bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immunomodulatory activity of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
Authors: Loges Sonja , Gjertsen Björn Tore , Heuser Michael , Chromik Jörg , Vigil Carlos Enrique , Paschka Peter , Ben-Batalla I , Akyüz Nuray , Micklem David , Brown Anthony , Lorens James , Kebenko Maxim , Janning Melanie , Binder Mascha , Fiedler Walter M. , Cortes Jorge E. 
Published: February 2018

70 Background: The tyrosine kinase AXL acts as suppressive immune checkpoint of the innate immune system. AXL signalling leads to immunosuppression and tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. Therefore it represents an interesting novel immune oncology target. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models, inhibition of AXL signalling with bemcentinib reversed multiple established immune suppressive mechanisms leading to increased infiltration of CTLs, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). We explored safety, PK, efficacy and the effects of treatment with bemcentinib on the T- and B cell repertoire in patients with relapsed AML or MDS. Methods: BGBC003 (NCT02488408) is an open-label, dose finding study of bemcentinib in patients with R/R AML or MDS. Three dose levels have been explored and a loading dose of 400 mg on days one to three followed by 200 mg daily thereafter has been established as safe and recommended phase 2 dose. The TCRß repertoire was quantified by NGS of DNA isolated from PBMNCs using an Illumina MiSeq sequencer. TCRß genes and the IGH repertoire were analysed with BIOMED2-TCRß-A and –B and BIOMED2-FR1/-FR3 primer pools, respectively. Using genomic DNA as template, the amplicons were tagged with Illumina adapters and indices in two consecutive PCR reactions. Demultiplexing and FastQ formated data output was generated by the MiSeq reporter. Analysis of TCRß and IGH data was performed on a Microsoft Cloud using our in-house analysis pipeline Pippa. Results: Early evidence of antileukemic activity was seen. Diversification of the TCR and IGH repertoire could be detected in peripheral blood at day 21 of therapy compared to pre-treatment in three and two out of five matched samples, respectively. Conclusions: Bemcentinib shows preliminary evidence of immune modulation in AML. Clinical trial information: NCT02488408.
Correlation of IL-17 with immune suppression involving MDSC, malnutrition, and prognosis in patients with gastric and colorectal cancer.
Authors: Gonda Kenji , Shibata Masahiko , Ujiie Daisuke , Ashizawa Mai , Kikuchi Tomohiro , Okayama Hirokazu , Fujita Shoutarou , Sakamoto Wataru , Nakajima Takahiro , Endo Hisahito , Saito Motonobu , Monma Tomoyuki , Saze Zenichiro , Ohki Shinji , Kono Koji , Takenoshita Seiichi 
Published: February 2018

83 Background: Although a causal relationship linking inflammation and cancer immunity is more widely accepted today, precise cell mechanisms mediating this relationship have not been elucidated. IL-17, a pro-inflammatory cytokine primarily secreted by T helper (Th)17 cells, has previously been associated with inflammatory processes in autoimmune disease. The presence of IL-17 and Th17 cells has been confirmed in various invasive cancers and recently linked to immunosuppression in cancer patients. We investigated systemic inflammation, immune suppression, malnutrition, and prognosis associated with IL-17 in patients with gastric and colorectal cancer. Methods: We measured IL-17 in 106 patients, including 43 with gastric and 63 with colorectal cancer, Production of IL-17 stimulated by PHA was measured by ELISA. MDSC (myeloid-derived suppressor cells), which significantly contribute to immunosuppression, were measured by flow cytometry (CD11b+CD14-CD33+). Neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were used as inflammatory markers. Production of IL-12 and the SI (stimulation index) of lymphocytes’ blastogenic response were used as markers of cell-mediated immune response. Results: Production of IL-17 increased in advanced stages of gastric and colorectal cancer. IL-17 positively correlated with levels of MDSC, serum concentrations of VEGF, NLR, and levels of CRP, and was inversely correlated with IL-12 production, SI, and nutritional markers including prealbumin and retinol binding protein. Patient cohorts were divided into two groups with IL-17 level (540 pg/ml) and OS (overall survival) of patients with stages III and IV gastric or colorectal cancer both significantly worse in patients with high production of IL-17 than in those with low IL-17, although the differences were not significant in patients at stages I and II. Conclusions: The present study suggests that IL-17 may reflect an inflammatory impact on the advancement and progression of cancer, and it may serve as useful marker of immune suppression involving MDSC, malnutrition, and poor prognosis in patients with gastric and colorectal cancer.
Frequency and prognostic role of tumor infiltrating lymphocytes and MMR status in advanced non-colorectal GI malignancies.
Authors: Khan Uqba , Hamza Ameer , Abraham Renny , Khurram Muhammad S , Hadid Tarik H. , Mazzara Paul , Kafri Zyad 
Published: February 2018

89 Background: Tumor infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with respect to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable non-colorectal GI (NCGI) cancers. Methods: This is a retrospective cohort study of patients who were diagnosed with metastatic or unresectable NCGI cancers between 2009 and 2015 at St. John Hospital and Medical Center. Immunohistochemistry panels were performed on representative tissue sections for MMR testing. TILs were assessed on the hematoxylin and eosin stained slide of the same tissue section. MMR was interpreted as deficient (d) or proficient and TILs were categorized as ≤5 or > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 132 patients; the mean age at diagnosis was 66.7 years, 62.1% were male. All samples had proficient MMR status. The percentage of patients with TILs ≤ 5 was 46.2. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031), table 1. Conclusions: Our study suggests that MMR-d tumors are quite rare in advanced NCGI malignancies. TILs can be present in tumor microenvironment of NCGI malignancies. Though the number of patients in our study was small, there was a statistically significant difference in median OS of patients with HCC when stratified by TILs status.[Table: see text]
Quantitative comparison of PD-L1 immuno-histochemical assays in hepatocellular carcinoma: The Blueprint-HCC study.
Authors: Pinato David James , Mauri Francesco A , Spina Paolo , Cain Owen , Siddique Abdul , Goldin Robert D , Victor Stephane , Pizio Corinna , Akarca Ayse , Boldorini Renzo , Mazzucchelli Luca , Black James M , Shetty Shishir , Marafioti Teresa , Sharma Rohini 
Published: February 2018

91 Background: Programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) enriches for responses to PD-1/PD-L1 inhibitors, however its role as a predictive biomarker in hepatocellular carcinoma (HCC) is inconclusive, with no consensus on any particular assay. We evaluated the performance of 4 different PD-L1 detection assays previously published in landmark clinical studies. Methods: PD-L1 IHC was performed on 4 serial sections from tissue microarray (TMA) blocks containing 100 archival cases of HCC that included tumour and surrounding non-tumorous tissue. Antibody clones E1LN3, 28-8, 22c3, SP263 were compared on the basis of percentage and intensity of staining in malignant cells (M) to generate an H-score (range 0-300). Immune cells infiltrating (ICI) and at the periphery, in non-tumorous tissue (ICP) were scored on a 4-tier system (0-3). Results: Patients were 76% males, 20% HCV-positive, 64% cirrhotic with a median age of 67 years. Median tumour size was 4 cm, 70% of patients had T1-T2 tumours and 48% were of grade 2. The proportion of PD-L1 positive cases according to M-ICI-ICP pattern was 2-6-2% for E1LN3, 10-18-19% for 28-8, 9-22-18% for 22c3 and 5-14-13% for SP263. Pairwise comparison of M H-scores revealed heterogeneity across antibodies, with highest concordance between E1L3N/SP263 (R2 = 0.95), E1L3N/22c3 (R2 = 0.65), 22c3/SP263 (R2 = 0.66) and increasing discordance for 28-8/22c3 (R2 = 0.44), E1L3N/28-8 (R2 = 0.29), and 28-8/SP263 (R2 = 0.26). Detection of PD-L1-positive immune infiltrates using a semi-quantitative scoring system revealed significantly different scores in pairwise non-parametric comparisons of ICI (p < 0.05) but not ICP (p > 0.05 for chi-square test). Conclusions: In the Blueprint-HCC study we demonstrated that quantification of PD-L1 protein levels in tumour cells, intra-tumoural and peri-tumoural infiltrate is characterised by inter-assay discordance in HCC. This has profound implications in the clinical development of predictive correlates of efficacy to immunotherapy in HCC. Sources of such discordance should be explored.
Preclinical development of tumor-infiltrating lymphocyte therapy for metastatic colorectal cancer.
Authors: Sakellariou-Thompson Donastas , Forget Marie-Andree , Roszik Jason , Jackson Kyle R , Kim Young Uk , Crosby Shadarra , Hurd Mark W , Wu Ji , Jiang Zhi-Qin , Hwu Patrick , Lizee Gregory , Menter David , Kopetz Scott , Overman Michael J. , Haymaker Cara L. , Bernatchez Chantale 
Published: February 2018

95 Background: Immunotherapy has become an effective cancer therapy, particularly in the case of checkpoint blockade and adoptive T-cell therapy (ACT). ACT exploits the presence of tumor-infiltrating lymphocytes (TIL) by exponentially expanding their numbers ex vivo and re-infusing them into the patient in an autologous setting. With the effectiveness of TIL therapy already well established in multiple phase II studies in melanoma, there is a push to translate it to other cancers in need of improved therapies. Colorectal cancer (CRC) is a cancer where the presence of TIL has been strongly correlated with increased survival. Metastatic CRC (mCRC) has a poor outcome with median overall survival of less than 3 years. At present anti-PD1 therapy is only active in the small subset of mCRC patients (4%) that are MSI-high. We sought to evaluate the ability to generate and characterize TIL from patients with mCRC to provide a rationale for future TIL therapy in this disease. Methods: To assess the feasibility of utilizing TIL ACT for this patient population, we characterized the immune infiltrate of mCRC, TIL growth from tumor fragments (n = 24), as well as the TIL repertoire (n = 4) and anti-tumor potential in samples with available autologous tumor target. Results: Flow cytometry analysis detected a CD4-rich T-cell infiltration at the tumor site as well as a scarce yet activated CD8+ TIL population. The outgrowth of CD8+ TIL from tumor fragments in media containing IL-2 was potentiated by the addition of an agonistic 4-1BB antibody (Urelumab, BMS). Additionally, the use of a 4-1BB mAb improved the likelihood of growing TIL (63% [14/24] to 83% [20/24]) and increased the total yield of TIL grown. T-cell receptor sequencing showed enrichment in the tumor of CD8+ T-cell clones shared between the blood and tumor, suggesting selective expansion at the tumor site. Using IFNγ ELISPOT, CD8+ TIL from one patient with an MSS tumor were found to be reactive against a peptide derived from mutated TP53R116W restricted to HLA-B*39:01. Conclusions: It is possible to expand CD8+ T cells from microsatellite stable (MSS) mCRC that are able to target tumor antigens. Although preliminary, the initial data suggest the feasibility of TIL therapy for mCRC.
MDSC clinical assay for cancer detection and monitoring in urothelial carcinoma.
Authors: Basu Arnab , Rafatnia Ali , Manoli Hugh , Danenberg Genevieve , Epstein Alan L. , Pinski Jacek K. 
Published: February 2018

TPS110 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in urothelial carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with or without localized or metastatic bladder cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized muscle invasive disease prior to cystectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized, muscle-invasive bladder cancer who undergo neoadjuvant and surgical treatment. 2. Change in MDSC level in patients with known metastatic bladder cancer who undergo systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02735512.
A phase II trial of consolidation nivolumab or nivolumab plus ipilimumab following concurrent chemoradiation in unresectable stage III NSCLC: BTCRC LUN16-081.
Authors: Durm Greg Andrew , Perkins Susan M. , Hanna Nasser H. 
Published: February 2018

TPS179 Background: Unresectable stage III NSCLC demonstrates poor 5-yr OS outcomes. The current standard of care for fit patients in this setting is concurrent chemoradiation. Previous studies evaluating the addition of induction or consolidation chemotherapy, EGFR-targeted agents, ant-angiogenic agents, and higher doses of radiation have failed to definitively improve OS over chemoradiation alone. Recently, a trial of consolidation PD-L1 inhibition demonstrated improved PFS over chemoradiation alone, and a second trial of consolidation PD-1 inhibition is awaiting data maturation. This may herald a change to the standard of care in this setting. The addition of CTLA-4 inhibition to anti-PD-1 monoclonal antibodies has shown improved OS in melanoma and has demonstrated encouraging early phase data in stage IV NSCLC. Therefore, we initiated a trial evaluating the addition of a CTLA-4 inhibitor to PD-1 inhibition for consolidation treatment of unresectable stage III NSCLC. Methods: This is a multi-center, randomized, phase II study of nivolumab or the combination of nivolumab and ipilimumab as consolidation therapy following concurrent chemoradiation in unresectable stage III NSCLC. Patients will receive concurrent chemoradiation with one of three standard chemotherapy backbones (Cis-Etop, Cis-Pem, or Carbo-Pac), and repeat imaging will be done 4-8 weeks following completion of therapy. Patients without progressive disease will be randomized 1:1 to receive either niv 480mg IV every 4 weeks or the combination of niv 3mg/kg IV every 2 weeks and ipi 1mg/kg IV every 6 weeks for up to 6 months. The trial will enroll a total of 108 patients with 54 in each arm. The two arms are non-comparator arms and will be compared with historical controls. The primary endpoint is the improvement of PFS at 18 months, and key secondary endpoints include OS and the toxicity of consolidation niv and niv/ipi. Exploratory endpoints will look at the correlation between multiple clinical, radiographic, and laboratory parameters and outcomes, as well as the association of these parameters with the development of pneumonitis. This trial opened to accrual in September 2017. Clinical trial information: NCT03285321.
KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC).
Authors: Cortés Javier , Guo Zifang , Karantza Vassiliki , Aktan Gursel 
Published: February 2018

TPS18 Background: In the phase Ib KEYNOTE-012 study, the anti–PD-1 antibody pembro demonstrated promising antitumor activity and acceptable safety as monotherapy in pretreated patients (pts) with PD-L1+ mTNBC. Adding pembro to chemo may enhance antitumor activity. KEYNOTE-355 (NCT02819518) is a global phase III study of pembro+chemo vs PBO+chemo in pts with previously untreated, locally recurrent, inoperable TNBC/mTNBC. Methods: Eligible pts are ≥18 y and have centrally confirmed, locally recurrent, inoperable TNBC or mTNBC not previously treated with chemo (prior chemo in [neo]adjuvant setting is allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; ≥6 mo between definitive surgery or last dose of adjuvant chemo, whichever was last; and first disease recurrence (≥12 mo if prior treatment with same-class agent). Part 1 is an open-label, unblinded safety run-in of ~30 pts in 3 arms (pembro+nab-paclitaxel, pembro+paclitaxel, pembro+gemcitabine/carboplatin). Part 2 is a double-blind, PBO-controlled study of ~828 pts randomized 2:1 to pembro 200 mg every 3 weeks + chemo (nab-paclitaxel 100 mg/m2 on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m2 on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m2+ carboplatin AUC 2 on d 1 and 8 every 21 d) or PBO+chemo. Crossover is not allowed. Stratification factors are study chemo (taxane vs gemcitabine/carboplatin), tumor PD-L1 expression (+/-), and prior therapy with same-class agent in the (neo)adjuvant setting (yes/no). Treatment will occur for ≤35 administrations (pembro/PBO only) or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or decision to discontinue. Primary end points are safety in part 1 and PFS (by RECIST v1.1, central radiology review) and OS in part 2; secondary end points include ORR (by RECIST v1.1, central radiology review) and duration of response. AEs will be graded per NCI CTCAE v4.0. Response will be assessed at wk 8, 16, 24, then at 9-wk intervals up to 1 y, and at 12-wk intervals thereafter. Interim safety analysis will occur after pts complete 1 treatment cycle in part 1. Clinical trial information: NCT02819518.
Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer.
Authors: Dillon Patrick Michael , Horton Bethany J , Bullock Timothy , Brenin Christiana , Brenin David R. 
Published: February 2018

TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.