-Fc-WT) or trastuzumab, our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. In contrast to trastuzumab, no direct effect of the constructs on tumor cell viability was observed. In cultures of NK cells and breast cancer cells, NKG2D-Fc-KO significantly reduced NK reactivity due to blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT substantially enhanced NK reactivity by induction of ADCC, while the effects of NKG2D-Fc-ADCC by far exceeded that of NKG2D-Fc-WT and, in case of HER2/neu-low targets also that of Herceptin. Conclusions: Fc-engineered NKG2D-Ig fusion protein effectively target breast cancer cells for NK anti-tumor reactivity. Due to the tumor-restricted expression of NKG2DL, NKG2D-Fc-ADCC may constitute an attractive means for immunotherapy especially of HER2/neu-low or -negative breast cancer.
A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic (P) and colorectal (CR) cancers.
Authors: Morse Michael , Patel Sandip Pravin , Beatson Melony A. , Arlen Philip M. 
Published: March 2020

3070 Background: NPC-1C is a chimeric mab developed to treat P and CR cancers. This mab was selected from a panel of hybridomas derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC expressed specifically by human P and CR tumors with minimal cross-reactivity to normal GI mucosa. Methods: A phase IIa study with NPC-1C is enrolling patients (pts) with advanced P and CR cancer refractory to standard therapy. Primary objectives are to measure efficacy by analysis of CT scans pre- and post-therapy, clinical lab tests, and physical examinations. Secondary objectives are to determine safety, pharmacokinetics (PK), and select immune responses to the mab. Analyses of pts peripheral blood mononuclear cells (PBMCs) for antibody-dependent cell-mediated cytotoxicity (ADCC) and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome and correlation with clinical benefit. Results: Pts received 1.5 mg/kg IV of NPC-1C every two weeks. 10 subjects (8 colorectal, 2 pancreatic) have enrolled on study (2/10 non-evaluable). Treatment was well tolerated with grade 1 and 2 constitutional symptoms noted. Coombs positivity was reported in 4/8 pts shortly after the infusions, but only grade 1 hemolysis was reported (in 2/8 patients). There was 1 episode of each of the following grade 3 AE’s: weakness, increased bilirubin, and abdominal pain, possibly related to NPC-1C. 5 of 19 pts treated in this and the phase Ia study demonstrated stable disease (SD) on scans after completing the first course of treatment (4 doses). Conclusions: Preliminary results with NPC-1C show signs of clinical activity based on SD in heavily pretreated pts with P and CR cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy. Clinical trial information: NCT01040000.
A randomized phase II/III study of naptumomab estafenatox plus IFN-α versus IFN-α in advanced renal cell carcinoma.
Authors: Hawkins Robert E. , Gore Martin Eric , Shparyk Yaroslav , Bondar Vladimir , Gladkov Oleg , Ganev Tosho , Harza Mihai , Polenkov Serhii , Bondarenko Igor , Karlov Petr A , Karyakin Oleg , Khasanov Rustem , Hedlund Gunnar Eric , Forsberg Goran , Nordle Orjan , Eisen Tim 
Published: March 2020

3073 Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap + IFN-α (A) vs IFN-α (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (<7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-α improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. [Table: see text]
High hydrostatic pressure to induce immunogenic cell death in human tumor cells.
Authors: Truxova Iva , Fucikova Jitka , Moserova Irena , Partlova Simona , Bartunkova Jirina , Spisek Radek 
Published: March 2020

3076 Background: Recent studies have identified molecular events characteristic of immunogenic cell death. These include surface exposure of calreticulin, HSP70 and HSP90, release of intranuclear HMGB1 and secretion of ATP from dying cells. Several chemotherapeutic agents, including anthracyclins, oxaliplatin and bortezomib, and hypericin-based photodynamic therapy have been described to induce the immunogenic cell death in human tumor cells. We investigated the potential of high hydrostatic pressure (HHP) to induce immunogenic cell death in human tumor cells. Methods: Prostate and ovarian cancer cell lines and primary tumor cells were treated by HHP and we analyzed the kinetics of the expression of immunogenic cell death markers. HHP killed tumor cells expressing immunogenic cell death markers were tested for their ability to activate dendritic cells (DCs), to induce tumor specific T cells and regulatory T cells. Results: HHP induced rapid expression of HSP70, HSP90 and calreticulin on the cell surface of all tested cell lines and primary tumor cells. HHP also induced release of HMGB1 and ATP from treated cells. The kinetics of expression was similar to doxorubicin, HHP, however, induced 1.5-2 fold higher expression of HSP70, HSP90 and calreticulin. The interaction of DCs with HHP-treated tumor cells led to the faster rate of phagocytosis, significant upregulation of CD83, CD86 and HLA-DR and release of IL-6, IL-12p70 and TNFα. The ability of HHP-killed tumor cells to promote DCs maturation was cell contact dependent. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific CD4+ and CD8+IFN-g-producing T cells even in the absence of additional maturation stimulus. DCs pulsed with HHP treated tumor cells also induced the lowest number of regulatory T cells among the tested conditions. Cells treated by HHP can by cryopreserved in liquid nitrogen and retain their immunogenic properties upon thawing thus allowing for their convenient use in the manufacturing of cancer immunotherapy products. Conclusions: High hydrostatic pressure is a reliable and very potent inducer of immunogenic cell death in the wide range of human tumor cell lines and primary tumor cells.
A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine in combination with CCL21 in stage IV lung adenocarcinoma: Preliminary results.
Authors: Gray Jhanelle Elaine , Chiappori Alberto , Williams Charles C. , Pinder Mary Colleen , Haura Eric B. , Kim Jongphil , Gonzalez Germaine , Noyes David , Antonia Scott J. 
Published: March 2020

3091 Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immune-related response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p=0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.
Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study.
Authors: Anastasopoulou Eleftheria A , Pappou Efi , Tzonis Panagiotis , Ardavanis Alexandros , Ponniah Sathibalan , Baxevanis Constantin N. , Murray James L. , Papamichail Michael , Perez Sonia A. , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

3095 Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS). Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH > 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays. Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p<0.0001). The number of IFN-γ specific spots/106 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated. Clinical trial information: NCT00524277.
Activity of PU-H71, a novel HSP90 inhibitor, and bortezomib in Ewing sarcoma preclinical models.
Authors: Ambati Srikanth R. , Caldas Lopes Eloisi , Kosugi Kohji , Mony Ullas , Zehir Ahmet , Moreira Andre L. , Meyers Paul A. , Chiosis Gabriela , Moore Malcolm A.S. 
Published: March 2020

3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezomib and in combination. Results: In vitro, PU-H71 and bortezomib treatment resulted in caspase mediated cell death in a dose-dependent and time-dependent manner. Using PU-H71 beads we showed that some of the critical proteins, including IGF1R, hTERT and EWS-FLI1, are stabilized by HSP90. Exposure to PU-H71 resulted in depletion of AKT, ERK, MYC, C-kit, IGF1R and EWS-FLI1. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. We noted increased expression of cleaved PARP and cleaved caspase 3 when Ewing cell lines were exposed to a combination of PU-H71 and bortezomib. Based on PK studies we treated mice (4 groups) using vehicle, PU-H71 75mg/kg i.p three times/wk, bortezomib 0.8mg/kg i.v twice/wk or a combination of PU-H71 and bortezomib for 4 wk. Ewing xenografts were significantly inhibited when treated with combination of PU-H71 and bortezomib compared to vehicle or either drug alone. Conclusions: Both PU-H71 and bortezomib have single agent activity against Ewing sarcoma. However they exhibit synergism when combined in in vitro and in vivo models providing a strong rationale for clinical evaluation in Ewing sarcoma.
Effect of 3-5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial.
Authors: Mant David , Perera Rafael , Gray Alastair , Rose Peter , Fuller Alice , Corkhill Andrea , George Steve , Little Louisa , Regan Scott , Mellor Jane , Pugh Sian Alexandra , Northover John , Weaver Andrew , Barsoum Gamal , Tan Li Tee , Mortensen Neil , Scholefield John , Wasan Harpreet , Ferry David , Primrose John Neil 
Published: March 2020

3500 Background: Intensive long-term follow-up after surgery for colorectal cancer is common practice but neither the actual benefit nor the optimal methodology is known. Methods: Pragmatic factorial randomised controlled trial in 39 UK hospitals, comparing minimum follow-up (which included a single CT scan at 12-18 months) with 3-6 monthly blood carcinoembryonic antigen (CEA) testing and 6-12 monthly computerised tomography (CT) imaging of the chest, abdomen and pelvis following 1202 participants for 3-5 (mean 3.7) years. Results: The proportion of participants with recurrence treated surgically with curative intent was lower than predicted (6.0% overall) but was about 3x higher in the more intensive than minimum follow-up arms (p=0.019). The adjusted odds were 2.7 for CEA only (p=0.035) and 3.4 for CT only (p=0.007); the absolute differences in detection rate in the more intensive arms compared to minimum follow-up were 4.3-5.7% (5.8-8.0% per protocol). Combining CEA and CT provided no additional benefit (adjusted odds for CT+CEA arm = 2.9). The absolute difference in the proportion of participants with recurrence treated surgically with curative intent in the factorial comparison was 1.4% for CEA (p=0.28) and 2.8% for CT (p=0.04). There was no statistical difference in colorectal cancer deaths nor overall deaths in the minimum compared to the intensive follow-up arms. Conclusions: Both regular CEA measurement and CT scanning result in significantly higher rates of diagnosis of operable recurrent colorectal cancer compared to minimal follow up. There is no benefit in monitoring with both CEA and CT. To date no difference in the overall mortality has been demonstrated. CEA monitoring combined with a single CT scan at 12-18 months seems likely to be cost effective. Clinical trial information: 41458548.
Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer.
Authors: Saunders Mark P. , Lang Istvan , Marcuello Eugenio , Lorusso Vito , Ocvirk Janja , Shin Dongbok , Jonker Derek J. , Osborne Stuart , Loeffler Markus , Waterkamp Daniel , Cunningham David 
Published: March 2020

3521 Background: Elderly patients (pts) are underrepresented in clinical trials. The open-label phase III trial AVEX evaluated the benefit of adding bevacizumab (BEV) to capecitabine (cape) in elderly pts with previously untreated metastatic colorectal cancer (mCRC). This analysis explores clinical outcomes by age subgroup. Methods: In AVEX, 280 pts ≥70 y with mCRC for whom single-agent chemotherapy was deemed appropriate, were randomized to first-line cape (1000 mg/m2bid days 1–14) alone (n=140) or with BEV (7.5 mg/kg) q3w (n=140). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate, and safety. The study was powered to show a difference in PFS but not OS. A post hoc analysis was conducted to assess PFS, OS, and safety in pts 70–74 y, 75–79 y, and ≥80 y. Results: Median age was 76 y (range, 70–87). In the overall population, BEV + cape significantly prolonged PFS compared with cape (median 9.1 vs 5.1 mo; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<.001). Differences in OS did not reach statistical significance in the overall population (HR, 0.79; 95% CI, 0.57–1.09; p=.182). Treatment was well tolerated. Results according to age are shown (Table). Conclusions: The addition of BEV to cape was associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups. The safety profile of BEV + cape was consistent across age groups. Clinical trial information: NCT00484939. [Table: see text]