tbuckley/cabot-search huggingface dataset:
Phase I study of durvalumab and tremelimumab together with radiotherapy for the adjuvant treatment of intermediate-risk head and neck squamous cell carcinoma.
Authors: Siddharth Sheth, Bhishamjit S. Chera, Benjamin Garrett Vincent, Colette J. Shen, Mark Christian Weissler, Jeffrey Blumberg, Samip Patel, Adam M. Zanation, Wendell Gray Yarbrough, Shetal Arvind Patel, Juneko E. Grilley-Olson, Trevor Hackman, Jared Weiss
Journal: Journal of Clinical Oncology (2019)

TPS73 Background: When surgery is used as the primary therapeutic modality for locally-advanced HNSCC, radiation therapy (XRT) is frequently recommended post-operatively due to high rates of recurrence. In high-risk patients; i.e., those with positive surgical margins or extra-nodal extension (ENE) on surgical pathology, the addition of chemotherapy to post-operative XRT (cCRT) provides a survival benefit. In contrast, there is no standard indication for adjuvant systemic therapy in intermediate risk HNSCC—defined in this study as having a T3/T4 primary tumor, perineural or lymphovascular space invasion, and/or lymph node metastasis without ENE. The anti-programmed cell death-ligand 1 (PD-L1) antibody durvalumab (D) has a manageable safety profile and encouraging clinical activity studies across multiple tumor types. Combining D with the anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody tremelimumab (T) may amplify antitumor T-cell responses and provide synergistic activity. D+T showed antitumor activity and manageable tolerability in advanced NSCLC. Furthermore in preclinical studies, D+T combined with XRT decreased regulatory T-cells and myeloid derived suppressor cells and increased CD8 T-cell recruitment to the tumor microenvironment. Methods: This two-part phase I study will include a safety run-in period using a 3+3 dose de-escalation design based on dose limiting toxicities (DLT). In Cohort 1, D (q3 weeks) +T (q3 weeks) will be given on cycle 1 followed by concurrent XRT for Cycles 2-4. Cycle 5 and 6 will include D only. If DLT’s are met, Cohort -1 will include D (q3 weeks) and T (q6 weeks). If DLT's are found in Cohort -1, Cohort -2 would include only D. A dose expansion cohort (N=24) will follow based on the safest combination in the safety run-in. Translational studies include correlation of pre-treatment immune characteristics including PD-L1 score, TMB, and IFN-gamma signature with disease free survival. DNA and RNA sequencing of pre-treatment tissue and at treatment failure/recurrence will attempt to identify genetic and molecular determinants of IO treatment resistance. (NCT02000947). Clinical trial information: NCT03529422.
Abstract 15375: Time Course of Coronary Microvascular Dysfunction During Long Term Metabolic Derangement in Swine
Authors: Oana Sorop, Mieke van den Heuvel, Vincent de Beer, Nienke van Ditzhuijzen, Ilkka Heinonen, Daphne Merkus, Sietse Jan Koopmans, A.H. Jan Danser, Wim van der Giessen, Dirk Jan Duncker
Journal: Circulation (2013)

Coronary microvascular dysfunction (CMVD) has been proposed as an important component of diabetes mellitus (DM) associated coronary artery disease (CAD). How different aspects of such CMVD manifest...
Exercise Capacity Is Reduced in Cancer Survivors Previously Treated With Anthracycline-Based Chemotherapy Despite a Preserved Cardiac Output Response
Authors: Peter Brubaker, Ashley Jensen, Jennifer Jordan, Zanetta Lamar, Shannon Mihalko, Mark Haykowsky, Lee Jones, Ralph D`Agostino, Dalane Kitzman, Kerryn Reding, W. Gregory Hundley
Journal: JACC. Cardiovascular imaging (2019)
Liquid biopsy using plasma proteomic profiling to reveal predictors of immunotherapy response.
Authors: Arnav Mehta, Gyulnara Kasumova, Marijana Rucevic, Markus Sallman-Almen, Lina Hultin Rosenberg, Michelle S. Kim, David Lieb, Xue Bai, Dennie T. Frederick, Ryan J. Sullivan, Keith Flaherty, Nir Hacohen, Genevieve Marie Boland
Journal: Journal of Clinical Oncology (2019)

130 Background: The response of metastatic melanoma to anti-PD1 is heterogeneous. We performed proteomic profiling of patient plasma samples to build a predictor of immunotherapy response and uncover biological insights underlying primary resistance. Methods: 58 metastatic melanoma patients receiving anti-PD1 (Pembrolizumab or Nivolumab) at MGH comprised the initial cohort, and 150 additional patients comprised a validation cohort. Plasma samples were collected (MGH IRB #11-181) at baseline and several on-treatment time-points. Samples were analyzed for 1102 proteins by a multiplex proximity extension assay (Olink Proteomics). A subset of patients had single-cell RNA-seq (Smart-Seq2 protocol) performed on tumor tissue. Group differences and treatment effects were evaluated using linear mixed models with maximum likelihood estimation for model parameters, and Benjamini and Hochberg multiple hypothesis correction. Results: 70 significantly differentially expressed (DE) proteins were identified across the treatment period, including markers of immune activation (PD1, CXCL9, CXCL10, CD25, IL-17a, among others). 38 significantly DE proteins were identified with on-treatment time points between anti-PD1 responders (R) and non-responders (NR), including several implicated in primary or acquired resistance (IL8, MIA, ERBB2, among others). Importantly, we demonstrate the relationship of these serum biomarkers to overall and progression-free survival, and employed statistical learning approaches to build classifiers of treatment response, leveraging early and late on-treatment time points. Analysis of single-cell RNA-seq data (Sade-Feldman et al, Cell, 2018) of tumor tissue from a subset of these patients revealed that gene expression of most proteins predictive of response were enriched among tumor myeloid cells, with the remainder of proteins being reflective of exhausted T cell states. Conclusions: Whole plasma proteomic profiling of anti-PD1 treated patients revealed DE proteins between R and NR that may enable a liquid biopsy to predict anti-PD1 response. These results unveil a putative role of myeloid cells within the tumor microenvironment in anti-PD1 response or primary resistance.
Phase I study of CpG ODN(K3), a novel toll-like receptor 9 agonist, for advanced lung cancer: Interim analyses of safety and immunity in subcutaneous injection cohort.
Authors: Tomoyuki Otsuka, Sumiyuki Nishida, Masanari Hamaguchi, Takayuki Shibahara, Takayuki Shiroyama, Keiko Kimura, Haruhiko Hirata, Hiroshi Kida, Ken J. Ishii, Atsushi Kumanogoh
Journal: Journal of Clinical Oncology (2019)

126 Background: CpG oligodeoxynucleotide (CpG ODN) (K3), a toll-like receptor 9 agonist, is a novel synthetic single-strand DNA immune adjuvant for cancer immunotherapy. CpG ODN(K3) induces the production of type 1 IFNs and pro-inflammatory cytokines in innate immune cells, leading to a potential Th1-type adaptive immune response against cancer cells, leading to an immunogenic tumor microenvironment. To determine the recommended dose (RD) of CpG ODN(K3) via subcutaneous injection (sc) or intravenous administration (iv) and to investigate the immune response induced by CpG ODN(K3) in advanced lung cancer patients, we designed an open-labeled, dose-escalation phase I study. Methods: Pts with advanced lung cancer who had achieved CR, PR or SD after the prior Pt-based chemotherapy were enrolled. The primary endpoint was the proportion of DLTs at each dose level. Secondary endpoints included safety profile, immune response including dynamic changes of immune cell and cytokine production, and PFS. In a 3+3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body sc and 0.2 or 0.6 mg/kg iv on day1, 8, 15 and 29. Pts without PD or unacceptable toxicity were allowed to receive CpG ODN(K3) up to a maximum of 6 months. Results: 6 pts were treated in sc part. 5 had NSCLC (3 had adenocarcinoma, 1 squamous cell carcinoma, and 1 mucoepidermoid carcinoma) and 1 had SCLC. There were no DLTs at any dose levels. Treatment-related toxicities were limited to G1 and G2 including local skin reactions. No pts experienced serious AEs including immune-related AEs. Some pts exhibited the dynamic change of immune-related cells and the immediate production of inflammatory cytokines and chemokines, such as IL1-beta, CCL2, and CXCL10, and Th1 cytokines including IFN-gamma, in response to CpG ODN(K3), suggesting that CpG ODN(K3) elicited innate immunity followed by Th1 adaptive immune response. Conclusions: This was the first clinical application of CpG ODN(K3) for cancer pts. CpG ODN(K3) sc was well-tolerated and was expected to activate innate immunity followed by Th1 adaptive immune response. Clinical trial information: UMIN000023276.
Abstract 15431: Transluminal Attenuation Gradient in Coronary Computed Tomography Angiography Does Not Predict Hemodynamic Significance of Coronary Artery Stenosis: Comparison Against FFR
Authors: Wijnand J Stuijfzand, Ibrahim Danad, Pieter G Raijmakers, C B Marcu, Martijn W Heymans, Cornelis C van Kuijk, Albert C van Rossum, Niels van Royen, Paul Knaapen
Journal: Circulation (2013)

Background: Transluminal attenuation gradient (TAG) is defined as the contrast opacification gradient across the length of a coronary artery at coronary computed tomography angiography (CCTA). Prel...
Molecular prediction of chronic myeloid leukemia risk and resistance to imatinib.
Authors: Radmila Jankovic, Ana Krivokuca, Ivana Boljevic, Sinisa Radulovic, Milena Cavic
Journal: Journal of Clinical Oncology (2019)

e18543 Background: Chronic myeloid leukemia (CML) is characterized by the Bcr-Abl genetic translocation which leads to constitutive tyrosine kinase signaling. Treatment with tyrosine kinase inhibitors as imatinib eliminates CML cells, but resistance often occurs. No specific molecular risk factors or imatinib-resistance predictors have been validated so far, thus the aim of this study was to determine genetic factors that would allow for a better management of this disease. Methods: An age and gender matched case-control study of 57 CML patients and 63 healthy controls was performed. In vitro experiments were performed on K562 cells and an imatinib-resistant K562R cell line. CML patients were treated with imatinib and stratified into responders (complete molecular response after three months, CMR) and non-responders. RNA was isolated from blood leukocytes or cells and used for cDNA synthesis. Gene expression levels were evaluated by real-time PCR and the results analyzed using the delta-delta-Ct method. Differences in expression levels and their prognostic/predictive potentials were evaluated by t-test, linear regression analysis and receiver operating characteristics curve, with statistical significance set at p &lt; 0.05. Results: In CML patients, the Bcl2 and IGF-1R mRNA expression level were higher than in controls (1.03 ± 0.06 vs. 0.92 ± 0.18, p &lt; 0.0001; 1.14 ± 0.15 vs. 1.03 ± 0.15, p = 0.0001, respectively). Prior to treatment, the Bcl2 mRNA levels were lower for the K562 than for the resistant K562R cell line (1.13±0.04 vs. 1.62±0.01, p &lt; 0.0001), and the same was observed for IGF-1R (1.22±0.01 vs. 1.29±0.01, p = 0.001). Patients who achieved a CMR after imatinib treatment had significantly lower pre-treatment levels of Bcl-2 and IGF-1R (0.99 ± 0.05 vs. 1.04 ± 0.06, p = 0.005; 1.12 ± 0.02 vs. 1.15 ± 0.04, p = 0.0123, respectively) compared to patients who did not achieve a CMR, which confirmed the in vitro observed data. Conclusions: High levels of Bcl-2 and IGF-1R mRNA were detected in CML patients, and the analysis of their expression might be used as a low-cost CML screening tool. Successful imatinib treatment was correlated with significantly lower pre-treatment Bcl-2 and IGF-1R levels in vitro and in vivo, which might also be used as a low-cost molecular predictor of a favorable clinical response .
Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial
Authors: Maria-Victoria Mateos, Hilary Blacklock, Fredrik Schjesvold, Albert Oriol, David Simpson, Anupkumar George, Hartmut Goldschmidt, Alessandra Larocca, Asher Chanan-Khan, Daniel Sherbenou, Irit Avivi, Noam Benyamini, Shinsuke Iida, Morio Matsumoto, Kenshi Suzuki, Vincent Ribrag, Saad Z Usmani, Sundar Jagannath, Enrique M Ocio, Paula Rodriguez-Otero, Jesus San Miguel, Uma Kher, Mohammed Farooqui, Jason Liao, Patricia Marinello, Sagar Lonial, Andrew Nicol, George Grigoriadis, John Catalano, Richard LeBlanc, Mohamed Elemary, Nizar Bahlis, Thierry Facon, Lionel Karlin, Vincent Ribrag, Michel Attal, Hartmut Goldschmidt, Monika Engelhardt, Katja Weisel, Andreas Mackensen, Arnon Nagler, Dina Ben Yehuda, Irit Avivi, Noam Benyamini, Hila Magen-Nativ, Antonio Palumbo, Michele Cavo, Kensei Tobinai, Shinsuke Iida, Takaai Chou, Kenshi Suzuki, Hiroshi Kosugi, Masafumi Taniwaki, Kazutaka Sunami, Morio Matsumoto, Kiyoshi Ando, Peter Ganly, Hilary Blacklock, David Simpson, Anupkumar George, Fredrik Schjesvold, Bjorn Gjertsen, Juan Lahuerta, Joan Blade, Albert Oriol Rocafiguera, Maria Mateos, Paula Rodriguez-Otero, Sarah Larson, Djordje Atanackovic, Srinivas Devarakonda, Jacob Bitran, Jeffrey Zonder, Neil Morganstein, Mohammad Hay, Asher Chanan-Khan, Gene Saylors, Ebenezer Kio, Ira Oliff, Dean Kirkel, Mikhail Shtivelband, Carrie Yuen, Andrew Yee, Jatin Shah, Myo Htut, Shahzad Raza, Saurabh Chhabra, Patrick Stiff, Parameswaran Hari, Bruce Bank, Ehsan Malek, Cristina Gasparetto, Ycaoub Faroun, Daniel Sherbenou, William Kreisle, Seema Singhal, Jacalyn Rosenblatt, Saad Usmani, Wes Lee, Hana Safah, Jose Lutzky, Jason Suh, Dorothy Pan, Ari Baron, Robert Manges, Ronald Steis, Moacyr Oliveira, Jan Moreb, Natalie Callander, Bertrand Anz, Anastasios Raptis, Laura Stampleman, Jason Melear, Thomas Boyd, Lawrence Garbo, Leonard Klein, Spencer Shao, Roger Lyons, Kristi McIntyre, Stefano Tarantolo, Christopher Yasenchak, Habte Yimer
Journal: The Lancet Haematology (2019)
Are Atherogenic Lipoprotein Phenotype and Inflammation Indicative of Plaque Phenotype and Clinical Stability in Coronary Artery Disease?—Reply
Authors: Rocco Vergallo, Italo Porto, Filippo Crea
Journal: JAMA Cardiology (2019)

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Risk for Heart Failure
Authors: Alicia Uijl, Stefan Koudstaal, Ilonca Vaartjes, Jolanda M.A. Boer, W.M. Monique Verschuren, Yvonne T. van der Schouw, Folkert W. Asselbergs, Arno W. Hoes, Ivonne Sluijs
Journal: JACC Heart Failure (2019)
Breaking immune tolerance for the treatment of pancreatic cancer: Phase I/II clinical experience.
Authors: David Nam, Larn Hwang, Vuong N. Trieu
Journal: Journal of Clinical Oncology (2019)

54 Background: Escalating Intratumoral heterogeneity resulting in xenogenization which is countered by overexpression of TGF-β. Here we report on the use of OT-101/Chemo to break immune tolerance to cure pancreatic cancer (PC). OT-101 is an antisense against TGF-β2. Methods: Total of 37 pts 2 nd line and beyond received OT-101 with option to go on subsequent Chemo (OT-101/Chemo) or Best Supportive Care (BSC) (OT-101/BSC). Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. Plasma levels of 31 cyto-/chemokine were measured in a subset of 12 pts. Results: mOS of the 18 pts receiving OT-101/Chemo was 9.4 mos vs. OT-101/BSC (2.8 mos, p=0.0004). No significance was observed on stratification. However, pts with only liver metastasis had a mOS of 9.5 mos while those with liver metastasis and others only had a mOS of 4.7 mos (p=0.0077). Among the former, 1006 has Complete Response beyond 77.3 mos and 1022 had Stable Disease with OS of 40.3 mos; and OS was higher with OT-101/Chemo – 12.4 mos versus 1.9 mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7 mos vs. 3.0 mos (p&lt;0.0001); and OS was higher with OT-101/Chemo – 11.8 mos vs. 5.0 mos, p=0.0021. Pts exhibited spike in IL-8 level which returned to basal level at treatment stop. R squares relating the IL-8 spike and OS were 0.8522 and 0.9895 and p values were 0.0011 and 0.0053 for OT-101/Chemo and OT-101/BSC, respectively. Preclinically, OT-101 enhanced PBMC activity in cell kill assay and in vivo xenograft. Conclusions: The MOA for OT-101/Chemotherapy is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during Chemo. Contrary to traditional tumor vaccine- this is universally applicable to all patients.
Checkpoint Expression By Acute Myeloid Leukemia (AML) and the Immune Microenvironment Suppresses Adaptive Immunity
Authors: Patrick Williams, Sreyashi Basu, Guillermo Garcia-Manero, Jorge E. Cortes, Farhad Ravandi, Zainab Al-Hamal, Marina Konopleva, Jing Ning, Lian-Chun Xiao, Juliana Hidalgo Lopez, Steven Kornblau, Michael Andreeff, Wilmer Flores, Carlos E. Bueso-Ramos, Narmeen Somani, Jorge Blando, Gheath Alatrash, James P Allison, Hagop M. Kantarjian, Padmanee Sharma, Naval Daver
Journal: Blood (2017)
Impact of geriatric vulnerability on outcomes of older patients in allogeneic hematopoietic cell transplantation.
Authors: Richard Jirui Lin, Theresa A Elko, Sean M. Devlin, Jessica Flynn, Ann Alice Jakubowski, Armin Shahrokni, Parastoo Dahi, Miguel-Angel Perales, Miriam Sanchez-Escamilla, Roni Tamari, Brian Carl Shaffer, Craig Steven Sauter, Esperanza Bouza Papadopoulos, Hugo Castro-Malaspina, Boglarka Gyurkocza, Juliet Naomi Barker, Molly A Maloy, Beatriz Korc-Grodzicki, Sergio Giralt
Journal: Journal of Clinical Oncology (2019)

7017 Background: Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant assessments by interdisciplinary clinical providers may help uncover additional geriatric deficits. Methods: Using an institutional database of 457 adults age 60 years and older (range 60-78.7) who underwent first allo-HCT for hematological malignancies from 2010 to 2017, we retrospectively examined the prevalence and the prognostic impact of pre-transplant geriatric deficits identified by interdisciplinary clinical providers including geriatric domains of functional activity, cognition, medication, nutrition, mobility, and routine laboratory tests. Results: With a median follow-up of 37 months for survivors, the 3-year probability of overall survival (OS) was 50% (95% CI 45-55). The 2-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 22-28). Among pre-transplant geriatric variables, we found that impairment in instrumental activities of daily living (IADL) was associated with increased NRM and inferior PFS and OS. In multivariate analyses, mismatched donor, age-adjusted HCT-CI &gt; 4 (aaHCTCI), and IADL impairment were associated with NRM, while high/very high disease risk index (DRI), IADL impairment, and positive CMV status were associated with OS. The combination of IADL impairment with either aaHCTCI or DRI readily stratifies NRM and OS, respectively. Conclusions: Our findings establish a simple assessment tool to risk stratify older patients prior to allo-HCT using IADL and aaHCTCI and DRI. These results may provide an entry point for prospective, interventional trials to reduce NRM and toxicities for older allo-HCT patients.
CAP-100: First-in-class antibody for CCR7<sup>+</sup> hematological malignancies.
Authors: Carlos Cuesta, Cecilia Munoz-Callega, Javier Loscertales, Fernando Terron, Wim Mol
Journal: Journal of Clinical Oncology (2019)

e19008 Background: CCR7 is highly expressed in many hematological malignancies including CLL, several B-cell non-Hodgkin lymphomas (NHL), and various T-cell neoplasias with nodal involvement. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of cells to locations where these chemokines are expressed, such as the lymph node (LN) and central nervous system. In these protective microenvironments CCR7 ligands contribute to tumor cell survival and proliferation. Indeed, both high CCR7 surface expression levels and high migratory responses to CCR7 ligands correlate with LN involvement, adverse prognostic factors, and shorter patient survival. Thus, strategies targeting CCR7 could provide a novel therapeutic approach for CCR7+ hematological malignancies. Methods: We have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21, and evaluated the antibody in various in-vitro and in-vivo preclinical models. Results: CAP-100 effectively inhibited in vitro migration of primary patient samples of CLL, B-cell NHLs and T-cell neoplasias such as T-PLL or T-ALL. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. CAP-100 also abrogated survival elicited by CCR7 in CLL, and showed potent cell killing activity against CLL or CCR7 + T-lymphomas cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed anti-CD20 or anti-CD52 standard-of-care antibodies in B-NHL and T-lymphomas respectively. In all cases, ADCC and migration inhibition were both independent of prognostic markers for high risk disease. Finally, when given as monotherapy in disseminated B-NHL and CLL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition and extended survival significantly. Conclusions: Our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in several CCR7+ hematological malignancies, including relapsed/refractory disease. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in these diseases. CAP-100’s unique propensity to block migration of tumor cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100, either as monotherapy or in combination with novel agents. Clinical trials in CLL and CCR7-expressing NHL will be initiated soon.