tbuckley/cabot-search huggingface dataset:
Bryan Eric Humphriss
Authors: David Humphriss
Journal: BMJ (2021)

Bryan Eric Humphriss was born in Woolton, a village suburb of Liverpool, and spent most of his professional life there. A general practitioner for over 30 years, he had an overriding interest in people and how he might help them.

He was educated at Quarry Bank School in Liverpool. Many years later he recalled a teenage trip to Pembrokeshire, to visit a family friend dying from tuberculosis in a cottage with water running down the walls, while next door the pig pen in which the man had worked had a new roof. The experience left him with a drive to see people treated fairly and help them where he could.

He became the first member of his family to attend …
The efficacy of PD-1 antibody sintilimab on ground glass opacity lesions in patients with early-stage multiple primary lung cancer (CCTC-1901, NCT04026841).
Authors: Bo Cheng, Bo Cheng, Caichen Li, Yi Zhao, Jianxing He
Journal: Journal of Clinical Oncology (2021)

8545 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been proven its significant efficacy on advanced non-small cell lung cancer (NSCLC). However, it remains unknown and is of great interest whether the PD-1 antibody affects early-stage lung cancer. Here, we reported the preliminary efficacy and safety outcomes of sintilimab on these early-stage GGO lesions in patients (pts) with multiple primary lung cancer in the CCTC-1901 study, the first trial evaluating PD-1 antibody in preinvasive or low invasive lung cancer worldwide. Methods: This single-center, phase II, Simon's two-stage design trial included pts who had a pathological diagnosis of resected lung cancer and at least one unresectable GGO lesion suspicious malignant which evaluated by a multidisciplinary team's consensus. The enrolled pts received 4 cycles of intravenous sintilimab 200 mg every 3 weeks. The primary endpoint is the objective response rate (ORR) of unresectable GGO lesions. For persistent GGO lesions that did not respond to treatment, either observation or second operation was taken. Also, immune biomarkers (T/B/NK subpopulation etc.) were monitored during treatment to validate the immune activity. Results: A total of 36 pts were included, with median age 59.5 (53.5-69), 66.7% females, 80.6% never smokers. All resected lesions were adenocarcinomas, of which 52.8% were EGFR mutated. 49 unresected GGOs (pure 11[22.4%], mixed 38[77.6%]) were defined as target lesions from 36 enrolled pts, with a mean size of 13.20±5.06 mm. The ORR (RECIST v1.1) was 5.6% (2/36, 1 PR and 1 CR); none of the pts had PD. Additionally, 3 non-target lesions (unresected solid lesions) from 3 included pts showed PR after the treatment of sintilimab, and the rest lesions (target or non-target) of 31 pts performed SD. Grade 1-2 fatigue (13, 36%), rash (13, 36%) and arthralgia (8, 22%) were the most common treatment-related adverse events (TrAEs), and no grade 3-5 TrAEs occurred. The proportion of CD8 + T-cell and the ratio of CD8 + /CD4 + in 5 patients who showed PR of unresected lesions were significantly higher compared to those with SD lesions at baseline (CD8 + 36.6% vs 24.6%, p &lt; 0.01; CD8 + /CD4 + 1.09±0.18 vs 0.64±0.22, p &lt; 0.01). Conclusions: This study is the first to confirm that PD-1 antibody sintilimab has immune-related antitumor activity on GGO-featured lung cancer and could be well tolerated among pts with early-stage lung cancer. Clinical trial information: NCT04026841.
A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01).
Authors: Kiyotaka Yoh, Yasushi Goto, Michael Thomas, Alexander I. Spira, Jacob Sands, Melissa Lynne Johnson, Jonathan Greenberg, Adam Matthew Petrich, Ferdinand M. Guevara, Penny Phillips, Ekaterine Alexandris, Jessie Gu, Yong Zhang, Dale Edward Shuster, Aaron Elliott Lisberg
Journal: Journal of Clinical Oncology (2021)

TPS9127 Background: Treatment options are limited for patients with advanced/metastatic NSCLC without driver genomic alterations after failure of a platinum-based chemotherapy and immunotherapy; median survival is &lt; 1 year. Datopotamab deruxtecan (Dato-DXd; DS-1062) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Results from the ongoing phase 1 study (TROPION-PanTumor01; Spira, WCLC 2020) demonstrated an overall response rate (ORR) of 21%, a disease control rate (DCR) of 67%, and a preliminary median progression-free survival (PFS) of 8.2 months (all by blinded independent central review [BICR]), with a manageable safety profile, in patients with NSCLC who were treated with 6 mg/kg of Dato-DXd. This phase 3 study (NCT04656652) will compare the efficacy of Dato-DXd with that of docetaxel as 2/3L therapy in patients with advanced/metastatic NSCLC. Methods: TROPION-Lung01 is an open-label, phase 3, randomized study of Dato-DXd vs docetaxel in patients with advanced/metastatic NSCLC without EGFR, ALK, or other actionable genomic alterations. Patients must have been previously treated with platinum-based chemotherapy and a PD-(L)1 monoclonal antibody in combination or sequentially and have radiographic disease progression on or after the most recent therapy. Those with asymptomatic and stable/treated brain metastases are eligible. A tumor specimen is required for biomarker analyses. Patients (N = 590) are randomized 1:1 to either Dato-DXd 6 mg/kg or docetaxel 75 mg/m 2 given intravenously on day 1 of each 3-week cycle. Randomization is stratified by histology (squamous vs nonsquamous), immunotherapy in last regimen (yes vs no), and region (US/Japan/Western Europe vs rest of world). Treatment continues until disease progression or intolerance or other discontinuation criteria are met. The study will be conducted globally at approximately 184 study sites. Dual primary endpoints are PFS by BICR and overall survival. Secondary outcome measures include PFS by investigator, ORR, duration of response, DCR, and time to response (all assessed by BICR and by investigator per RECIST version1.1), patient-reported outcomes, safety, pharmacokinetics, and proportion of patients who develop antidrug antibodies. Biomarkers will be evaluated for potential associations with efficacy. Clinical trial information: NCT04656652.
Proton pump inhibitor use (PPI) in patients treated with immune checkpoint inhibitors (ICI) for advanced cancer: Survival and prior therapy.
Authors: Marium Husain, Menglin Xu, Sandipkumar Patel, Andrew Johns, Madison Grogan, Mingjia Li, Gabrielle Lopez, Abdul Miah, Rebecca Hoyd, YunZhou Liu, Mitchell Muniak, Tyler Haddad, Gabriel Tinoco, Kari Lynn Kendra, Gregory Alan Otterson, Carolyn J Presley, Daniel Spakowicz, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2021)

2633 Background: Emerging data suggest that concomitant medications (CM) influence response to ICI. CM impact the host microbiome which may mitigate tumor-immune responsiveness. PPI use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effects of PPI use in terms of prior chemotherapy or in risk for immune related adverse events (irAE) (e.g., colitis). Methods: This retrospective study of patients with advanced cancer treated with ICI between 2011 and 2019 was conducted at The Ohio State University. Patients who received ICI as either single agent or combination were included. Clinical data was abstracted from chart review, including CM, toxicity, and survival. Overall survival (OS) was evaluated to date of death or last contact. Associations between OS and proton pump inhibitor (PPI) use were studied using log-rank tests and Cox regression analyses overall and by the groups of whether prior chemotherapy was administered and timing from chemotherapy to ICI. The associations between PPI and incidence of irAE (overall and colitis) were assessed by chi-square tests. Results: We identified 1,091 patients treated with ICI, of whom 415 (38%) received PPI at time of ICI. Most common cancers were NSCLC and melanoma; most common therapy was PD1/L1 (Table). PPI use was associated with shorter OS in patients treated as first line therapy (HR = 1.46, 95% CI = [1.11, 1.91], p=0.006) and in second line and beyond (HR = 1.30, 95% CI = [1.10, 1.53], p=0.002). PPI use was associated with shorter OS in patients treated with ICI for those without prior chemotherapy (HR = 1.47, 95% CI = [1.17, 1.86], p=0.001). When evaluated by timing from chemotherapy to ICI, PPI use was associated with shorter OS only in patients where last chemotherapy was &gt; 1 year from ICI (HR = 1.99, 95% CI [1.15, 3.45], p=0.014) but not for patients with chemotherapy within 1 year of ICI (HR = 1.01, 95% CI = [0.79, 1.29], p=0.960). The use of PPI was not associated with incidence of irAE (p=0.317) or colitis in particular (p=0.781). Conclusions: PPI use was associated with shorter survival in patients treated with ICI across a broad variety of cancers and in first line of therapy or beyond. In patients with recent chemotherapy (&lt;1 year), PPI use was not associated with survival, which may be due to disruption of the microbiome by chemotherapy. Further study is needed to determine the impact of CM (e.g, PPI), on outcomes of patients treated with ICI.[Table: see text]
Timing of Defibrotide Initiation in Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) and Multi-Organ Dysfunction (MOD) after Hematopoietic Stem Cell Transplantation (HSCT): Results from a Retrospective Chart Review
Authors: Kathy Del Pino, Nathan Rustay, Kira Mamedov
Journal: Blood (2017)
Abstract NT-091: TGF-β1-INDUCED CHEMORESISTANCE IS REVERSED BY BG-4 PEPTIDE
Authors: Vermont P Dia
Journal: Clinical Cancer Research (2019)

Abstract Transforming growth factor-β (TGF-β) superfamily plays a significant role in ovarian physiology but dysregulated TGF-β signaling is associated with promotion of ovarian carcinogenesis. TGF-β signaling in ovarian cancer favors cancer invasion and metastasis and controls ovarian cancer cell proliferation. The objective of this study is to determine the ability of a food-derived peptide, called BG-4, to suppress TGF-β1 signaling in ovarian cancer cells. BG-4 is a novel bioactive peptide isolated from the seeds of Momordica charantia with demonstrated anticancer and strong trypsin inhibitory properties. Different ovarian cancer cells (A2780-1A9, BR and PEO4) were exposed to 10 ng/mL TGF-β1 with or without non-cytotoxic dose of BG-4 (100 µg/mL) and response to chemotherapeutic reagents paclitaxel and cisplatin was evaluated. In addition, markers of epithelial-to-mesenchymal transition (EMT) and apoptosis were evaluated using western blot and immunofluorescence microscopy. TGF-β1 treatment resulted in cisplatin resistance in three cell lines as evidenced by increase in ED50 values from 42.9 µM to 88.5 µM, 53.7 µM to 108.3 µM and 44.8 µM to 67.3 µM for BR, PEO4 and A2780-1A9 cells, respectively. In the presence of BG-4, ED50 values of 35.6 µM, 56.4 µM and 46.6 µM were obtained for BR, PEO4 and A2780-1A9 cells, respectively. These values are similar to non-TGF-β1-treated cells indicating the ability of BG-4 to reverse TGF-β1-induced chemoresistance in ovarian cancer cell lines. Mechanistic studies showed that TGF-β1 signaling induces EMT in ovarian cancer cells as shown by differential expression of epithelial marker E-cadherin and mesenchymal markers N-cadherin, vimentin and transcription factors Snail, Slug and Twist1. In addition, the expression of apoptosis markers were affected by TGF-β1 signaling. On the other hand, treatment of TGF-β1 in the presence of 100 µg/mL BG-4 led to reversal of the EMT process. These results showed that the ability of BG-4 to reverse TGF-β1-induced chemoresistance in ovarian cancer cell lines may be associated with inhibition of the EMT process. Citation Format: Vermont P Dia. TGF-β1-INDUCED CHEMORESISTANCE IS REVERSED BY BG-4 PEPTIDE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-091.
IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts
Authors: Sorel Kurbegovic, Karina Juhl, Kasper Kildegaard Sørensen, Julie Leth, Gro Linno Willemoe, Anders Christensen, Yvonne Adams, Anja Ramstedt Jensen, Christian von Buchwald, Jane Skjøth-Rasmussen, Michael Ploug, Knud J. Jensen, Andreas Kjaer
Journal: Theranostics (2021)

Glioblastoma (GBM) is a devastating cancer with basically no curative treatment. Even with aggressive treatment, the median survival is disappointing 14 months. Surgery remains the key treatment and the postoperative survival is determined by the extent of resection. Unfortunately, the invasive growth with irregular infiltrating margins complicates an optimal surgical resection. Precise intraoperative tumor visualization is therefore highly needed and molecular targeted near-infrared (NIR) fluorescence imaging potentially constitutes such a tool. The urokinase-type Plasminogen Activator Receptor (uPAR) is expressed in most solid cancers primarily at the invading front and the adjacent activated peritumoral stroma making it an attractive target for targeted fluorescence imaging. The purpose of this study was to develop and evaluate a new uPAR-targeted optical probe, IRDye800CW-AE344, for fluorescence guided surgery (FGS). Methods: In the present study we characterized the fluorescent probe with regard to binding affinity, optical properties, and plasma stability. Further, in vivo imaging characterization was performed in nude mice with orthotopic human patient derived glioblastoma xenografts, and we performed head-to-head comparison within FGS between our probe and the traditional procedure using 5-ALA. Finally, the blood-brain barrier (BBB) penetration was characterized in a 3D BBB spheroid model. Results: The probe effectively visualized GBM in vivo with a tumor-to-background ratio (TBR) above 4.5 between 1 to 12 h post injection and could be used for FGS of orthotopic human glioblastoma xenografts in mice where it was superior to 5-ALA. The probe showed a favorable safety profile with no evidence of any acute toxicity. Finally, the 3D BBB model showed uptake of the probe into the spheroids indicating that the probe crosses the BBB. Conclusion: IRDye800CW-AE344 is a promising uPAR-targeted optical probe for FGS and a candidate for translation into human use.
Venous thromboembolism in patients on check point inhibitors.
Authors: Upama Giri, Xiao Yu, Karen Resnick, Travis Larsen, Gino Kim In
Journal: Journal of Clinical Oncology (2021)

e14582 Background: Checkpoint inhibition (CPI) therapy, including PD-1/PD-L1 and CTLA-4 inhibition strategies, has significantly improved the prognosis for patients with advanced malignancies. Anticancer treatments like chemotherapy and antiangiogenic agents are associated with higher rate of cancer associated thrombosis. However, the association of CPI with venous thromboembolism (VTE) is not well established. Methods: We conducted a retrospective cohort study of patients with advanced malignancy who were started on CPI between 2016 and 2019 at a tertiary care medical center in Southern California. We used descriptive statistics to describe the occurrence of VTE. Logistic regression was used to identify factors that had a significant impact on occurrence of VTE. Results: The cohort comprised 240 patients with median age of 60 years (range 27-96) at initiation of CPI and majority of the patients were males (57%). 45% were Hispanic, followed by Asian (19%), Caucasian (18%) and African American (8%). 80% had metastatic disease and the most common indication for use of CPI was lung cancer (20%), followed by gynecological malignancies (19%) including ovarian, endometrial and cervical cancer, melanoma (15%) and genitourinary malignancies (15%) including renal and urothelial cancer. The most used agent was nivolumab (68%) followed by pembrolizumab (25%), with most patients receiving single agent CPI (94%). Combination CPI and CPI with other agents including chemotherapy or targeted therapy was given to 3% and 4% respectively. The incidence of VTE was 10% (24/240) – pulmonary embolism (5), upper extremity deep vein thrombosis (5), lower extremity deep vein thrombosis (10) and visceral vein thrombosis (4). Patients were also stratified by Khorana score (KS) based on laboratory values and body mass indices at initiation of CPI (median score 1, range 0-4). VTEs occurred in patients on nivolumab in 8.02% of cases and in 18.2% of cases for pembrolizumab. VTEs occurred in 7.04% of patients with initial KS 0; 8.33%, KS 1; 17.5%, KS 2; and 15.4%, KS 3. Logistic regression analysis using a significance level of p &lt; 0.05 showed no significant association between occurrence of VTE and age, sex, race, type of cancer or Khorana score. Conclusions: In our study, VTE risk in patients receiving CPI was similar to that with other systemic therapy. Further larger studies are needed to assess clinical significance of these findings, stratify for risk factors, and account for dose-dependence.
In-depth immune and molecular profiling of melanoma patients receiving adoptive T-cell therapy reveals biomarkers of efficacy in ATATIL study.
Authors: Angela Orcurto, Johanna Chiffelle, Eleonora Ghisoni, David Barras, Isaac Crespo, Blanca Navarro Rodrigo, María Ochoa de Olza, Martina Imbimbo, Sylvie Rusakiewicz, Stephanie Tissot, Philippe O Gannon, Urania Dafni, Stefan Zimmermann, Lana E. Kandalaft, Olivier Michielin, Michal Bassani-Sternberg, Denarda Dangaj, Lionel Trueb, Alexander Harari, George Coukos
Journal: Journal of Clinical Oncology (2021)

2533 Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has demonstrated a curative potential for patients with metastatic melanoma (MM). Nevertheless, activity remains unsatisfactory in many patients, requiring development of biomarkers that predict therapeutic efficacy. We report results of a single-center phase I study to assess feasibility, safety and efficacy of TIL-ACT in MM patients (NCT03475134). Methods: Patients with MM refractory to at least one prior line of therapy received TIL therapy with lymphodepleting chemotherapy before T-cell infusion, followed by high-dose interleukin-2. RDG- and FDG-PET imaging was performed before and after TIL infusion. Multispectral immuno-fluorescence (mIF) imaging and bulk-RNA sequencing (Seq) were performed on tumor samples pre-ACT and post-ACT (day+30 and upon progression). Single-cell RNA-Seq and TCR-Seq were performed on pre-ACT tumor and ACT product, as well as on tumor-reactive and neoantigen-specific TILs and on longitudinal blood samples. Results: As of 02/02/2021, thirteen patients (enrolled between March 2018 and December 2020) have successfully completed TIL-ACT therapy, with a median follow-up of 9.5 months (IQR 3.0 -24.6). Median age was 53 years (range 20-69) and all were previously treated with PD-1 based blockade. Median number of TILs infused was 55.0 x10 9 cells (range 12.8-84.7). The best overall response rate by RECIST 1.1 and disease control rate in evaluable patients was 41.7% (5/12) and 50% (6/12) respectively at 3 months. Two patients have an ongoing near-complete response at 3 years. Up to data cut-off, 10 patients have progressed by RECIST v1.1, with median PFS of 4.8 months (95% CI 1.5 - 9.6), while median OS is not reached. mIF revealed biomarkers of response, which may allow proper identification of patients in subsequent studies. In addition, deep sequencing of bulk and neoepitope-specific TIL clonotypes highlighted transcriptomic signatures revealing cell programs regulating in vitro expansion, in vivo blood persistence as well as tumor infiltration post-ACT. RGD-PET data will also be presented. Conclusions: We demonstrate reproducibility of TIL-ACT in our center, consistently with previous reports. Comprehensive translational studies reveal immune correlates of clinical responses that contribute to the understanding of mechanisms of TIL potency and will guide the development of next-generation cell products. Clinical trial information: NCT03475134.
Outcome of concurrent treatment with a-CTLA4 and metronidazole in murine model of colon adenocarcinoma.
Authors: Yusra B. Medik, Yifan Zhou, Laura M. Kahn, Bhakti Patel, Rachel L. Babcock, Taylor T. Chrisikos, Xianxiu Wan, Allison Dyevoich, Nadim J. Ajami, Jennifer Ann Wargo, Stephanie S. Watowich
Journal: Journal of Clinical Oncology (2021)

e14566 Background: Immune checkpoint blockade (ICB) therapy transformed clinical oncology by inducing durable responses and increasing survival rates in many types of cancers. However, ICB is effective in only in a subset of patients. Recent studies delineated the role of gut microbiome as both a biomarker and a therapeutic in ICB responsiveness. We aimed to increase understanding of the microbiome-immune system axis in ICB therapy by using antibiotics to knock out certain components of gut microbiome. Methods: We treated MC38 colon adenocarcinoma-bearing mice with a widely-used antibiotic, metronidazole, that is effective against anaerobic and protozoal infections including Clostridioides difficile – a major mediator of colitis. Metronidazole was administered via oral gavage or mixed in drinking water before and after tumor injections. Mice received twice weekly treatment with a-CTLA4 ICB. Results: Metronidazole treatment alone slowed the growth rate of MC38 tumors, consistent with the current literature regarding colon cancer murine models. When metronidazole treatment was combined with a-CTLA4 therapy, we found ̃90% complete tumor regression. In the metronidazole and a-CTLA4 combination group, we also observed an increase in the number of CD103 + type 1 conventional dendritic cells (cDC1s) in colon lamina propria, which suggests enhanced antigen sampling from lumen. Also, in the mesenteric lymph nodes (mLN), we detected upregulation of CD80 and CD86 co-stimulatory molecule expression on CX3CR1 + antigen presenting cells. Multiplex analysis of colon cytokines and colon pathology evaluation was comparable among groups, which implies a non-inflammatory environment in colon. Analysis of tumor-draining lymph nodes eight days after tumor injections showed higher expression of CD86 on CD103 + cDC1s implying superior anti-tumor immunity. 16S rRNA gene sequencing analysis of fecal samples revealed loss of Lachnospiraceae and enrichment of Bifidobacteriaceae and Sutterellaceae families in metronidazole-treated mice. Conclusions: Shifting microbiome composition with metronidazole treatment elicits a favorable anti-tumor immune response to a-CTLA4 treatment in murine colon adenocarcinoma.