bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD205, a target antigen for a novel antibody drug conjugate (ADC): Evaluation of antigen expression on non-Hodgkin lymphoma (NHL).
Authors: Canzonieri Vincenzo , Gattei Valter , Spina Michele , Polizzi-Anselmo Annalisa , Attanasio Nickolas , Kaplan Angelo , Bigioni Mario , Merlino Giuseppe , Matera Mariagiuseppa , Manunta Silvia , Dusek Rachel , Rohlff Christian , Fedi Valentina , Binaschi Monica , Pellacani Andrea Ugo Enrico , Simonelli Cecilia 
Published: September 2018

e14039 Background: CD205 is a type I C-type lectin receptor normally expressed on various APC and some leukocyte sub-populations, characterized by a cytoplasmic domain containing protein motifs crucial for endocytosis and internalization. These features make CD205 ideal to be exploited as target of a novel ADC. MEN1309/OBT076 is a humanized IgG1 antibody against CD205, conjugated through a cleavable linker to a potent maytansinoid microtubule disruptor, DM4. Indeed, impressive results were obtained in high and low CD205 expressing xenografts for solid tumours and NHL. In vitro experimental model describing the by-stander effect of MEN1309 was implemented. Methods:A retrospective analysis to evaluate the CD205 expression on archival NHL biopsies was performed in the CRO-National Cancer Institute, Aviano IT. An immunohistochemistry (IHC) was performed on 1 slide per case, using a commercial antibody NCL-L-DEC205 (clone 11A10, Leica Biosystems). All slides were visually evaluated and a validated staining scoring system was applied, ranging from negative score 0 to strong immunostaining score 3+. Percentages (from 0 to 100%) of negative and positive tumor cells (scored as follows: 1-25% = score 1; 26-50% = score 2; 51-75% = score 3; 76-100% = score 4) were reported for each individual slide.Evaluation of correlations between CD205 expression and clinical characteristics is ongoing. Results: 100 cases of Diffuse Large B Cells Lymphomas (DLBCL) and 33 of Follicular Lymphomas (FL) were analysed. 60% of DLBCL cases were positive for CD205 and 39% had more than 25% of positive cells (score ≥2), while the 16% showed 2+/3+ staining intensity. 79% of FL cases were CD205 positive and 66% had more than 25% of positive cells, while the 27% showed 2+/3+ staining intensity. Conclusions: CD205 is heterogeneously expressed in the majority of DLBCL and FL cases. Data on the correlation between CD205 expression and clinical features will be discussed.MEN1309 has shown anti-tumour activity in vitro and in vivo even in low antigen expressing tumours. Hence CD205 expression among NHL, even if heterogeneous, makes, both DLBCL and FL, promising settings in which to explore MEN1309 activity in an upcoming FIH trial.
Some characteristics of invasive candidiasis pathogens.
Authors: Kutsevalova Olga Yu. , Kit Oleg Ivanovich , Panova Natalia I. , Lysenko Irina B. , Dmitrieva Viktoria V. , Rozenko Dmitry , Gevorkyan Yuri , Legostaev Vladislav , Shatokhina Olga N. , Pak Elena E. , Nikolaeva Nadezhda V. , Kozel Yuliya Yu. , Kuznetsov Sergei A. , Kozyuk Olga V. , Kapuza Elena A. , Mkrtchyan Gulnara A. , Bespalova Aleksandra I. , Starzhetskaya Maria V. , Kovalenko Vera A. , Shashkina Larisa Yu. 
Published: September 2018

e14084 Background: The purpose of the study was to determine the etiology of invasive candidiasis (IC) and investigate in vitro activity of caspofungin and azoles for blood isolates of Candida fungi. Methods: We performed a multidisciplinary prospective study of isolates of patients with clinical signs of IC obtained in intensive care units (ICU), oncohematology and oncology departments of hospitals in Rostov-on-Don and Rostov region in 2012-2015. Candida fungi were identified using MALDI-TOF MS; interpretation was performed according to CLSI 2012, M27-S4 criteria. Sensitivity testing was performed using the Sensititre system (Trek Diagnostic Systems, England). Results: 92 Candida isolates were obtained from blood culture: C.albicans - 31.5% (29) and non-albicans - 68.5% (63), including C.tropicalis 30.2% (19), C.parapsilosis 28.6% (18), C.glabrata 19.0% (12), C.krusei 15.9% (10) and C.guilliermondii 6.3% (4). C. albicans were found mostly in oncological departments (44%) compared with ICU – 30% (р=0.003) and departments of oncohematology – 26%. The table demonstrates comparative activities of caspofungin, fluconasole and voriconasole (susceptible – S, intermediate – I, resistant – R) in % to Candida spp. Conclusions: Candida non albicans prevailed among IC pathogens (68.5%), which could be associated with the use of azole antifungal agents for prophylaxis and empirical therapy. Dominating isolates showed decreased activity to caspofungin and azoles. Acquired resistance to azoles was noted for C. parapsilosis and C. albicans. All cases of invasive candidiasis require susceptibility testing for caspofungin and azoles before starting therapy with these agents. [Table: see text]
Pharmacodynamic phase I study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel.
Authors: Harmon Gil Edward , Rampurwala Murtuza M. , Scarpelli Matt , Eickhoff Jens C. , Carmichael Lakeesha , Kolesar Jill , Binger Kimberly , Heideman Jennifer , Perlman Scott , Liang Chris , Dukart Gary , Jeraj Robert , Liu Glenn , Bruce Justine Yang 
Published: September 2018

e14088 Background: Increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy, known as withdrawal flare, which has been demonstrated using [18-F] fluorothymidine [FLT] PET/CT . Sequencing chemotherapy may increase therapeutic window by better synchronizing treatment with tumor proliferation during the flare. This study utilizes FLT PET/CT to assess X-82, a novel VEGFR TKI, used in sequence with docetaxel. Methods: Pts with at least 1 lesion evaluable with FLT PET/CT underwent 21-day treatment cycles with X-82 daily on days 2-15. Starting in cycle 2 (C2), docetaxel was given on day 1 of each cycle. FLT PET/CTs were obtained on days 1 and 15 in cycles 1 and 2. Tumors were identified by a nuclear medicine physician and manually segmented. The maximum tumor FLT uptake SUVmax and the total tumor FLT uptake SUVtotal were extracted for each tumor. To quantify changes in tumor FLT uptake, SUVs were log transformed and included in mixed effects models with random effects accounting for intrapatient correlation of tumor responses. Results: 14 pts were treated with median 3.5 cycles (range 0-12). 4 pts with 13 metastatic tumors completed all PET scans and were included in the pharmacodynamic assessment. 1 pt had an unconfirmed PR and 7 pts had stable disease per RECIST 1.1. The mean percent (%) change in tumor SUV during C1 (X-82 monotherapy) was -13% for SUVmax (P = 0.04) and -17% for SUVtotal (P = 0.14). The mean % change in tumor SUV during C2 (X-82 + docetaxel) was -44% for SUVmax (P = 0.03) and -59% for SUVtotal (P < 0.01). There was a significantly greater decrease in SUV in C2 than in C1 for both SUVmax (P = 0.03) and SUVtotal(P = 0.02). Ten grade 3 AEs possibly related to X-82 were noted in 6 pts, including infections, cytopenias, and vascular complications. Conclusions: Diminished tumor proliferation was observed during X-82 treatment, indicating successful targeting of VEGFRs. Sequential combination of X-82 plus docetaxel showed greater decreases in tumor proliferation compared to X-82 monotherapy indicating value in sequencing chemotherapy during VEGFR TKI treatment breaks. There is evidence that combination therapy is both safe and effective. Clinical trial information: NCT 02146222.
Novel porcupine (PORCN) inhibitor RXC004: Evaluation in models of RNF43 loss of function cancers.
Authors: Bhamra Inder , Adams Nick , Armer Richard , Bingham Matilda , McKeever Helen , Phillips Caroline , Thompson Ben , Woodcock Simon 
Published: September 2018

e14094 Background: Wnt signalling initiates oncogenic pathways involved in tumour initiation, growth, differentiation and metastasis.1 Targeting the Wnt pathway is an attractive approach to cancer treatment. Porcupine (PORCN) is a membrane-bound O-acyltransferase dedicated to the palmitoylation of Wnt ligands, an essential step in the processing of Wnt into active ligands.2 A PORCN inhibitor may benefit patients with cancers in which Wnt signalling is implicated. It has been shown that PORCN inhibition is efficacious in cell lines with upstream mutations in this pathway, eg RNF43 loss of function.3 Methods: Analysis of TCGA data was carried out to identify cancer types harbouring RNF43 mutations.4 Redx PORCN inhibitor RXC004 was evaluated in vitro for Wnt pathway inhibition and anti-proliferative effects using assays previously described for early lead compounds.5Anti-tumour effects of RXC004 were evaluated using a pancreatic CAPAN-2 xenograft in SCID Bg. mice and a gastric PDX model in nu/nu mice. Both models have RNF43 loss of function mutations. Results: TCGA data revealed that both gastric cancer and pancreatic cancer exhibit mutations in the RNF43 gene (18% and 4% respectively),4expected to result in loss of function. RXC004 showed activity in preclinical models of cancers with this genetic background. RXC004 significantly inhibited tumour growth in a CAPAN-2 pancreatic cancer xenograft and in a gastric cancer PDX model when dosed orally once or twice daily. Conclusions: Taken together, these data indicate that RXC004 is a potent inhibitor of tumour growth in RNF43 loss of function preclinical cancer models. RXC004 will be evaluated in a first in human Phase 1 study in 2017. Phase 1a aims are to characterise the safety profile and PK/PD relationship in cancer patients and establish a Phase 1b dose. The efficacy of RXC004 in gastric and pancreatic cancer patients prospectively selected for RNF43 loss of function mutations will be the focus of Phase 1b expansion groups. 1 . Nat. Rev. Cancer, 2013, 13 (1): 11-26.2. J. Biol. Chem., 2012, 287 (27): 23246-23254. 3. PNAS, 2013, 110 (31): 12649-12654 4. Sci. Signal, 2013, 269 (6): 1-34; Cancer Discov., 2012, 2 (5): 401-404 5. AACR Annual Meeting, 2015, 75 (15): abs. 5071.
Markers of response to PD-1 inhibition.
Authors: Hiltermann Thijo Jeroen Nicolaas , Hijmering-Kappelle Lucie , Groen Harry J.M. 
Published: September 2018

e14505 Background: Nivolumab (Nivo) has a durable tumour response in 20 % of patients. While a PD-L1 IHC complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Serum biomarkers predicted by the cancer immunogram (Blake Science 2016) and response to Nivo defined by a clinical benefit ≥6 month (DR) and response by CR, PR or SD according to RECIST v1.1 are shown. Methods: Advanced NSCLC pts progressing after 1L platinum-based chemotherapy were treated with Nivo. Baseline blood markers drawn: CRP, absolute lymphocyte count, plasma glucose and LDH. Kaplan-Meier used to estimate survival data. Cox regression was used to predict associations with possible (bio-) markers and survival (age, gender, ECOG PS, histology, presence of brain metastasis, CRP, LDH, glucose, lymphocyte count). Results: Patient characteristics see table. 20% showed a DR with CR (n = 3), PR (n = 31 of 33) and SD (n = 9 of 20). Only ECOG PS was associated with OS and PFS. Soluble biomarkers were not. When tumour response (RECIST or DR) was added to the regression model ECOG PS was no longer significant but responses were. HR for PFS for DR was 0.07 (0.03-0.14) and HR according to the classical RECIST1.1 was 0.22 (0.16-0.32). HR for OS for DR 0.09 (0.03-0.21) and for classical RECIST1.1 0.26 (0.17-0.40). Conclusions: Serum blood markers at baseline were not associated with survival. Response to treatment as DR seems a stronger predictor for survival than RECIST. 45% of pts with SD had a DR. [Table: see text]
Model-based prediction of outcome of the atezolizumab Phase 3 study OAK in non-small cell lung cancer based on early tumor kinetic data.
Authors: Claret Laurent , Jin Jin Y , Winter Helen , He Pei , Ballinger Marcus , Rittmeyer Achim , Gandara David R. , Girish Sandhya , Joshi Amita , Bruno Rene 
Published: September 2018

e14517 Background: Standard early endpoints (ORR, PFS) are often poor predictors of overall survival (OS) for immunotherapies. Model-based tumor kinetic (TUK) metrics may offer an alternative (Claret, JCO 2009 and 2013). We investigated the predictive performance of TUK metrics using early data from atezolizumab clinical trials in patients (pts) with non-small cell lung cancer (NSCLC). Methods: OS benefit with atezolizumab (atezo) vs. docetaxel (doc) was observed in both Phase II POPLAR (hazard ratio 0.73, p = 0.040, n = 297, Fehrenbacher Lancet 2016) and Phase III OAK (HR = 0.73, p = 0.0003, n = 850, Rittmeyer Lancet 2016) studies although PFS was similar between arms. A multivariate model linking baseline patient characteristics and tumor growth rate (TGR, estimated using time profile of sum of longest diameters of target lesions, RECIST 1.1) to OS was developed using POPLAR data and qualified to predict outcome by PD-L1 status in both POPLAR and OAK. This model was used to predict OAK OS outcome based on patient characteristics and estimated TGR from TUK data at several OAK data cut-offs ranging from 10 to 122 weeks. Results: In POPLAR, TUK profile in atezo and doc arms crossed at about 25 weeks with more initial shrinkage in doc-treated patients and slower TGR in atezo-treated patients. A lognormal OS model with albumin and number of metastatic sites as independent baseline prognostic factors and estimated TGR predicted OS HR in sub-populations of pts based on baseline PD-L1 expression both in POPLAR as well as in OAK e.g model-predicted OAK HR: 0.73 [0.63-0.85]. Based a retrospective analysis on TUK data cuts, the POPLAR OS model predicted significant OS HR in OAK as soon as 40 week cut-off: HR: 0.67 [0.56-0.80] with success in 99% of the replicates with only 50% of the total number of tumor assessments. At this 40 week data cut, immature observed OS HR was 0.84 [0.59-1.21, p = 0.347] and HR only reached significance at 70 weeks. Conclusions: Model predictions based on TUK can be used to predict success early before maturation of OS data as shown with OAK. The model-based biomarker TUK metric TGR has strong potential as an alternative early endpoint to evaluate efficacy in cancer immunotherapy studies.
Evaluation of clinical endpoints as surrogates for overall survival in patients treated with immunotherapies.
Authors: Kaufman Howard , Schwartz Lawrence Howard , William William N. , Sznol Mario , del Aguila Michael , Whittington Craig , Fahrbach Kyle , Xu Yingxin , Masson Eric , Dempster Sara , Vergara-Silva Andrea Leninka 
Published: September 2018

e14557 Background: In immuno-oncology (IO), the correlation between clinical trial endpoints, specifically, objective response rate (ORR), disease control rate (DCR) or progression free survival (PFS), and overall survival (OS) is poorly understood. The effect of IO agents as opposed to chemotherapy, is not on tumor cells, but on immune cells and OS benefit has been observed in absence of PFS benefit. However, decisions on registration trials often rely on PFS from Phase II trials. Methods: We conducted a systematic literature review with PubMed and Embase (Jan. 2005–Nov. 2016), supplemented with oncology conference proceedings (2014–2016). Eligible studies were randomized controlled trials (RCT) that investigated ≥1 immune checkpoint blockers (CBs) targeting programmed death proteins (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and reported their relative effect on OS and on ≥1 of the clinical endpoints, DCR, ORR, and PFS. Log-transformed hazard ratios were fitted using weighted regression models to determine the power of relative effects on clinical endpoints to predict OS effects, with correlation coefficients estimated and presented with adjusted R2 (high values indicating better goodness-of-fit). Results: This analysis included 18 RCTs involving 7140, patients. Most studies (10/18) evaluated the efficacy of CBs vs conventional chemotherapy, whereas 8 studies compared the efficacy of ≥1 CB. Among trials that evaluated anti-CTLA-4, the adjusted R2 for the relative efficacy of CBs on DCR, ORR, PFS, and relative efficacy of CBs on OS were 0.160 ( P= 0.156), 0.016 ( P= 0.332), and 0.000 ( P= 0.623) respectively. Among trials that evaluated either anti-PD-1 or anti-PD-L1, the adjusted R2 were 0.038 ( P= 0.401), 0.066 ( P= 0.251), and 0.432 ( P= 0.032), for DCR, ORR and PFS respectively. Among trials that evaluated CBs in melanoma, the adjusted R2 were 0.030 ( P= 0.267), 0.028 ( P= 0.279), and 0.192 ( P= 0.154), for DCR, ORR, and PFS respectively. Conclusions: No clear correlations were observed between relative effects of conventional clinical endpoints and OS for CBs. New surrogate endpoints may be needed to better predict OS benefit for CBs and other forms of cancer immunotherapy.
Relationship of lymphocyte and eosinophil counts and immune-related adverse events in recipients of programmed death-1 (PD-1) inhibitor therapy: A single-center retrospective analysis.
Authors: Diehl Adam , Yarchoan Mark , Yang Ting , Scott Blake , Johnson Burles Avner , Hopkins Alexander , Azad Nilofer Saba , Jaffee Elizabeth M. , Grossman Stuart A. 
Published: September 2018

e14586 Background: Inhibition of the PD-1 checkpoint can cause immune activation in non-target tissues, resulting in immune-related adverse events (irAE) in up to 50% of patients. Biomarkers that are associated with irAEs in patients treated with PD-1 inhibitors may have implications for patient selection and clinical management. Methods: We performed an IRB-approved retrospective chart review of adult solid tumor patients treated with nivolumab or pembrolizumab at a single institution from January 2015 until November 2016. Patients were excluded if concurrently receiving investigational therapies, or on unreported clinical trials. Data were collected on treatment history, leukocyte counts, and irAE, defined as adverse events with a potential immunologic basis with grading performed using CTCAE v.4.0. Results: 172 patients were included (lung n = 54; melanoma n = 61; kidney n = 25; esophageal n = 12; bladder n = 8; other tumors n = 12) with median age 67. 18% were treated with concurrent ipilimumab. 31% experienced an adverse event of any grade with a mean time to develop an irAE of 3.5 months. Of those with an irAE, 85% required treatment, 68% were grade ≥ 2, 32% were grade 3 or 4 and 35% required therapy discontinuation due to the irAE. In univariate analysis, a higher ALC at both the start of therapy and at 1 month was associated with increased risk of an irAE of grade ≥ 2 (p < 0.05). A higher absolute lymphocyte count (ALC) or higher absolute eosinophil count (AEC) at 1 month into therapy was associated with increased risk of all irAE (p < 0.05) as well as irAE requiring treatment (p < 0.05). In addition, in a multivariate regression analysis including age, race, tumor type, prior chemotherapy, prior radiation, and concurrent ipilimumab therapy, an ALC > 2000 at the start of therapy was a significant predictor of irAE of grade ≥ 2 (p < 0.05 and OR 2.0), as was an ALC > 2000 at 1 month into therapy (p < 0.05 and OR 1.86). Conclusions: These results suggest that high lymphocyte and eosinophil counts early in the course of anti-PD1 therapy may be associated with a higher risk for clinically significant irAE.
Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumors with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx.
Authors: Kulangara Karina , Hanks Debra Ann , Waldroup Stephanie , Peltz Lindsay , Shah Supriya , Roach Charlotte , Juco Jonathan Wes , Emancipator Kenneth , Stanforth Dave 
Published: September 2018

e14589 Background: Developing clinically relevant and highly reproducible scoring methods for PD-L1 to identify patients who will respond effectively to anti-PD-1 therapy is key in the development of companion or complementary diagnostic assays. Methods: Scoring method for PD-L1 IHC 22C3 pharmDx in NSCLC have only captured the percentage on stained tumor cells using the tumor proportion score (TPS) (Roach et al. 2016, Appl Immunohistochem Mol Morphol.) (Garon et al. 2015, N Engl J Med.). In the KN012 study 2 out of 11 responders to pembrolizumab were detected with the TPS for the gastric indication. More and more additional data indicate that in some tumor indications PD-L1 staining on both tumor and tumor-associated immune cells is associated with clinical outcome. Therefore a method evaluating both tumor and immune cells in one sitting using the combined positive score was evaluated. Results: Scoring the same patient specimens with the new combined positive score method resulted in the detection of 9 out of 11 responders. Our internal inter- and intra- observer data shows that the CPS can be scored reproducibly with an overall agreement point estimates of 93% for intra-observer and an overall agreement of 87.6% for inter-observer reproducibility in gastric carcinoma. Additionally, CPS builds on the scoring method for NSCLC as it shares the same denominator, namely total number of tumor cells. CPS is evaluated based on the number of PD-L1 positive cells (tumor, lymphocytes and macrophages) in relation to total tumor cells, and hence allows the capture of tumor and immune cells in a single read. Conclusions: Our data demonstrates that the CPS scoring method is reproducible when scored by pathologists and clinically relevant for a number of indications.
Intraepithelial CD94+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression as a new immune checkpoint to predict prognosis in colorectal carcinomas.
Authors: Bossard Celine , Eugene Juliette , Jouand Nicolas , Dansette Delphine , Leveque Edouard , Podevin Juliette , Matysiak Tamara , Bezieau Stephane , Chetritt Jerome , Kerdraon Olivier , Fourquier Pierre , Thibaudeau Emilie , Mosnier Jean-François , Jarry Anne , Gervois Nadine 
Published: September 2018

e14592 Background: A better understanding of the immune-modulating interactions between tumor cells and immune cells underlying the balance between immune control and immune resistance in colorectal cancer (CRC) is crucial for the design of immunotherapies. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin - by tumor cells in CRC was associated with an unfavorable prognosis, suggesting its involvement in immune escape. However, the specific receptor of HLA-E/β2m - CD94/NKG2A, inhibitory or CD94/NKG2C, activating - expressed by tumor-infiltrating lymphocytes (TIL), as well as the influence of the microsatellite status in HLA-E/β2m overexpression, remain unknown. Methods: We investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TIL (IEL-TIL) with the microsatellite status, 2) the nature of CD94+ TIL and the receptor expressed - CD94/NKG2A or CD94/NKG2C - and 3) the prognostic influence of CD94+ IEL-TIL. Results: HLA-E/β2m was preferentially overexpressed in MSI compared with MSS CRC (44,6 % vs 18,4 % respectively, p = 0.0001), and significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m– CRC, p = 0,001), and in MSS CRC (0,38% vs 0,15%, p < 0,0001). These CD94+ TIL mostly corresponded to CD8+ αβ T cells preferentially expressing the inhibitory NKG2A chain. Finally, a high density of CD94+ IEL-TIL was independently associated with a worse OS (p = 0.03). Conclusions: These results strongly suggest that HLA-E/β2m - CD94/NKG2A interactions, preferentially up-regulated in MSI CRC, represent a promising inhibitory immune checkpoint. From a clinical point of view, this inhibitory immune checkpoint could be blocked by the new anti-NKG2A monoclonal antibody.