tbuckley/cabot-search huggingface dataset:
Phase I/II, open-label, 2-arm study to evaluate safety, tolerability, and clinical activity of GSK2857916 in combination with 2 standard-of-care (SoC) regimens in relapsed/refractory multiple myeloma: (DREAMM 6).
Authors: Luciano J. Costa, Hang Quach, Keith Stockerl-Goldstein, Bradley Augustson, Geraldine Ferron-Brady, Bikramjit Chopra, Allie Moore, Sophia Hudson, Jiangxiu Zhou, Veronique Bragulat, Mala Kiran Talekar, Joanna Opalinska
Journal: Journal of Clinical Oncology (2019)

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.
Abstract 1547: DNA-encoded bispecific T-cell engagers and antibodies present long-term antitumor activity
Authors: Alfredo Perales-Puchalt, Elizabeth K. Duperret, Kar Muthumani, David B. Weiner, Xue Yang, Xizhou Zhu, Krzysztof Wojtak, Edgar Tello-Ruiz, Megan C. Wise
Journal: Cancer Research (2019)

Abstract Specific antibody therapy, including monoclonal antibodies and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery and in vivo production would be an important advance. Here we describe development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2DMAb) and delivered it into animals through adaptive electroporation. HER2DMAb was efficiently expressed in vitro and in vivo, reaching levels of 50ug/ml in mouse sera. Mechanistically, HER2DMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2DMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2DMAb scFv portion to engineer a DNA-encoded BiTE. This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate a novel approach to generate DBiTEs in vivo which represent promising immunotherapies for HER2+ tumors including ovarian and potentially other cancers. Citation Format: Alfredo Perales-Puchalt, Elizabeth K. Duperret, Kar Muthumani, David B. Weiner, Xue Yang, Xizhou Zhu, Krzysztof Wojtak, Edgar Tello-Ruiz, Megan C. Wise. DNA-encoded bispecific T-cell engagers and antibodies present long-term antitumor activity [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 1547.
Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis.
Authors: Joel W. Neal, Daniel Hausrath, Heather A. Wakelee, Kristen Cunanan, Stephen V. Liu, Mandeep Banwait, Lecia V. Sequist, Kevin Stirling, Zofia Piotrowska
Journal: Journal of Clinical Oncology (2019)

9083 Background: First generation EGFR TKIs are well tolerated with chemotherapy (chemo), and have evidence of improved efficacy in EGFR-mutant NSCLC. Osimertinib (osi) is a 3rd-generation EGFR TKI with improved T790M and CNS activity. Safety and outcome data combining osi and concurrent chemo are limited. Methods: EGFR-mutant pts who received osi with chemo between 12/2015 and 8/2018 were retrospectively identified at two institutions. Pt demographics, toxicities and outcomes were collected by chart review. Results: 35 pts received osi + chemo, 29/35 pts had CNS mets. 16/35 had &gt; = one prior chemo and/or immunotherapy, 34/35 previously received a 1 st /2nd gen EGFR TKI (25/35 T790M+ at progression), and all 35 had prior progression on osi. 47 osi + chemo regimens were abstracted: carboplatin/pemetrexed+/-bevacizumab (n = 17), cisplatin/pem (1), carbo/taxane (2), pem+/-bev (7), taxane (7), gemcitabine (8), irinotecan (3), vinorelbine (2); 32/35 pts had platinum. Osi was dosed at 80 mg QD (32), 160 mg QD (2), or 80mg QOD (1). Toxicities (table) occasionally led to treatment delay (n = 5), osi dose-reduction (2) and discontinuation (3). Median overall survival (mOS) from metastatic diagnosis was 48.4 mo (95% CI 30.7-NR); mOS from first osi was 19.6 mo (95% CI 16.1-32.6). Median duration of treatment (mDOT) for first regimen of chemo + osi was 5.3 mo (95% CI 4.1-9.5); stratifying by chemo, mDOT for platinum doublet + osi was 6.1 mo (95% CI 4.7-NR) and mDOT for osi + single agent was 3.2 mo (95% CI 2.4-5.3). In the 29 pts with brain mets receiving their first regimen of osi + chemo, 6 had CNS progression but only 2 required radiation at progression. Conclusions: Osimertinib is tolerable in combination with many standard chemo regimens for EGFR-mutant NSCLC. mDOT for platinum doublet and single agent are similar to historical controls, but CNS disease control appears better than expected for chemotherapy alone. Adding chemotherapy at the time of progression on osimertinib may be considered for selected pts, particularly those with known CNS mets. [Table: see text]
Abstract 1196: Induction of NKG2D ligand expression by CD8+ T cells through a nuclear factor-kappa B and P300/CBP-associated factor-dependent mechanism
Authors: Jiemiao Hu, Xueqing Xia, Shulin Li
Journal: Cancer Research (2019)

Abstract The ligands for the natural-killer group 2 (NKG2D) protein are frequently expressed on tumor cell surfaces, rendering tumor cells susceptible to NKG2D-dependent immune cell attack. However, cancer cells escape from immune surveillance by downregulating NKG2D ligands. We previously discovered that the engagement of activated CD8+ T cells and tumor cells induces NKG2D ligands on tumor cells, but the underlying mechanism remains to be defined. TCGA database analyses suggested that the expression of CD40 and CD137L (their cognate receptors are CD40L and CD137, respectively, expressed on CD8+T cells) is associated with pan-NKG2D ligand expression in sarcoma and colorectal adenocarcinoma patients (Pearson’s correlation coefficient r=0.2225 and 0.1947, respectively; and P=.0003 and .0002, respectively). In agreement with these human data analysis results, both in vivo mouse tumor models and in vitro cell assays validated that upon the engagement with the cognate receptors, the tumor necrosis factor receptor superfamily (TNFRSF), particularly CD137 ligand and CD40, initiates the activation of nuclear factor-kappa B (NF-κB) signaling in tumor cells even in the absence of CD8+ T cells. The same as tumor and CD8+ T contact-dependent NKG2D ligand induction, this CD137L/CD40-mediated signaling activation was associated with elevated levels of acetyltransferase P300/CBP-associated factor (PCAF), whereas inhibition of phosphorylated NF-κB abrogated PCAF induction. Although the stimulation of CD137L/CD40-mediated signaling by cognate receptors is vital for NKG2D ligand upregulation, the inflammatory cytokines, including interferon γ (IFNγ) and tumor necrosis factor α (TNFα) released from CD8+ T cells also facilitate NKG2D ligand-induced immune surveillance. These inflammatory cytokines not only trigger NF-κB signaling and PCAF activation, and they also boost T cell chemotaxis, recruit large numbers of CD8+T cells to tumor sites, and result in high yield expression of NKG2D ligands. Collectively, our results unveil a novel mechanism of NKG2D ligand upregulation involving reverse signaling of CD40 and CD137L on in tumor cells, which along with inflammatory cytokines IFNγ and TNFα, stimulate downstream NF-κB and PCAF activation. Understanding this mechanism may help to develop induced NKG2D ligand-dependent T-cell therapy against cancers. Citation Format: Jiemiao Hu, Xueqing Xia, Shulin Li. Induction of NKG2D ligand expression by CD8+ T cells through a nuclear factor-kappa B and P300/CBP-associated factor-dependent mechanism [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 1196.
Abstract 12657: Socioeconomic Environment and Vascular Disease in Different Arterial Territories: An Analysis of 3 Million Participants in the Life Line Screening Program
Authors: Matthew S Durstenfeld, Binita Shah, Yu Guo, Jinfeng Xu, Caron B Rockman, Jeffrey S Berger
Journal: Circulation (2018)

Introduction: Cardiovascular risk factors associated with the development of systemic atherosclerosis relate in part to socioeconomic environment, but the relationship between the socioeconomic env...
Abstract 14770: Myocardial Scar Predicts Mortality in Patients With Ischemic and Non-ischemic Cardiomyopathy Who Have Undergone Cardiac Resynchronization Therapy (CRT)
Authors: Serge C Harb, Nisarat Chareonsri, Zoran Popovic, Wahaj Aman, Niraj Varma, Scott Flamm, Deborah Kwon
Journal: Circulation (2015)

Introduction: Mortality in patients (pts) with cardiomyopathy (CM) remains high despite advances CRT. We sought to determine the effect of myocardial scar, as depicted by cardiac MRI (CMR), on overall mortality in patients with both ischemic (ICM) and non-ischemic cardiomyopathies (NICM) who underwent CRT placement. Methods: We studied 101 pts (48% NICM, age 62 +/- 11, 33% women) who had a CMR pre-CRT. Total scar % was measured and patients were categorized into tertiles: No scar = 0 % scar (43% of pts); moderate scar: &gt;0 but ≤19% scar (25% of pts) and extensive scar: &gt;19% (32% of patients). CRT placement occurred on average 1 year after CMR. Ejection fraction (EF) pre-CRT and more than 6 months post CRT were assessed. Pts were followed up to 14 years for the occurrence of death. Means were compared using T-test and Cox regression survival analysis was used to compare survival among groups. Results: Mean EF pre-CRT was 22.8% (SD=8) and significantly increased post CRT to 31.5% (SD=15); p&lt;0.01. There were 26 deaths over a mean of 5 years (SD +/- 3 years) from time of CRT implant. Patients with ICM had more % scar (mean=24+/-15%) compared to non-ICM (mean=2+/-5%; p&lt;0.01). On univariate survival analysis, EF pre-CRT (HR=0.9, CI=0.87-0.98, p=0.01) and EF post-CRT (HR=0.9,CI=0.93-0.99,p=0.03) were both significantly associated with survival . Death occurred significantly more in patients with ICM (HR=4.8; CI=1.4-16.3; p=0.01) and in those with any % scar compared to no scar (HR = 4.0 CI=1.2-13.5, p=0.02). Compared to those with extensive scar, pts with no scar (HR=0.2; CI=0.1-0.6, p&lt;0.01) and those with moderate scar (HR=0.3; CI=0.1-0.9; p=0.04) had better survival - figure 1. Even after controlling for the etiology of the CM (ICM vs. NICM), total scar % remained predictive of survival (p=0.02). Conclusion: In a population of patients with ICM and NICM who have undergone CRT, patients with more extensive scar had lower survival, even after adjusting for the etiology of the cardiomyopathy.
Abstract 3964: Chemotherapeutic drug-induced tumor neoantigen discovery
Authors: Julie M. Rumble, James L. Mobley, Richard Jones, Michael Ford, Michael Pisano
Journal: Cancer Research (2019)

Abstract Checkpoint inhibitors have shown significant efficacy against a variety of cancers, changing the way many cancers are treated. However, only a subset of patients can benefit from these therapies currently, and finding ways to increase the number of patients who can is a primary interest. Tumor mutational burden is one biomarker for checkpoint inhibitor efficacy, which may point to effective strategies for increasing tumor response to therapy. Combination of checkpoint inhibitors with existing chemotherapy is being pursued in several clinical trials, and has been shown to have synergistic effects in a mouse tumor model. Chemotherapeutic drugs work in many ways to kill tumor cells, notably by attacking DNA and its replication machinery to prevent proliferation. These DNA-targeting drugs can cause mutations in cells that are not killed outright. We hypothesize that some chemotherapeutics can cause DNA mutations that are translated into proteins and peptides that make their way into the HLA class I peptide presentation pathway. If these neoantigens are seen by CD8+ T cells as foreign, T cells will attack these tumor cells. This could provide one mechanism of action for an increase in therapeutic efficacy in tumors treated with combinations of chemotherapeutics and checkpoint inhibitors. We test the ability of two drugs, SN-38 (an active metabolite of irinotecan) and oxaliplatin to induce neoantigens by sequencing peptides from class I molecules in a colon cancer cell line. Citation Format: Julie M. Rumble, James L. Mobley, Richard Jones, Michael Ford, Michael Pisano. Chemotherapeutic drug-induced tumor neoantigen discovery [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 3964.
Abstract 365: Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib
Authors: Laetitia Marzi, Ludmila Szabova, Zoe Weaver Ohler, Shyam Sharan, Mike Beshiri, Junko Murai, Kathy Kelly, Yves Pommier
Journal: Cancer Research (2019)

Abstract To overcome the limitations of topoisomerase inhibitors, irinotecan and topotecan (chemical instability, drug efflux substrates, short half-life, dose-limiting bone marrow and gastrointestinal toxicity), we have developed the indenoisoquinolines (LMP400, LMP776 and LMP744). To rationally select patients for phase 2 clinical trials, we have taken two approaches. First, we mined the cancer cell lines genomic databases with CellMinerCDB and found that a dominant response determinant to the indenoisoquinolines is Schlafen 11 (SLFN11), a recently identified executor of cells undergoing replication stress. We validated this finding in isogenic cell lines. Second, because the major lesions generated by the trapping of TOP1 are replication-induced DNA double-strand breaks that are repaired by homologous recombination (HR), we determined whether the indenoisoquinolines exhibit a “synthetic lethality” in cells presenting BRCA1, BRCA2 or PALB2 deficiency. In addition, we tested wether this selectivity could be enhanced when combined with the PARP inhibitor, olaparib. Survival and cell cycle alterations were tested after treatment with the indenoisoquinolines as single agents in isogenic DT40, DLD1 and OVCAR cell lines, with BRCA1, BRCA2 or PALB2 deficiencies, and organoids cultured from patient-derived xenografts with BRCA2 loss, as well as in combination with olaparib. We found that BRCA1-, BRCA2- and PALB2-deficient cells are 3 to 5 times more sensitive to the indenoisoquinolines compared to isogenic cell lines. Moreover, combination treatments showed high synergy between all three indenoisoquinolines and olaparib. We also established the synergy between LMP400 (Indotecan) and olaparib in orthotopic allograft models derived from genetically engineered mouse models for serous epithelial ovarian cancer harboring BRCA1 loss. Better efficacy was observed with the combination over single agent treatments of LMP400 or olaparib. Our results provide a rationale for Phase 2 indenoisoquinoline clinical trials with the indenoisoquinolines in HR-deficient cancers as single agents and in combination with PARP inhibitors, and for measuring Schlafen 11 (SLFN11) as a clinical response determinant. Citation Format: Laetitia Marzi, Ludmila Szabova, Zoe Weaver Ohler, Shyam Sharan, Mike Beshiri, Junko Murai, Kathy Kelly, Yves Pommier. Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib [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 365.
Preoperative neutrophil to lymphocyte ratio as a prognostic factor for patients with colorectal cancer
Authors: I. Zarev, M. Maksimovic, R. Ljubisavljevic, M. Bozovic, Z. Maksimovic, M. Pavlovic, Z. Veselinovic, G. Kamidzorac, A. Curcic, Z. Kosanin
Journal: Annals of Oncology (2019)
Abstract 1760: Plasma vitamin D levels and DNA repair capacity in four molecular subtypes of women with breast cancer
Authors: Carmen Ortiz, Jarline Encarnacion, Ralphdy Vergne, Luis Padilla, Jaime Matta
Journal: Cancer Research (2019)

Abstract Background: Vitamin D regulates estrogen synthesis among other mechanisms involved in breast cancer (BC) carcinogenesis. An important gap, to our knowledge, is whether blood levels of vitamin D are associated with DNA repair capacity in women with BC. Previously, we reported that a low DNA repair capacity (DRC) is a risk factor for BC and that DRC levels are associated with estrogen receptor (ER) positivity in women with BC. Moreover, we also reported that there is an intrinsic variability in DRC levels among the four principal BC subtypes. Therefore, our aim is to study the link between DRC and plasma vitamin D levels in BC and among BC subtypes. Methods: Treatment-naïve BC cases and controls were selected from our cohort of Hispanic women (n=1,187). DRC was assessed in lymphocytes through the host-cell reactivation assay. Vitamin D was measured using LC/MS/MS. Results: Women with BC (n=91) had higher (+6.6 ng/ml) vitamin D than controls (n=22) (p=0.007). There were significant differences in vitamin D levels (p&amp;lt;0.05) between BC cases with high (≥3.8%) (n=17) and low (&amp;lt;3.8%) (n=74) DRC levels. Vitamin D and DRC were negatively correlated in BC cases (r=-0.2296, p=0.03). When women with BC and low DRC levels (n=56) were stratified into: luminal A (n=17), luminal B (n=11), HER2+ (n=10), and triple-negative (n=18), women with HER2+ and TNBC showed the highest levels of vitamin D (p&amp;lt;0.05). Women with ER- had higher levels (+7.6 ng/ml) of vitamin D than women with ER+ tumors (p=0.005). After finding that plasma vitamin D levels from women with BC and controls were significantly different when stratified by DRC levels and BC subtypes, ROC curves were constructed to examine whether these levels could allow us to discriminate between our four study groups. Significant differences (p=0.0126) were found for cases and controls with low DRC; AUC of 0.7178. When considering all women with BC independently of DRC levels, the AUC was 0.7353 (p=0.0300). Conclusions: This study provides the first evidence of a link between vitamin D and DRC levels in women with BC. We also present data as to how vitamin D varies across four molecular subtypes of BC in Hispanic women. Impact: Our results fills an important gap on the link between plasma vitamin D and DRC levels in women with BC. Funding: This study was supported by grants #S06GM008239-20, 9SC1CA182846-04, and 5SC1CA157250-02, 5U54CA163071-04, 5R25GM096955-08. Citation Format: Carmen Ortiz, Jarline Encarnacion, Ralphdy Vergne, Luis Padilla, Jaime Matta. Plasma vitamin D levels and DNA repair capacity in four molecular subtypes of women with breast cancer [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 1760.