tbuckley/cabot-search huggingface dataset:
Accurate control of dual-receptor-engineered T cell activity through a bifunctional anti-angiogenic peptide
Authors: Erhao Zhang, Jieyi Gu, Jianpeng Xue, Chenyu Lin, Chen Liu, Mengwei Li, Jingchao Hao, Sarra Setrerrahmane, Xiaowei Chi, Weiyan Qi, Jialiang Hu, Hanmei Xu
Journal: Journal of Hematology & Oncology (2018)

Chimeric antigen receptors (CARs) presented on T cell surfaces enable redirection of T cell specificity, which has enormous promise in antitumor therapy. However, excessive activity and poor control over such engineered T cells cause significant safety challenges, such as cytokine release syndrome and organ toxicities. To enhance the specificity and controllable activity of CAR-T cells, we report a novel switchable dual-receptor CAR-engineered T (sdCAR-T) cell and a new switch molecule of FITC-HM-3 bifunctional molecule (FHBM) in this study.We designed a fusion molecule comprising FITC and HM-3. HM-3, an antitumor peptide including an Arg-Gly-Asp sequence, can specifically target integrin αvβ3 that is presented on some tumor cells. Moreover, to improve the specificity of CAR-T cells, we also generated the sdCAR-T cell line against cognate tumor cells expressing human mesothelin (MSLN) and integrin αvβ3. Finally, the activity of sdCAR-T cell and FHBM is verified via in vitro and in vivo experiments.In the presence of FHBM, the designed sdCAR-T cells exerted high activity including activation and proliferation and had specific cytotoxicity in a time- and dose-dependent manner in vitro. Furthermore, using a combination of FHBM in nude mice, sdCAR-T cells significantly inhibited the growth of MSLN+ K562 cells and released lower levels of the cytokines (e.g., interleukin-2, interferon γ, interleukin-6, and tumor necrosis factor α) relative to conventional CAR-T cells, obtaining specific, controllable, and enhanced cytotoxicity.Our data indicate that FHBM can accurately control timing and dose of injected CAR-T cells, and sdCAR-T cells exert significant antitumor activity while releasing lower levels of cytokines for the cognate tumor cells expressing both MSLN and integrin αvβ3. Therefore, combination therapies using sdCAR-T cells and the switch molecule FHBM have significant potential to treat malignancies.
A phase 1 study of the MDM2 inhibitor DS-3032b in patients (pts) with advanced solid tumors and lymphomas.
Authors: Mrinal M. Gounder, Todd Michael Bauer, Gary K. Schwartz, Tyler Masters, Richard D. Carvajal, Saeheum Song, Prasanna Kumar, Roohi Gajee, Oleg Zernovak, Michael M. Rosen, Jarema Peter Kochan, Shuquan Chen, David Michael Hyman, Sugun Gokmen, Funda Meric-Bernstam, Patricia LoRusso, Neeta Somaiah, Amy M. Weise, David S. Hong
Journal: Journal of Clinical Oncology (2016)

2581 Background: About 50% of tumors harbor inactivating mutations in TP53. Aberrant MDM2 signaling is an alternate mechanism to inactivate wild type (WT) p53. In preclinical studies, DS-3032b disrupted the MDM2-WTp53 interaction resulting in cell cycle arrest, senescence and/or apoptosis. We characterized the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetic and pharmacodynamic (PD) profiles and efficacy of DS-3032b in a phase 1 trial. Methods: Using accelerated and Bayesian design in the dose-escalation phase of this 2-part study (part 1), we escalated DS-3032b from 15 to 240 mg orally once daily (QD) on a continuous or interrupted (QD 21/28 days) schedule. Results: Thirty-one of 34 pts enrolled in part 1 were evaluable for dose-limiting toxicities (DLTs). Median age was 59.5 years, 44% male, and 62% had ≥ 3 prior therapies. The majority of pts (79%) had wt TP53 and the most frequent tumor type was well/de-differentiated liposarcoma (LPS; n = 15). MTD was 120 mg (interrupted) and 90 mg (continuous) schedule. The most common drug-related adverse events were hematologic and gastrointestinal. Six pts had DLTs, 5 were due to thrombocytopenia alone or with neutropenia. Of 26 pts evaluable for efficacy, none had an objective response but 77% had stable disease (SD); consistent with cell cycle arrest/senescence seen in preclinical studies. Tumor shrinkage was seen but did not meet RECIST criteria. Two pts with previously progressing LPS and carcinoid remain on study for 26+ mos and tumor sequencing showed MDM2 gene amplification. Exposures of DS-3032b were significantly higher in pts with lower body weight. Induction of MIC- 1 (PD biomarker of WT p53 reactivation) correlated with drug exposure. Conclusions: DS-3032b has an acceptable safety profile at the MTD of 120 mg (QD 21/28). Clinical benefit with durable SD was seen in tumors with aberrant MDM2 signaling and WT p53. MDM2 is universally amplified in LPS and TP53 is the most commonly mutated gene in cancer; warranting further investigation of DS-3032b. Pts with melanoma or diffuse large B-cell lymphoma (DLBCL) are being enrolled in 2 dose-expansion cohorts (part 2) at the tentative recommended phase 2 dose 120 mg QD 21/28. Enrollment is ongoing (NCT01877382). Clinical trial information: NCT01877382.
Engineering chimeric antigen receptor-T cells for cancer treatment
Authors: Baixin Ye, Creed M. Stary, Xuejun Li, Qingping Gao, Chunsheng Kang, Xiaoxing Xiong
Journal: Molecular Cancer (2018)

Intratumor heterogeneity of tumor clones and an immunosuppressive microenvironment in cancer ecosystems contribute to inherent difficulties for tumor treatment. Recently, chimeric antigen receptor (CAR) T-cell therapy has been successfully applied in the treatment of B-cell malignancies, underscoring its great potential in antitumor therapy. However, functional challenges of CAR-T cell therapy, especially in solid tumors, remain. Here, we describe cancer-immunity phenotypes from a clonal-stromal-immune perspective and elucidate mechanisms of T-cell exhaustion that contribute to tumor immune evasion. Then we assess the functional challenges of CAR-T cell therapy, including cell trafficking and infiltration, targeted-recognition and killing of tumor cells, T-cell proliferation and persistence, immunosuppressive microenvironment and self-control regulation. Finally, we delineate tumor precision informatics and advancements in engineered CAR-T cells to counteract inherent challenges of the CAR-T cell therapy, either alone or in combination with traditional therapeutics, and highlight the therapeutic potential of this approach in future tumor precision treatment.
Racial disparities in the use of programmed death-1 checkpoint inhibitors.
Authors: Jeremy O'Connor, Kathi Seidl-Rathkopf, Aracelis Z. Torres, Paul You, Nathan C. Nussbaum, Kristen L. Fessele, Katie Darius, Kerin B. Adelson, Emily Yin, Carolyn Jean Presley, Anne C. Chiang, Joseph S. Ross, Amy Pickar Abernethy, Cary Philip Gross
Journal: Journal of Clinical Oncology (2017)

3068 Background: There are concerns about racial disparities in access to trials of new cancer drugs, including the programmed death 1 checkpoint inhibitors (anti-PD1s). It is unknown whether these disparities extend to anti-PD1 treated patients in real-world practice. Methods: We used retrospective data from Flatiron Health’s electronic health record database, which includes more than 250 cancer clinics and 1.5 million patients with cancer. We identified patients diagnosed after January 1, 2011 who underwent systemic therapy for: advanced non-small cell lung cancer (aNSCLC; n = 13,473), metastatic renal cell carcinoma (mRCC; n = 1,537), and advanced melanoma (n = 1,221). Within each cohort, we identified treatment type (anti-PD1 versus non-anti-PD1). Therapy lines containing study drugs were excluded. We used logistic regressions to model the use of anti-PD1s by race, adjusting for factors such as age, sex, stage at diagnosis and line of therapy. Results: Of 16,231 patients in our sample, 4,643 (28.6%) were treated with anti-PD1s. Racial distributions differed for anti-PD1 treated patients compared to non-anti-PD1 treated patients in the aNSCLC cohort (Table: p &lt; 0.01), but not in the mRCC cohort (p = 0.84) or the advanced melanoma cohort (p = 0.96). In bivariate analyses of patients with aNSCLC, anti-PD1 treatment was associated with other race, male sex, stage II at diagnosis, squamous histology, smoking history and line of therapy (all p &lt; 0.05). Adjusted models showed there were no significant differences in likelihood of receiving anti-PD1s when comparing black and white patients undergoing systemic therapy for aNSCLC (aOR for black vs. white: 0.86, 95% CI 0.72-1.02), mRCC (aOR 0.90, 95% CI 0.53-1.49), or melanoma (aOR 2.02, 95% CI 0.42-14.59). Conclusions: Among patients undergoing systemic therapy in a large national network of cancer clinics, we found no significant racial disparities in the use of anti-PD1s. [Table: see text]
Abstract 15474: Genetic Testing in patients with Acute Coronary Syndromes to Determine Optimal Anti-Platelet Strategy: a Cost Effective Analysis
Authors: Anuradha Lala, Gaurav Sharma, Judith S Hochman, Jeffrey S Berger, Ronald S Braithwaite
Journal: Circulation (2011)

Background:  Prasugrel is effective at decreasing cardiovascular events compared to clopidogrel, but increases the risk of bleeding. In 2010, the FDA issued a black box warning to consider genetic testing in clopidogrel users. Our aims were to evaluate (1) the balance of potential benefits and harms and (2) the cost-effectiveness that would result from adopting a genotype-guided strategy of dual anti-platelet therapy following PCI for ACS vs. no testing strategies of prasugrel plus aspirin (prasugrel) or clopidogrel plus aspirin (clopidogrel).   Methods:  A Markov state transition model was used to conduct a decision analysis and compare strategies. Probabilities of adverse outcomes were derived from TRITON-TIMI 38 trial. Event rates on clopidogrel for carriers of CYP2C19*2 vs. wild-type were derived from the TRITON genetic substudy and a recent meta-analysis. Costs are expressed in January 2011 US dollars and estimated based on Medicare reimbursements for diagnosis-related group codes. Medication costs were used from the net wholesale price for prasugrel ($5.45/d) and a generic estimate for clopidogrel ($1/d).   Results:  In base case analyses, the genetic testing guided strategy yielded more benefits than harms, and was less costly compared to both “no testing” strategies. Over 15 months, total costs were $83.8 ($1200.9 at 10 yrs) lower with a gain of 0.0007 QALY (0.0216 QALY at 10 yrs) in the genotype-guided strategy compared to prasugrel. Compared to clopidogrel, it was $0.38 ($2168.8 at 10 yrs) lower with a gain of 0.0036 QALY (0.112 QALY at 10 yrs). The strongest predictor of the preferred strategy was the relative risk (RR) of a thrombotic event occurring in CYP2C19*2 carriers versus wild-type. Below a RR of 1.5, a genotype-guided strategy is no longer more effective (but is less expensive) when compared to prasugrel. Compared to clopidogrel, below a RR of 1.3 a genotype-guided strategy is no longer cost effective (>$100,000/QALY). Clopidogrel costs ($1-$4/d) did not alter our results.   Conclusions:  Among ACS patients undergoing PCI, a genotype-guided strategy is economically favorable in determining which anti-platelet regimen is used, assuming that the risk of thrombotic events in CYP2C19*2 carriers is approximately 30-50% higher than wild type patients.
The Receptor-like Cytoplasmic Kinase BIK1 Localizes to the Nucleus and Regulates Defense Hormone Expression during Plant Innate Immunity
Authors: Neeraj K. Lal, Ugrappa Nagalakshmi, Nicholas K. Hurlburt, Rosalva Flores, Aurelie Bak, Pyae Sone, Xiyu Ma, Gaoyuan Song, Justin Walley, Libo Shan, Ping He, Clare Casteel, Andrew J. Fisher, Savithramma P. Dinesh-Kumar
Journal: Cell Host & Microbe (2018)
Clinical Features and Treatment Approaches in Patients with Rosai-Dorfman Disease: The Mayo Clinic Experience
Authors: Gaurav Goyal, Aishwarya Ravindran, Mrinal M. Patnaik, Grzegorz S Nowakowski, Gita Thanarajasingam, Thomas M Habermann, Taimur Sher, Karen L Rech, David J Inwards, Patrick B Johnston, Robert Vassallo, Sameer A. Parikh, Ronald S. Go
Journal: Blood (2017)
Mechanisms of rapid cancer cell reprogramming initiated by targeted receptor tyrosine kinase inhibitors and inherent therapeutic vulnerabilities
Authors: Emily K. Kleczko, Lynn E. Heasley
Journal: Molecular Cancer (2018)

Receptor tyrosine kinase (RTK) pathways serve as frequent oncogene drivers in solid cancers and small molecule and antibody-based inhibitors have been developed as targeted therapeutics for many of these oncogenic RTKs. In general, these drugs, when delivered as single agents in a manner consistent with the principles of precision medicine, induce tumor shrinkage but rarely complete tumor elimination. Moreover, acquired resistance of treated tumors is nearly invariant such that monotherapy strategies with targeted RTK drugs fail to provide long-term control or cures. The mechanisms mediating acquired resistance in tumors at progression treated with RTK inhibitors are relatively well defined compared to the molecular and cellular understanding of the cancer cells that persist early on therapy. We and others propose that these persisting cancer cells, termed "residual disease", provide the reservoir from which acquired resistance eventually emerges. Herein, we will review the literature that describes rapid reprogramming induced upon inhibition of oncogenic RTKs in cancer cells as a mechanism by which cancer cells persist to yield residual disease and consider strategies for disrupting these intrinsic responses for future therapeutic gain.
Correction: Pancreatoscopy-guided laser lithotripsy in a patient with difficult ductal stone
Authors: Gonçalo Alexandrino, Luís Lourenço, Catarina Rodrigues, David Horta, Jorge Reis, Jorge Canena
Journal: Endoscopy (2018)

Correction to: Pancreatoscopy-guided laser lithotripsy in a patient with difficult ductal stoneEndoscopy eFirstDOI: 10.1055/a-0574-2278
Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation
Authors: Anne Bergeron, Sylvie Chevret, Régis Peffault de Latour, Karine Chagnon, Constance de Margerie-Mellon, Frédéric Rivière, Marie Robin, Jean Mani, Gwenael Lorillon, Gérard Socié, Abdellatif Tazi
Journal: European Respiratory Journal (2018)

Epidemiological data on late-onset noninfectious pulmonary complications (LONIPCs) following allogeneic haematopoietic stem cell transplantation (HSCT) are derived exclusively from retrospective studies and are conflicting. We aimed to evaluate prospectively the incidence, risk factors and outcomes for LONIPCs.All consecutive patients scheduled to receive allogeneic HSCT between 2006 and 2008 at a university teaching hospital in France were screened for inclusion in the study. Eligible patients were those surviving at day 100. Among 243 screened patients, 198 patients were included in the analysis. The median (interquartile range) follow-up was 72.3 (15.2-88.5) months. 55 LONIPCs were diagnosed in 43 patients. Bronchiolitis obliterans syndrome (n=22) and interstitial lung disease (n=12) were the most common LONIPCs. At 36 months after inclusion, the estimated cumulative incidence of LONIPCs was 19.8% (95% CI 14.2-25.3%). The estimated median survival after the diagnosis of LONIPCs was 78.5 months (95% CI 20.0-not reached). Based on a multivariate Cox model, a history of chest irradiation anytime prior to HSCT, a history of pneumonia within 100 days post-HSCT and a low mean forced expiratory flow at 25-75% of forced vital capacity at day 100 were associated with the development of LONIPCs.Our data provide clues to identify patients at high risk of developing LONIPCs. These patients should be targeted for close monitoring to provide earlier LONIPC treatment or prophylactic treatment.
76P Robustness of radiomic features in [18F]-FDG PET/CT and [18F]-FDG PET/MR
Authors: D. Vuong, M. Bogowicz, M. Huellner, P. Veit-Haibach, N. Andratschke, J. Unkelbach, M. Guckenberger, S. Tanadini-Lang
Journal: Journal of Thoracic Oncology (2018)
Long noncoding RNA lncHand2 promotes liver repopulation via c-Met signaling
Authors: Yanying Wang, Pingping Zhu, Jing Wang, Xiaoxiao Zhu, Jianjun Luo, Shu Meng, Jiayi Wu, Buqing Ye, Luyun He, Ying Du, Lei He, Runsheng Chen, Yong Tian, Zusen Fan
Journal: Journal of Hepatology (2018)
Suppression of EBV-induced LCLs using CAR T cells redirected against HLA-DR.
Authors: Chungyong Han, Rohit Singh, Seon-Hee Kim, Beom K. Choi, Byoung S. Kwon
Journal: Journal of Clinical Oncology (2017)

146 Background: Recent studies demonstrated a therapeutic potential of T cells with chimeric antigen receptor (CAR) targeting CD19 in refractory B cell malignancies. However, CD19-CAR T cells frequently caused on-target off-tumor side effect, i.e. B cell aplasia, and led to the recurrence of CD19-negative leukemic cells. Alternative target antigen for B cell malignancies has to be excavated. Methods: We developed antibody clone, MVR, which specifically bound to HLA-DR that is highly expressed on malignant B cells. In particular, MVR recognized polymorphic region of HLA-DR, and indicated different binding affinity against various HLA-DR alleles. Based on MVR binding strength, PBMCs from high binder (MVR High ) and low binder (MVR Low ) were tested to generate MVR-CAR T cells. To evaluate the anti-tumor efficacy on B cell malignancies, MVR-CAR T cells were assessed for immune responses against Epstein-Barr virus (EBV)-induced lymphoblastoid cell line (LCL) in vitro and in vivo. Results: Final yield of MVR-CAR T cells generated from MVR High PBMCs was 10-fold lower than that of CD19-CAR T cells, presumably caused by "fratricide" among HLA-DR-upregulated MVR-CAR T cells. In contrast, fratricidal effect was ameliorated in MVR-CAR T cells generated from MVR Low PBMCs indicating that the interaction between MVR-CAR and MVR Low -HLA-DR was weak enough to achieve tolerance to fratricide. Of note, in spite of such low binding, MVR Low -LCLs were killed efficiently by the CAR T cells. Further quantitative analysis revealed that HLA-DR was far more upregulated on LCLs compared with normal T and B cells which did not undergo EBV-transformation. In accordance with this observation, MVR-CAR T cells successfully induced LCL-specific cytotoxicity without causing normal B cell damage in vitro and efficiently suppressed the outgrowth of metastasized tumors in LCL-xenografted immune-deficient mice. Conclusions: MVR-CAR T cells redirected against HLA-DR for B cell malignancies were evaluated for the cytotoxic efficacy in vitro and in vivo. Considering the alleviated on-target off-tumor side effect and the feasibility of targeting HLA-DR for CD19-deficient malignant B cells, MVR-CAR T cells can be an alternative option for B cell malignancies.
Association of tumor mutational burden with smoking and mutation status in non-small cell lung cancer (NSCLC).
Authors: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Nisha Anjali Mohindra, Victoria Meucci Villaflor, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

24 Background: Reponses to immunotherapy have been observed in multiple solid tumors including non-small cell lung cancer (NSCLC). Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies remains critical. Tumor mutational burden (TMB) may indicate genomic instability and potential neoantigen binding sites to activated effector T cells. Methods: We retrospectively examined tumor mutational burden (TMB) using next-generation sequencing (Foundation Medicine) for 83 patients with NSCLC in our institution. TMB included both coding and non-coding regions, but excluded potentially functional mutations. We correlated TMB (mutations per megabase) with smoking history, number of potentially functional mutations, variants of unknown significance, and the driver mutations EGFR, ALK, and KRAS. TMB high versus low was stratified based on 15 mutations per megabase pair. Results: Our findings demonstrated that TMB was significantly associated with current/former smoking status (p = 0.01, Table 1). TMB was also significantly associated with number of potentially functional mutations, number of variants of unknown significance (VUS), and total reported mutations (p &lt; 0.01). The absence of mutations in EGFR, ALK, or KRAS tended to be associated with higher TMB as well (p = 0.07). Conclusions: TMB was associated with smoking status, as well as potentially functional mutations, VUS, and total number of reported mutations. Our results indicate that number of coding region mutations predict genomic instability in non-coding regions. Future studies are needed to correlate this measure with other immune biomarkers and patient outcome in NSCLC. [Table: see text]
S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death
Authors: Sabrina Romagny, Sarra Bouaouiche, Géraldine Lucchi, Patrick Ducoroy, Jean B. Bertoldo, Hernan Terenzi, Ali Bettaieb, Stéphanie Plenchette
Journal: Cancer Research (2018)

Abstract TNFα is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-κB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies. Significance: Combination of an NO donor with chemotherapeutic drug–induced TNFα represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948–57. ©2018 AACR.
Respiratory health status among primary school children in 25 communities in Central Europe: The Central Europe study on air pollution and respiratory health (CESAR).
Authors: G. Leonardi, B. Nikiforov, J. Volf, P. Rudnai, J. Zejda, E. Gurzau, E. Fabianova, O. Breugelmans, W. Roemer, T. Fletcher
Journal: European Respiratory Journal (1997)