tbuckley/cabot-search huggingface dataset:
Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy
Authors: Fernando C. Fervenza, Gerald B. Appel, Sean J. Barbour, Brad H. Rovin, Richard A. Lafayette, Nabeel Aslam, Jonathan A. Jefferson, Patrick E. Gipson, Dana V. Rizk, John R. Sedor, James F. Simon, Ellen T. McCarthy, Paul Brenchley, Sanjeev Sethi, Carmen Avila-Casado, Heather Beanlands, John C. Lieske, David Philibert, Tingting Li, Leslie F. Thomas, Dolly F. Green, Luis A. Juncos, Lada Beara-Lasic, Samuel S. Blumenthal, Amy N. Sussman, Stephen B. Erickson, Michelle Hladunewich, Pietro A. Canetta, Lee A. Hebert, Nelson Leung, Jay Radhakrishnan, Heather N. Reich, Samir V. Parikh, Debbie S. Gipson, Dominic K. Lee, Bruno R. da Costa, Peter Jüni, Daniel C. Cattran
Journal: New England Journal of Medicine (2019)

B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06).Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).
Abstract 1178: Image-based quantification of tumor-immune cell interactions in 3D cultures
Authors: Gera Goverse, Nataliia Beztsinna, Kuan Yan, Leo Price, Lidia Daszkiewicz
Journal: Cancer Research (2019)

Abstract INTRODUCTION Increasing numbers of cancer patients that benefit from immunotherapies and maintain durable response requires understanding of cellular mechanisms that govern anti-tumor immune responses. However, the mechanisms of action of these treatment modalities are not fully understood and the progress in this direction is hampered by a lack of appropriate pre-clinical testing models that are both clinically relevant and suitable for routine screening of drug candidates. Therefore, we developed a robust in vitro assay that allows image based analysis of 3D cultures in a high-throughput set-up. Here, immune cells are co-cultured with cancer cells in a 3D environment which recapitulates the tumor micro-environment and its complex cellular interactions. Functional read-outs, such as active migration of immune cells towards tumoroids, infiltration of immune cells into the tumoroids and their killing lead to a better understanding of the immune-modulatory profile of different immunotherapies. MATERIAL and METHOD Tumoroids generated from cancer cell lines (e.g. breast, prostate) and colorectal cancer organoids (from HUB Organoid Technology) were cultured in protein hydrogel. Different immune cells, such as PBMCs, T cells, dendritic cells or macrophages, with and without activation were added to the 3D culture and their infiltration into tumoroids and subsequent killing was visualized using high-content microscopy. Quantification of immune cell effects was achieved with morphometric analysis with OMinerTM software. RESULTS and DISCUSSION Image-based analysis enabled the discrimination of immune-tumor cell interactions in 3D cultures. These results demonstrated the effect of immune cell targeting on the tumor progression. Different levels of immune cells infiltration and killing of tumoroids and organoids were measured depending on the activation status of immune cells. The 3D environment, both for the cell culture and image analysis, allows for measurement of spatially resolved information, not accessible by monolayer cultures or biochemical assays. CONCLUSION Our image-based platform described here allows for analysis of immunotherapy effects on different cell types that engage in a more physiologically relevant spatial setting than when culturing them in traditional 2D cultures. Visualization and quantification of these tumor-immune cells interactions offer a highly powerful tool for cancer immunotherapy drug developers to understand the mechanism of action of their treatments and ultimately translating to a better clinical performance. Citation Format: Gera Goverse, Nataliia Beztsinna, Kuan Yan, Leo Price, Lidia Daszkiewicz. Image-based quantification of tumor-immune cell interactions in 3D cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1178.
Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA.
Authors: Saad Zafar Usmani, Thierry Facon, Shaji Kumar, Torben Plesner, Philippe Moreau, Supratik Basu, Hareth Nahi, Margaret Macro, Hang Quach, Aurore Perrot, Chris Venner, Katja Weisel, Noopur S. Raje, Michel Attal, Xavier Leleu, Maria Krevvata, Jianping Wang, Rachel Kobos, Cyrille Hulin
Journal: Journal of Clinical Oncology (2019)

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts &lt;75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (&lt;75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for &lt;75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both &lt;75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10 -5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (&lt;75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in &lt;75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]
Abstract 11626: Predictors for Neoatherosclerosis: A Retrospective Observational Study from the Optical Coherence Tomography Registry
Authors: Taishi Yonetsu, Koji Kato, Soo-Joong Kim, Lei Xing, Haibo Jia, Iris McNulty, Hang Lee, Shaosong Zhang, Shiro Uemura, Yangsoo Jang, Soo-Jin Kang, Seung-Jung Park, Stephen Lee, Bo Yu, Tsunekazu Kakuta, Ik-Kyung Jang
Journal: Circulation (2012)

Background: Recent studies have reported development of neoatherosclerosis (NA) inside the stents several years after stent implantation. The aim of this study was to determine the predictors for N...
Abstract 169: Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior
Authors: Shantel M. Angstadt
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) composes more than 80% of all pancreatic cancers and about 95% of exocrine pancreatic cancers. Patients typically present with symptoms post metastatic spread, which contributes to its overall lethality as the 3rd leading cause of cancer-related deaths with a median 5-year survival rate of about 8%. We are investigating the role of the myosin phosphatase targeting subunit 1 (MYPT1) in PDAC. MYPT1 serves as an interaction platform between a catalytic phosphatase subunit and the phosphorylated regulatory light chain (MLC) of myosin, allowing for MLC dephosphorylation and myosin inactivation. MYPT1 has been shown to elicit an antibody response in PDAC patients treated with a cytokine-secreting whole tumor cell vaccine. Additionally, MYPT1 has been shown to be upregulated in PDAC cells through immunohistological staining of surgically resected patient samples and in established PDAC cell lines. As a major regulator of non-muscle myosin II, MYPT1 has implications in cancer cell shape control, adhesion, and migration. To elucidate its implications, we are characterizing tumor cell phenotype with and without MYPT1 expression using the CRISPR genome editing system. We are assessing MYPT1’s effect on cell mechanics (e.g. cortical tension), if MYPT1 responds to applied mechanical stresses, and how MYPT1 affects each of the non-muscle myosin II paralogs’ ability to respond to these mechanical stresses. We are characterizing MYPT1’s impact on cell and tissue behavior, including cell growth, migratory, and invasive phenotypes in culture and in mouse models. Overall, our work will provide insight into MYPT1’s role in cancer cell behavior and response to its surrounding environment. The work will also provide insight for early investigations into MYPT1’s targetability and immunogenic role in PDAC immunotherapy. Citation Format: Shantel M. Angstadt. Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 169.
Abstract 3241: Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models
Authors: Chaoshe Guo, Benny(Yi) Yang, Jian Ni, Yanan Guo, Tian Gan
Journal: Cancer Research (2019)

Abstract CD40 (Cluster of Differentiation 40) is a member of the TNF-receptor superfamily. CD40 is a co-stimulatory protein found primarily on antigen presenting cells, including B cells, macrophages and dendritic cells. Its ligand, CD40L (CD154) is predominantly expressed on T helper cells, whose engagement activates antigen presenting cells and induces a variety of positive downstream effects. Whereas most immune checkpoint receptors are expressed on the surface of T cells, CD40 stands out as it is expressed by antigen presenting cells and controls the proper activation of these cells. In turn, CD40 activation exerts a significant impact on T cell-mediated activity against cancer cells. Several pharmaceutical companies are pursuing anti-CD40 therapies for treating hematological and solid cancers. Therefore, it is imperative to develop novel CD40 antibodies to boost cancer patients’ own immunity in light of other successful immune checkpoint modulators. We asked whether we could find suitable anti-CD40 reagents that successfully combat developed tumors in preclinical settings. We designed a powerful screening strategy based on Biocytogen’s in vivo drug screening platform. Candidate antibodies were generated by immunizing wild-type mice with recombinant hCD40 protein. Hybridomas were then screened by high-throughput flow cytometry. Instead of examining the immune modulating activity in cell culture, we tested these antibodies in B-hCD40 mice bearing MC38 tumors and monitored the tumor growth. Through this straightforward screening strategy, several clones stood out by their unparalleled benefits. These clones were further selected for humanization. Furthermore, we identified that one clone works in concert with Keytruda in the dual humanized model of h-CD40 and h-PD1. In conclusion, we uncovered CD40 antibody candidates with the most potent anti-tumor activity which are promising as tools for cancer treatment in the preclinical setting. Citation Format: Chaoshe Guo, Benny(Yi) Yang, Jian Ni, Yanan Guo, Tian Gan. Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3241.
Statin Use Is Associated with Decreased Mortality in Multiple Myeloma— a SEER Medicare Study
Authors: Shivaprasad Manjappa, Mark A. Fiala, Pavan Kumar Bhamidipati, Keith E. Stockerl-Goldstein, Mark A. Schroeder, Armin Ghobadi, Ravi Vij, Tanya M. Wildes
Journal: Blood (2017)
Abstract 679: Quantitative systems pharmacology modeling of immunotherapies in B-cell acute lymphoblastic leukemia
Authors: Oleg Demin, Antonina Nikitich, Oleg Demin
Journal: Cancer Research (2019)

Abstract Introduction: Multiple T-cell engaging antibody-based molecules and CAR-T therapies are in development for the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Moreover, two therapies have already been approved by FDA: blinatumomab (CD19/CD3 bispecific T-cell engager) and tisagenlecleucel (anti-CD19 CAR-T therapy). This work employs quantitative systems pharmacology (QSP) modeling approach to investigate factors affecting outcomes of administration of such types of therapy. Methods: Model was developed on the basis of Immune Response Template (QSP model of immune system). It describes leukemic blasts, hematopoiesis of normal B cells, CD4+ and CD8+ T-cell subsets, and cytokines (IL-6, TNFα, IFNγ, TGFβ, etc.) in bone marrow and blood. The model takes into account the different level of expression of CD19 on various subsets of normal B cells and leukemic cells. Model parameters were estimated and fitted against in vitro, in vivo human data. Small part of clinical data on blinatumomab and anti-CD19 CAR-T therapies was used for model calibration, other part was used for model validation. Results: Our model reproduced clinically relevant blinatumomab and anti-CD19 CAR-T hallmark data including depletion of CD19+ cells, T-cell subset dynamics and cytokine release post infusion. The model successfully described the clinically observed phenomenon on progressive cytokine release attenuation with subsequent blinatumomab treatment cycles. It confirmed the dose step strategy for decreasing initial cytokine release. Model showed that treatment outcome is very sensitive to target expression, level of immune cells, disease progression rate and expression of PD-L1 on leukemic cells. The proportion of CD19+ and CD19- leukemic blasts before treatment can be used as a biomarker to predict probability of relapse in patients to stratify patients. Conclusions: This work provides a quantitative modeling framework to predict responses to immunotherapies in B-ALL on the basis of realistic baseline conditions and reveal the factors affecting treatment outcome. Citation Format: Oleg Demin Jr, Antonina Nikitich, Oleg Demin. Quantitative systems pharmacology modeling of immunotherapies in B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 679.
Abstract 4086: Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR Inhibitors
Authors: Dinesh Chikkanna, Kishore Narayanan, Sunil Panigrahi, Garima Priyadarshini, Megha Goyal, Jiju Mani, DS Samiulla, Sagar dadhania, AB Aravind, Girish Daginakatte, Thomas Anthony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra
Journal: Cancer Research (2019)

Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ecto-nucleotidases including CD73 hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Inhibitions of either adenosine generation or signaling by inhibiting CD73 or A2AR have been shown to be effective therapeutic approaches. Interestingly, the co-blockade of CD73 and A2AR results in a more pronounced anti-tumor activity than blockade of either, likely due to increased CD73 expression upon A2AR inhibition and compensatory activity of other adenosine receptors such as A2BR. In view of this, we sought to discover and develop small molecule inhibitors that dually target CD73 and A2AR with oral bioavailability for ease of administration and use in combination with other anti-cancer therapies. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and CD73 in respective biochemical and cellular assays. High potency translated into rescue of NECA or AMP induced repression of IFNΥ and IL2 in human PBMCs. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. In Syngeneic tumour model, treatment with lead compounds resulted in significant tumour growth inhibition while correlating well with tumour drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumour models and in vivo toxicity studies is currently under way. Citation Format: Dinesh Chikkanna, Kishore Narayanan, Sunil Panigrahi, Garima Priyadarshini, Megha Goyal, Jiju Mani, DS Samiulla, Sagar dadhania, AB Aravind, Girish Daginakatte, Thomas Anthony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR Inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4086.
P-80 TRYbeCA-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma
Authors: P. Hammel, R. Berardi, G. Creemers, E. Van Cutsem, A. Cubillo, R. Greil, H. Wasan, J. Metges, M. Noel, P. Nygren, P. Osterlund, T. Seufferlein, T. Macarulla, C. Fountzilas, A. Gupta, L. Grummer, S. Kacel, N. Biswas-Baldwin, R. Kay, H. Youssoufian, I. El-Hariry, M. Hidalgo
Journal: Annals of Oncology (2020)
Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice
Authors: Karin Steinbach, Ilena Vincenti, Kristof Egervari, Mario Kreutzfeldt, Franziska van der Meer, Nicolas Page, Bogna Klimek, Irène Rossitto-Borlat, Giovanni Di Liberto, Andreas Muschaweckh, Ingrid Wagner, Karim Hammad, Christine Stadelmann, Thomas Korn, Oliver Hartley, Daniel D. Pinschewer, Doron Merkler
Journal: Science Translational Medicine (2019)

Resolved brain virus infection early in life leaves persisting chemotactic cues that foster brain autoimmunity in adulthood.
A culturally adapted, multidisciplinary psychoeducation program for early-stage breast cancer survivors in Asia: A randomized, controlled trial [Conference Abstract]
Authors: Alexandre Chan, Terence Ng, Suan Kai Oh, Tewodros Eyob, Maung Shwe, Yan Xiang Gan, Ray Chan, Rebecca Dent, Raymond Ng, Mabel Tan, Brandon Goh, Yee Pin Tan, Gilbert Fan
Journal: Journal of Clinical Oncology (2016)

Background: As cancer mortality rates improve in Asia, there is an increasing need to improve the transition to post-treatment survivorship care. However, culturally appropriate standardized survivorship programs are lacking in this region. This study aimed to evaluate the effectiveness of a culturally adapted psychoeducation program (PE) compared with usual care (UC) to reduce distress and symptoms in Asian breast cancer survivors who have completed adjuvant chemotherapy. Methods: This was a randomized, controlled trial in 72 Asian early-stage breast cancer survivors who were randomized into either the PE (n = 34) or the UC (n = 38) arms. Participants in the PE arm underwent a weekly multidisciplinary psychoeducation program, delivered in a group format over 3 weeks, based on current recommendations from the United States Institute of Medicine, coupled with cultural adaptation. Both arms were assessed at baseline and 2 months post-intervention using the Rotterdam Symptom Checklist and EORTC-QLQ-C30. Effect sizes were calculated using Cohen’s d. Results: The mean age ± SD of all participants was 53.0 ± 8.9 years, with majority being Chinese (84.7%) and Malay (6.9%). At baseline, clinical characteristics and outcome measures were well balanced in both arms. Comparing to UC, there was a significant lower levels of physical symptom distress (d= 0.76, p = 0.01) and fatigue (d= 0.49, p = 0.04). There was also a trend towards less appetite loss (d= 0.46, p = 0.06), less constipation (d= 0.45, p = 0.06) and activity level improvement (d= 0.37, p = 0.14) in the PE arm comparing to the UC arm. Conclusions: A culturally adapted, multidisciplinary psychoeducation program was effective to reduce physical distress and symptoms in Asian breast cancer survivors. Clinical trial information: NCT02600299.