bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical in vitro and in vivo study of UD-017, a novel highly selective and orally available CDK7 inhibitor, in a variety of cancers.
Authors: Onuma Kazuhiro , Aga Yasuhiro , Ogi Sayaka , Matsushita Takashi , Sunamoto Hidetoshi , Ogawa Ayumi , Tokunaga Yasunori , Ushiyama Shigeru 
Published: September 2018

e14086 Background: Cyclin dependent kinase 7 (CDK7) modulates mRNA transcription and some oncogenes are reported to be sensitive to inhibition of transcription in certain cancer cells. CDK7 inhibitors have been considered as an intriguing approach to treat cancers that depend on transcriptional regulation of their oncogenes. We synthesized a novel highly selective CDK7 inhibitor, UD-017, and found that the compound showed antitumor potency in a variety of cancers in vitro and in vivo. We therefore explored underlying mechanisms especially focusing on an oncogenic driver, c-Myc. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated an antiproliferative activity of UD-017 in over 200 multiple types of cancer cell lines including patients-derived cancer cells. We then investigated the correlation between c-Myc expression levels and an antiproliferative activity of UD-017 in cancer cells. Antitumor efficacy of UD-017 was assessed in multiple types of cancer xenograft models and patients-derived xenograft model. We determined whether an intratumoral c-Myc expression levels correlated with in vivo antitumor efficacy of UD-017 in xenograft models. Results: UD-017 inhibited CDK7 enzyme (IC50= 16 nM) highly selectively among the CDKs (over 300-fold) and almost mono-specifically in a panel of 313 kinases assay. In a cellular antiproliferative panel assay, UD-017 broadly inhibited the proliferation of a variety of cancer cells and c-Myc expression levels showed the good correlation with antiproliferative activity. UD-017 showed favorable PK profile and good oral absorbability and showed the potent antitumor activity in multiple types of cancer xenograft models in mice. In correlation with the PK, UD-017 reduced the intratumoral c-Myc mRNA levels time-dependently after dosing of UD-017 in the colorectal cancer xenograft model. Conclusions: We identified a highly selective and orally available CDK7 inhibitor that showed the broad in vitro and in vivo antitumor activity in a variety of cancers, modulating c-Myc as an oncogenic driver. These data support the rationale for further advancing towards clinical development.
Efficacy, maximal tolerated dose, and toxicokinetics of TTC-352 in rats and dogs, a partial ER agonist for metastatic ER+ breast cancer.
Authors: Tonetti Debra A. , Xiong Rui , Zhao Jiong , Gutgesell Lauren , Dudek Arkadiusz Z. , Thatcher Gregory R. 
Published: September 2018

e14090 Background: The high prevalence of treatment resistance for estrogen receptor positive (ER+) breast cancer cause more deaths than all other breast cancers, despite the availability of endocrine therapeutics including selective ER downregulators (SERDs). Before tamoxifen, high dose estradiol (E2) delivered clinical efficacy slightly superior to tamoxifen. While recent clinical trials have shown efficacy of low dose E2, unacceptable side effects including vaginal bleeding, endometrial hypertrophy, and the negative perceptions of both patients and physicians limit acceptance. In preclinical models, tamoxifen resistant (TR) breast cancer is sensitive to treatment by E2. TTC-352 is an orally bioavailable selective human ERα partial agonist (ShERPA) designed to mimic E2 in causing tumor regression of TR breast cancer xenografts without uterine proliferation caused by E2 and tamoxifen. Methods: The published preclinical efficacy studies were extended to multiple TR ER+ cell lines in 3D spheroid cell cultures comparing to E2 and the SERD GDC0810. The maximum tolerated dose (MTD) was determined in Sprague-Dawley rats at: 200, 300, 600, 1000 and 2000 mg/kg by oral gavage (N = 3). Animals were observed for 7 days prior to necropsy. A single MTD range finding study was performed in dogs at: 50, 100, and 200 mg/kg TTC-352, administered orally in gelatin capsules. Based on these results, a 7-day repeated dose studies were completed at 30, 100, 300 and 1000 mg/kg/day in rats (3/sex/dose) and 15, 75, and 150 mg/kg (2/sex/dose) in dogs. Results: Growth of three TR ER+ breast cancer cell cultures in 3D was inhibited by TTC-352, which mimicked E2 and was equivalent to GDC0810. In female rats MTD was 1000 mg/kg and TTC-352 was well tolerated following a single oral dose of 200, 300, 600 mg/kg. The oral administration of TTC-352 at doses of 30, 100, and 300 mg/kg/day in rats (both sexes) and 15, 75 or 150 mg/kg/day in dogs (both sexes) for seven days was generally well tolerated. Conclusions: TTC-352 has demonstrated efficacy in preclinical models of TR breast cancer. Completed rat and dog studies indicated favorable tolerability and rapid absorption up to 300 mg/kg/day in rats and 150 mg/kg/day in dogs.
Concordance of tumor cell (TC) and immune cell (IC) staining with Ventana SP142, Ventana SP263, Dako 28-8 and Dako 22C3 PD-L1 IHC tests in NSCLC patient samples.
Authors: Scott Marietta L. , Ratcliffe Marianne J , Sharpe Alan , Barker Craig , Scorer Paul , Rebelatto Marlon , Al-Masri Hytham , Walker Jill 
Published: September 2018

e14503 Background: PD-1/PD-L1 directed antibodies are emerging as effective oncology therapeutics with multiple diagnostic PD-L1 tests available for patient segmentation. It is essential to compare these assays to understand the risk if assays are used interchangeably. Previous data showed strong concordance (OPA >85%) of TC PD-L1 expression at multiple clinically relevant cutoffs with the Ventana SP263, Dako 28-8 and 22C3 assays (Ratcliffe et al. Clin Cancer Res 2017; Ratcliffe et al. ESMO 2016 (955PD)). This work supplements previous data with concordance of IC scoring and data from Ventana SP142. Methods: IC PD-L1 IHC expression data were generated from 493 clinical NSCLC biopsy samples stained with Ventana SP263 and Dako 22C3 and 28-8 assays. In addition, consecutive sections from 200 blocks of the 493 samples were later sectioned and stained with SP142 and SP263. Concordance at matched cutoffs between the 4 assays is reported for IC, and concordance between SP263 and SP142 for TC. Results: Strong agreement in IC scoring between the SP263 and 22C3 and 28-8 assays is observed. The SP142 assay showed lower IC concordance and reduced TC PD-L1 staining/concordance vs SP263 (Table). Conclusions: Analytical similarity is shown between the SP263, 28-8 or 22C3 assays when measuring TC or IC PD-L1 expression, with high concordance between patient classification at matching TC cutoffs up to ≥50% or IC up to ≥10%, strengthening the evidence that these 3 assays could be used interchangeably at relevant clinical cutoffs. The SP142 assay shows clear analytical differences in both IC and TC staining. [Table: see text]
Immune response and adverse events to influenza vaccine in cancer patients undergoing PD-1 blockade.
Authors: Laubli Heinz Philipp , Balmelli Cathrin , Kaufmann Lukas , Stanczak Michal , Syedbasha Mohammedyaseen , Vogt Dominik , Mueller Beat , Gautschi Oliver , Stenner Frank , Zippelius Alfred , Egli Adrian , Rothschild Sacha 
Published: September 2018

e14523 Background: Cancer patients (pts) are at risk to develop complications when infected with seasonal influenza viruses. Current guidelines propose that pts on PD-1 directed therapies may receive concurrent inactivated influenza immunization if not medically contraindicated. In this observational study, we aimed to assess the vaccine induced immune response and safety of immunotherapy and influenza vaccine. Methods: Metastatic cancer pts treated with at least one dose of either nivolumab or pembrolizumab were vaccinated with a trivalent inactive influenza vaccination between October and November 2015. Partners of the pts were vaccinated and included in our analysis as age-matched controls. Antibody titers against vaccine virus strains were measured by hemagglutination inhibition assay at days 7, 30, 60 and 180. Cytokine/chemokine profile and changes in peripheral immune cells were assessed in cancer pts at the same time points. Immune-related adverse events (irAE) were documented according to CTCAE v4.0. Results: We included 23 pts and 7 age-matched healthy controls. Median time between initiation of PD-1 inhibition and influenza vaccination was 74 days (range, 44-57). 22 pts were treated with nivolumab and 1 pt with pembrolizumab. 16 pts had a diagnosis of non-small cell lung cancer, 3 pts had renal cell carcinoma and 3 pts a malignant melanoma. In total, 12 pts (52.2%) experienced an irAE. 6 pts (26.1%) had grade 3 or 4 (G3/4) irAEs. This frequency seems to be higher than reported in the literature. G3/4 irAEs include colitis (n = 2), encephalitis (n = 1), vasculitis (n = 1), pneumonitis (n = 1), peripheral neuritis (n = 1). There was no major difference over time in the generation of antibody titers against strains in the vaccine. Peripheral leukocyte counts and cytokine/inflammatory chemokine levels were unchanged after vaccination. We did not observe unexpected local toxicities at the injection site. Conclusions: The seasonal influence vaccination reaches a protective range in these pts. Unexpectedly, however, an increased rate of clinically relevant irAEs was observed. Confirmation in a larger population and mechanistic understanding is required.
High baseline lymphocyte count is a predictive biomarker of prolonged time to progression in patients with advanced solid tumors receiving checkpoint inhibitors.
Authors: Maltese Mariangela , Panni Stefano , Lazzarelli Silvia , Brighenti Matteo , Negri Federica , Ratti Margherita , Giganti Maria Olga , Passalacqua Rodolfo 
Published: September 2018

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.
Predicting patient response to cancer immunotherapy using quantitative computed tomography based texture analysis.
Authors: Gordon Joshua Ian , Gordon Michael S. , Korn Ronald Lee 
Published: September 2018

e14536 Background: Immuno-Oncology (I-O) therapies such as PD-L1/PD-1 antibodies disrupt a protective mechanism for tumor cells to evade the host immune system. To minimize toxicity and cost of care, we aim to determine if quantitative texture analysis (QTA) can be used as a predictive biomarker for response to these new drugs. Methods: A pilot study consisting of 20 cancer patients with metastatic disease who received PD-L1/PD-1 antibodies was performed. The subject pool consisted of 10 subjects (NSCLC 3, Urothelial CA 3, TNBC 1, RCC 3) who achieved objective responses to I-O therapy compared to 10 subjects (NSCLC 5, Urothelial CA 2, Ovarian 1, Pancreatic 1, Cervical 1) with primary progression as their best response. Pre-treatment diagnostic CT scans of the chest, abdomen, and pelvis were analyzed using QTA. A minimum of 1 objectively measurable lesion ( > 10 mm in diameter) per study was identified to undergo QTA. Histogram readouts of tumor texture based upon tissue densities per pixel were obtained. Output values from the QTA provided an estimate of tumor signal properties as expressed as the mean pixel density, standard deviation, entropy, kurtosis, skewness, and mean positive pixel value. Results: There was no identifiable signature when examining all of the lesions together. There was statistically significant correlation noted between QTA and RECIST response for lung lesions (n = 14) based on the mean pixel density. A mean pixel density cutoff of 11.91 at a spatial scale factor of 3 predicted response with a sensitivity of 75% and a specificity of 100%. This achieved a Mann-Whitney Z statistic of 2.6 (p = 0.0092). Conclusions: Despite the small number of patients in this pilot study, there were promising findings when examining the mean pixel density of lung lesions, suggesting that quantitative textural analysis can be used to predict response to PD-L1/PD-1 antibodies. Further investigation is warranted in a larger population that can be differentiated by tumor type to validate these results.
A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.
Authors: Wang Yuzi , Sun Lue , Li Xiaokang , Tsuboi Koji 
Published: September 2018

e14541 Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.
Incidence of thyroid function test abnormalities in patients receiving immune checkpoint inhibitor therapy for cancer: A single institution retrospective review.
Authors: Patel Nisha Subhash , Oury Anais , Bazhenova Lyudmila , Daniels Gregory A. , Patel Sandip Pravin 
Published: September 2018

e14569 Background: With the advent of immune-checkpoint inhibitor (ICI) therapy, thyroid function test abnormalities (TFTA) are common with reported incidence range of 2-15%. Our aim was to describe the incidence of TFTAs retrospectively in patients (pts) on ICI therapy. Methods: 285 pts reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had thyroidectomy (excluded). Pts received at least one dose of ipilimumab (I) and/or nivolumab (N) or pembrolizumab (P). Post-treatment TFTA was classified according to definitions of thyroid abnormalities when possible. Results: A total of 35% (76/218) pts had new onset TFTAs on ICI. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI. Median time to new onset or exacerbated baseline TFTA were 46 & 33 days respectively. Of note, 65% (20/31) of pts on both I+N had new onset TFTA, compared to 31.3% (15/48) with I, 31.5% (28/89) N, 26% (13/50) P. Conclusions: Incidence of TFTAs with ICI was higher than expected in our pts. Pts with baseline TFTA and/or I+N combination therapy had higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more frequent evaluation of TFT in the first two months, especially in those with baseline TFTA. [Table: see text]
Assay performance of the PD-L1 IHC 28-8 pharmDx assay in squamous cell carcinoma of the head and neck (SCCHN).
Authors: Alvarez Sara , Hanks Debra Ann , William Josette , Chan Joel A. , Felten Christopher L. , Northrup Adam , Jaiswal Dipeshkumar , Jansson Malinka , Phillips Therese , Segal Andrew , Satnick Ilana , McDonald Hendrick , Little Hunter , Pierce Coree , Wynne Bethany , Carnahan Josette , Reddy Swarnalatha Y. , Inzunza H. David , Novotny James , Oroudjev Emin 
Published: September 2018

e14588 Background: The PD-L1 IHC 28-8 pharmDx assay has been developed for use in detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-squamous NSCLC and melanoma tissues for associated treatment effect with nivolumab. Validation of the assay for measuring PD-L1 expression level in human squamous cell carcinoma of the head and neck (SCCHN) FFPE sections has been conducted and results are described. Methods: Visualization of the PD-L1 IHC 28-8 pharmDx assay is based on the EnVision FLEX IHC technology. As described in the Instructions For Use, antigen retrieval was performed using the Dako PT Link, and the automated staining was conducted with Autostainer Link 48. The assay performance was validated on commercially procured FFPE SCCHN specimens. Results: Assessment of assay sensitivity to PD-L1 expression was measured on 236 unique specimens originating from squamous cell carcinoma of the tongue, tonsil, nasopharynx, oropharynx, hypopharynx, and larynx. The study demonstrated PD-L1 positive staining across a range of 0-95% positive tumor cells and 0 to 3+ staining intensity. Among these tested specimens, 44% of specimens had PD-L1 expression levels ≥1%. Assay robustness was validated by assessing critical parameters such as target retrieval solution pH, target retrieval solution temperature, target retrieval time, and cut section thickness. Assay reproducibility was evaluated in a study at three external sites. Reproducibility of intra-site, inter-day, and inter-site agreement was assessed in addition to inter- and intra-observer agreement. Assay robustness and reproducibility demonstrated agreement estimates above 85% with values for lower bound 95% confidence intervals calculated above 85%. Conclusions: These studies demonstrate that the PD-L1 IHC 28-8 pharmDx assay is reproducible and robust when used for automated detection of PD-L1 protein in FFPE human SCCHN specimens using Autostainer Link 48.
Clinical and biochemical parameters as predictors of response to checkpoint inhibitors (CPI): A single institution experience.
Authors: Gandhi Shipra , Pandey Manu , Ammannagari Nischala , Wang Katy , Vona Karen L , Nestico Jill , Hamad Lamya , Dy Grace K. , Ernstoff Marc S. 
Published: September 2018

e14590 Background: The benefit of CPI is limited to a subgroup of patients. Significant toxicity and financial burden make it imperative to identify biomarkers predictive of clinical benefit. We aimed to analyze if immune related adverse events (irAE), laboratory parameters (besides PD-L1 status), prior chemotherapy and concomitant medication use could predict response to CPI. Methods: 216 consecutive patients treated at RPCI with single/multiple CPI from 2011 to 2016 were identified. Demographics, irAE (CTCAE v4.03), concomitant medication use, response (RECIST v1.1) and laboratory parameters were recorded. Progression free (PFS) and overall survival (OS) were calculated. Clinical benefit (responder) was defined as objective response or stable disease with PFS ≥ 6 months. Statistical analysis was performed using SAS v9.4. Results: 185/216 patients (86%) had clinical outcomes with first CPI available (55.7% melanoma, 28.1% lung, 10.8% kidney, 3.8% bladder, 1.6% others), 14% died before disease assessment. Median age was 61 years; 64% were males. 31% were responders (R); 69% non-responders (NR). Median PFS and OS for R were not reached and for NR were 4.7/7 months (p < 0.001). 26% R developed rash vs. 12% NR (p = 0.02). irAE diarrhea was associated with better OS (p = 0.03); rash with better PFS (p = 0.007) and OS (p = 0.05). Concomitant beta-blocker/NSAID use was noted in 35%/28% R vs 20%/12% NR (p = 0.04; p = 0.01). Higher median absolute eosinophil (AEC) and absolute lymphocyte count (ALC) were noted in R (400 and 2000/µl in R vs. 300 and 1600/µl in NR; p = 0.008 and 0.024). NR were noted to have a higher median lactate dehydrogenase (LDH) of 565 vs. 503 (p < 0.001). AEC > 100/µl and ALC > 1000/ µl were associated with better OS (P = 0.03; P = 0.001). Absolute neutrophil count (ANC) > 7500/µl and leucocyte count > 8750/ µl were associated with inferior PFS (p = 0.005; P = 0.02) and OS (p = 0.002; p = 0.03). Pre-CPI chemotherapy did not correlate with response to CPI. Conclusions: Among irAE, diarrhea and rash predicted improved outcomes. Eosinophilia, lymphocytosis, neutrophilia, leukocytosis and LDH could serve as potential prognostic biomarkers to CPI. Prospective studies are warranted to validate these findings.