tbuckley/cabot-search huggingface dataset:
Identification of epitopes of cancer testis antigen cyclin A1 for targeted T-cell therapy of acute myeloid leukemia (AML) and solid tumors.
Authors: Anja-Tatjana Teck, Sabrina Urban, Petra Quass, Annika Nelde, Juliane Walz, Ulrich Keilholz, Sebastian Ochsenreither
Journal: Journal of Clinical Oncology (2017)

e23080 Background: Cyclin A1 is a promising antigen for T-cell therapy being selectively expressed in ovarian cancer and AML stem cells. For adoptive T-cell therapy, a single epitope has to be selected, which should bind with high affinity to MHC class I and should be adequately processed and presented by malignant cells to trigger full activation of specific T-cells. Methods: Three algorithms were used to predict in silicopeptides of Cyclin A1 with high affinity to HLA A*02:01. Affinities were tested by HLA stabilization assay using TAP-deficient T2 cells. Immunogenicity of peptides was assessed by stimulation of T-cells with peptide pulsed dendritic cells and monocytes. Specificity of T-cells was assessed by intracellular cytokine staining. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA A*02:01-positive AML line THP-1. Data from immunopeptide analysis based on direct isolation of HLA peptides by affinity chromatography and mass spectometry of 20 primary AML samples were analyzed retrospectively to identify naturally presented epitopes of Cyclin A1. Results: Thirteen peptides nine to eleven amino acids of length were predicted. Ten showed stabilization of HLA A*02:01 on T2 cells. By repetitive stimulation of T-cells of two healthy donors with single peptides, 40 T-cell lines were generated, of which eight were specific for the respective peptides. Five peptides were immunogenic. Against two peptides (Cyclin A1 isoform c, p156-164, p410-420) T-cell lines could be generated from both donors. For T-cell clones against two peptides (p111-120, p289-297), specific lysis of THP-1 was shown indicating adequate processing. Peptide p410-420 was found by mass spectroscopy-based ligandome analysis to be presented by AML blasts in vivo. Conclusions: We identified ten peptides with adequate binding to HLA A*02:01. We describe three new HLA A*02:01–restricted epitopes as targets for T-cell therapy. Epitope p410-420 showed high affinity to HLA A*02:01 and immunogenicity in both donors. It proved to be naturally presented on AML blast, and therefore warrants further development for clinical application.
Effect of the combination of tumor necrosis factor related apoptosis inducing ligand (TRAIL) and the cyclin dependent kinase inhibitor dinaciclib on HPV+ cervical cancer cells.
Authors: David Kotlyar, Yoshimi Greer, Donna Voeller, Lidia Hernandez, Christina M. Annunziata, Stan Lipkowitz
Journal: Journal of Clinical Oncology (2016)

e17016 Background: Cervical cancer is a global burden. Yearly, more than 520,000 women worldwide are affected, and over 250,000 die. We investigated if TRAIL combined with dinaciclib, a multiple cyclin-dependent kinase inhibitor, would yield synergy in killing of cervical cancer cells. Published data have shown that dinaciclib inhibits CDK1, 2, 4, 5, 6, 7, and 9 at doses achieved in clinical trials. Methods: We used a colorimetric assay (MTS assay) to assess the effect of 24 hrs. of exposure with CDKi and TRAIL on 6 HPV+ cervical cancer lines (HeLa, SiHa, CaSki, C4I, ME180, SW756) and two HPV- cervical cancer lines (C33a, DOTC2). We used the CompuSyn platform to define synergy as a mean combination index of ≤ 0.7. We obtained microscopy images using a CCD camera. Western blotting was done to assess CDK expression. Results: The combination of TRAIL and dinaciclib resulted in growth inhibition (as assessed by MTS assays) in 5 of 6 HPV+ cell lines: HeLa, Caski, SiHa, ME-180, and C4I. Of the five susceptible HPV+ lines, CompuSyn revealed synergistic inhibition by TRAIL + dinaciclib in 4 of 5 HPV+ lines (80%) with the exception of the C4I line. Both HPV- lines showed susceptibility, though no synergy was seen in C33a cells. Synergy analysis of the HPV- DOTC2 line was non-interpretable as the IC50 was not calculable. Morphologically, most cells showed signs of apoptotic cell death due to TRAIL + dinaciclib and consistent with synergistic killing in the four cell lines as above. In 2 HPV+ cell lines (CaSki and Hela) in addition to evidence of apoptosis, there was evidence of cell swelling with heterogeneous nuclei, which can be seen in necroptosis. This finding was not seen in other HPV+ cell lines. At baseline, expression via western blotting revealed robust expression of CDK1, 2, 4, 5, 6, 7, 9 and 12 in HPV+ CaSki cells. There was no CDK6 expression but otherwise CDK expression was similar in C33a HPV- cells. Dinaciclib (100 nM, 24 hr) also caused marked reductions in CDK12 in all cell lines tested (CaSki, HeLa, C33a). Conclusions: Four of six HPV+ lines showed synergistic death with dinaciclib and TRAIL. Synergy was not seen in one HPV- line, which also did not express CDK6.
Final results of a phase III randomized controlled trial comparing modified gemcitabine + oxaliplatin (mGEMOX) to gemcitabine+ cisplatin in management of unresectable gall bladder cancer (GBC).
Authors: Atul Sharma, Nootan Kumar Shukla, Surendra Pal Chaudhary, Ranjit Sahoo, BK Mohanti, S. V. S. Deo, Sujoy Pal, Sanjay Thulkar, Sunil Kumar, Sushmita Pathy, Peush Sahni, Sreenivas Vishnubhatla, Sushma Bhatnagar, Nihar Ranjan Dash, Rakesh Kumar, Vinod Raina, Venkateswaran K Iyer, Seema Mishra
Journal: Journal of Clinical Oncology (2016)

4077 Background: Combination of gemcitabine and platinum (cisplatin/ oxalipatin) though standard for advanced/unresectable GBC has not been directly compared. This study was designed to see if OS with mGEMOX is equivalent to GemCis. Methods: Single center phase III randomized trial. Primary end point was OS in 2 groups. Main Secondary end points were: 1. PFS in 2 groups; 2. RR in two groups. Considering median OS of 9.5 month in mGEMOX (as per our previous study) and 11.7month in GemCis 108 patients were required in each arm to have γ ±2 month with 80% power. To account for protocol violation and lost to follow up additional 22 patients in each arm were enrolled. Treatment protocol: Arm A- mGEMOX Oxaliplatin 80 mg/m2 and Gemcitabine 900 mg/m2 day1 and 8 maximums of 6 cycles, Arm B- GemCis Cisplatin 25 mg/m2 Gemcitabine 1000 mg/m2 day1 and 8 maximums of 8 cycles, repeated every 3 weeks. Results: Between February 2010 and July 2015, 260 patients with unresectable/metastatic GBC subjects were randomly assigned in a 1:1 ratio to mGEMOX or GemCis. 243 patients (119 in mGEMOX and 124 in GemCis) received at least 1 dose of chemotherapy and were considered analyzable. Subjects in 2 groups were well matched for baseline characteristics. Median number of cycles was 4 in both the groups. 33.4% in mGEMOX and 25.8% in GemCis completed the assigned treatment. Median follow up of surviving patients is 10.5 months (range 4.5-47). Median OS in mGEMOX is 9 months (95% CI = 7.77-10.22) and 8 months in GemCis arm (95% CI = 7.40-8.59); p = 0.152. Median PFS in mGEMOX is 6 months (95% CI = 4.72-7.27) and 4.5 months in GemCis arm (95% CI = 3.44-5.55); p = 0.123. 29.4% (35) and 18.5% (23) patients survived 12 month or longer in mGEMOX and GemCis arms respectively (p = 0.442). 23.5% and 22.6% subjects achieved objective CR/PR in mGEMOX and GemCis arms respectively. Toxicity was comparable except more grade 3/4 diarrhea, and grade 1/2 peripheral neuropathy in mGEMOX arm. Conclusions: This study confirms that 6 cycles of mGEMOX is equivalent to 8 cycles of GemCis and one of these may be chosen for initial treatment. Clinical trial information: CTRI/2010/091/001406.
FDG-PET/CT in the prediction of histopathological response to neoadjuvant chemotherapy for adenocarcinoma of the esophagus and esophagogastric junction.
Authors: Tomas Harustiak, Pavel Fencl, Ludmila Hornofova, Alexandr Pazdro, Martin Snajdauf, Zdenka Pechacova, Lubos B. Petruzelka, Milada Zemanova
Journal: Journal of Clinical Oncology (2016)

e15545 Background: There have been reports suggesting that histopathological responders, who markedly benefit from neoadjuvant chemotherapy (NeoCT), may be identified by 18-fluorodeoxyglucose positron emission tomography (FDG-PET) early in the course of NeoCT for adenocarcinoma of the esophagus and esophagogastric junction. Our aim was to verify this assumption within a prospective clinical trial. Methods: Following PERCIST 1.0 protocol, FDG-PET/CT was performed before (PET1), 14 days after start of the first cycle (PET2) and 4 weeks after start of the third cycle (PET3) of standardized NeoCT (epirubicin, cisplatin and 5-fluorouracil or capecitabine). The peak of standardized uptake value (SUL) on PET1 and relative changes of SUL and total lesion glycolysis (TLG) on PET2 (Δ2) and PET3 (Δ3) were correlated with histopathological response (HPR). Responders were defined as patients with less than 50% viable tumor cells in resection specimen. Receiver operating characteristic analysis was used to calculate the cutoff values of SUL and TLG with the highest combined sensitivity and specificity of prediction of HPR. Results: In 96 included patients, 28 were histopathological responders. There was a significant association between the metabolic activity on PET1 and HPR and the decrease of metabolic activity on PET3 and HPR, but no association between the early decrease of metabolic activity on PET2 and HPR (Table). The sensitivity and specificity of prediction of HPR were 67.9% and 67.6% for PET1 (cutoff SUL 6.7), 81.5% and 57.4% for PET3 (cutoff SUL Δ3 -37.7%), 59.3% and 79.4% for PET3 (cutoff TLG Δ3 -95.7%), respectively. Conclusions: We did not prove that FDG-PET/CT performed early in the course of NeoCT was able to predict HPR. The prediction of HPR based on FDG-PET/CT before and after NeoCT was not sufficiently accurate for clinical use. Clinical trial information: EudraCT 2011-001856-12. Histopathological response p-value Yes (n=28) median [IQR] No (n=68) median [IQR] SUL PET1 5.8 [4.5,7.8] 8.2 [5.6,13.7] 0.004 SUL Δ2 (%) -29 [-47,-19] -34 [-51,-10] 0.892 TLG Δ2 (%) -66 [-88,-34] -57 [-84,-33] 0.416 SUL Δ3 (%) -54[-65,-39] -34 [-52,-18] 0.004 TLG Δ3 (%) -98 [-99,-78] -71 [-94,-38] 0.002 IQR – interquartile range.
Michael Arthur Pugh
Authors: Emma Pugh
Journal: BMJ (2018)

Michael Arthur Pugh (“Mike”) was born in Manchester and moved to London in 1936. During the second world war he was evacuated to Torquay, attending St Olave’s Grammar School, a London school. He was able to continue there after the war ended and started a lifelong association with St Olave’s. He went on to Barts, another institution …
Uptake of genetic testing and outcomes in a randomized study of remote genetic services as compared to usual care in community practices without genetic providers.
Authors: Angela R. Bradbury, Linda J. Patrick-Miller, Brian L. Egleston, Colleen Burke Sands, Syeda Abbas, Cara Cacioppo, Neeraja Reddy, Elisabeth McCarty Wood, Susan M. Domchek
Journal: Journal of Clinical Oncology (2018)

6506 Background: Providing remote genetic services by phone or videoconference for patients at community practices without access to genetic providers could increase access to genetic testing. How uptake of testing compares to usual care options for genetic testing has not been reported. Methods: To date, 106 patients at 6 community practices were randomized to remote genetic counseling (35 phone; 31 videoconferencing) and 40 to usual care (recruitment to end 3/2018). Primary outcomes were uptake of genetic counseling and testing at 6 months. Secondary outcomes include knowledge, state and general anxiety, depression, and cancer-specific distress in phone versus videoconferencing arms. We used Fisher's exact tests, T-tests, and logistic regressions for analyses. Results: 92% of participants are female, 17% are non-white, 33% are college graduates and 65% have a history of cancer. 86% had multigene panel testing. At 6 months, 79% (52/66) of participants in the remote services arms had pre-test genetic counseling as compared to 5% (2/40) in the usual care arm (p < 0.001). 56% (37/66) in the remote services arm completed genetic testing and 4 genetic carriers were identified (ATM, MUTYH and 2 with BRCA2) as compared to 12.5% (5/40) and 0 carriers in the usual care arm (p < 0.001 for genetic testing uptake). Highest income levels (p < 0.05), older age (p = 0.07) and being married (p = 0.06) were associated with uptake of testing. In secondary analyses comparing the videoconference and phone arms, we have found greater knowledge gains (phone: +7.4, SD 10.5 v. VC: 17.8, SD 16.5, p < 0.01) and reductions in depression (phone +0.1, SD 2.3 v. VC: -1.1, SD 2.0, p = 0.07) from baseline to post-disclosure with videoconferencing as compared to phone. Conclusions: These data suggest that offering remote genetic services by phone or real-time videoconference may increase the uptake of testing and identification of genetic carriers in community practices without access to genetic services. Continued evaluation of the relative benefits of videoconferencing over telephone counseling in patients at community practices is critical to understanding how to optimize patient outcomes. Clinical trial information: NCT02517554.
Tolerability of veliparib (V) in combination with carboplatin (C)/paclitaxel (P): Based chemoradiotherapy (CRT) in subjects with stage III non-small cell lung cancer (NSCLC).
Authors: David E. Kozono, Joseph Kamel Salama, Tom Stinchcombe, Jeffrey Bogart, William J. Petty, Michael J. Guarino, Lyudmila Bazhenova, James Mitchell Larner, Jared Weiss, Thomas A. DiPetrillo, Steven J. Feigenberg, Tu Xu, Beibei Hu, Silpa Nuthalapati, Lindsey Rosenwinkel, Lindsey Bensman, Eric Feral Johnson, Mark D. McKee, Everett E. Vokes
Journal: Journal of Clinical Oncology (2017)

8546 Background: CRT is a standard for patients with Stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A Phase 2 study indicated favorable efficacy of V vs placebo when added to C/P in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a Phase 1/2 trial was initiated to study the safety and efficacy of V/C/P-based CRT in the treatment of Stage III NSCLC. Methods: Subjects without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m 2 weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with allowed over-enrollment followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m 2 for up to two 21-day cycles. Results: Thirty-one subjects (median age 64; 10 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7) and 200 mg (8). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 subject, respectively. Four (13%) subjects discontinued study during CRT. No DLTs have been observed and an MTD has not yet been identified. The most common any grade AEs were fatigue (16), esophagitis (15), nausea (13), neutropenia (12), thrombocytopenia (12), constipation (10) and decreased appetite (10). 21 SAEs were observed including 8 with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1) and G5 sepsis during consolidation (1). Of 21 subjects evaluable for tumor assessment, best response was CR (1), PR (11), SD (6), and PD (3). Conclusions: V/C/P-based CRT followed by V/C/P consolidation therapy is a tractable regimen for the treatment of Stage III NSCLC. A randomized placebo-controlled Phase 2 extension of this study is planned. Clinical trial information: NCT02412371.
Activity of TGF-β inhibition combined with NK adoptive cell therapy..
Authors: Evelyn Ojo, Folashade Otegbeye, Stephen Moreton, David Wald
Journal: Journal of Clinical Oncology (2016)

e14520 Background: Natural killer (NK) cells are lymphocytes that specifically target tumor and virally-infected cells, and utilized for adoptive cell therapy (ACT). Though NK cell therapy has shown promise, its effectiveness is diminished by immunosuppressive factors that limit NK cell activity. One main cause of immunosuppression in the tumor microenvironment is transforming growth factor-β (TGF-β). We hypothesize that abrogation of TGF-β activity will markedly enhance the efficacy of NK ACT. Methods: NK cells were treated with 5ng/mL TGF-β and/or 5nM TGFβR1 inhibitor EW7197 for 1 week. A cytotoxicity assay was performed by co-incubating calcein AM-labeled OCI-AML3 (OCI) cells with NK cells for 4 hrs. OCI cell lysis was detected by calcein release using a plate reader and normalized to 100% lysis control. Colon cancer liver metastasis model: NSG mice were injected with 250,000 luciferase-labeled HCT116 cells into the portal vein. After a week, the mice received 10 million NK cells weekly for 3 weeks. Also, the mice were given the TGFβR1 inhibitor galunisertib (gal) twice daily by oral gavage (75mg/kg). Tumor burden was measured by bioluminescence imaging, gross necropsy and histology. Results: TGF-β treatment of NK cells for 1 week led to decreased killing of OCI cells (70%), rescued by a TGFβR1inhibitor (Fig 1). The metastasis model was employed to mimic cases in which NK ACT may add value. In this study, gal (currently in clinical trials) demonstrated a remarkable ability to enhance NK cell-mediated killing of liver metastasis. Compared to untreated mice, NK cells and gal combination (Group C) had 83.5% decrease in tumor burden after week 2 of treatment (Fig 2). Conclusions: Consistent with previous studies, we observed that TGF-β leads to NK cell dysfunction. This impaired activity is reversed by using TGFβR1 inhibitors. Particularly, the combination of NK cells and a clinically used inhibitor, gal, showed dramatic efficacy in reducing metastatic tumor burden in a colon cancer model. Further studies are being performed to validate the specificity and effectiveness of gal at enhancing NK ACT in other tumor models. It is hoped that this therapeutic strategy can be transitioned to clinical testing to improve the efficacy of NK ACT.
Correlation of changes in disposition of geriatric (≥ 65 years) cancer patients receiving hematopoietic stem cell transplantation with an increase in healthcare costs.
Authors: Achuta Kumar Guddati, Parijat Saurav Joy, Gagan Kumar, Iuliana Shapira
Journal: Journal of Clinical Oncology (2017)

6578 Background: The increasing proportion of geriatric cancer patients in the general population has contributed to rising health care costs. The disposition of hematopoietic stem cell transplant (HSCT) recipients in the geriatric population is an important factor determining the cost of their health care. A database with nationwide representation for outcomes of HSCT over a 12 year period was analyzed. Methods: Data regarding patients who underwent HSCT was extracted from the Nationwide Inpatient Sample (NIS) from 2000 to 2011 using ICD-9-CM codes. HSCT hospitalizations were classified into allogeneic transplantation, autologous transplantation, subsequent hospitalization (s/p transplant) with graft versus host disease (GVHD) and subsequent hospitalization (s/p transplant) with other complications. NIS variables were used to identify in-hospital complications and discharge disposition. Results: The proportion of elderly patients (≥ 65 years) who received any type of transplant or were admitted with GVHD or other related complications who were discharged with additional support and to specialized facilities has increased over the past decade. The exception to this trend has been noted for allogeneic transplants and may be due to a more conservative approach towards their disposition (ie, higher level of care and longer length of stay). The trends from 2000 to 2011 are summarized in the table below. Conclusions: A higher percentage of geriatric cancer patients who receive HSCT are being discharged to nursing homes. These rates have significantly changed over the past decade (p &gt; 0.05) and represents an additional contribution to the rising health care costs. This proportion of patients are expected to rise as increasingly older patients are being allowed to receive HSCT and represents a higher future demand for health care services. [Table: see text]
RNA sequencing to highlight the heterogeneity in circulating exosomes from patients with esophageal squamous cell carcinoma.
Authors: Lin Yang, Wenjing Zheng, Zheng Wang, Peikun Ding, Lijuan Ling, Bin Chen, Rihong Zhai
Journal: Journal of Clinical Oncology (2017)

e15546 Background: Dissecting tumor heterogeneity is crucial for understanding tumor prognosis, response to therapy, and metastasis. But current tissue biopsy-based strategies for characterizing molecular heterogeneity are invasive and may be confounded by intra-tumor heterogeneity. Here we explore whether exosomes that contain bioactive molecules from the cell of origin can provide new noninvasive means to delineate the heterogeneity of human cancers. Methods: We used RNA-sequencing (RNA-seq) to perform unbiased profiling of mRNAs and long noncoding RNAs (lncRNAs) in plasma exosomes isolated from patients with esophageal squamous cell carcinoma (ESCC, n = 6), patients with esophagitis (n = 6), and healthy controls (n = 6). Results: The number of expressed genes detected in our data set is 63355, including 29615 lncRNAs. We found that exosomes from ESCC have dramatically distinct transcriptome and lncRNA landscapes from that of esophagitis and healthy controls, with 2278 genes and 584 lncRNAs showing differential expression between ESCC and controls; and 854 genes and 126 lncRNAs displaying differential expression between ESCC and esophagitis. We also observed variable expression of diverse transcriptional patterns related to immune response, signal transduction, cell mobility, and transmembrane protein binding, as well as differentially expressed 953 lncRNAs between Stage I and Stage II ESCC samples. Finally, we discovered that both gene and lncRNA expression profiles are variably across exosomal samples from different ESCC patients. Conclusions: Our data reveals that exosomes from ESCC contain distinct transcriptional and lncRNA profiles that separate ESCC from benign esophagitis and healthy controls. Our analysis also identifies unappreciated molecular heterogeneity in exosomes of ESCC, which may pave the way for using exosomal RNA-seq to decode molecular heterogeneity in cancers.