tbuckley/cabot-search huggingface dataset:
Abstract 5663: Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models
Authors: Alex Nisthal, Matthew Dragovich, Erik W. Pong, Veronica Zeng, Michael Hedvat, Christine Bonzon, Kendra Avery, Rumana Rashid, Connie Ardila, Umesh S. Muchhal, Gregory L. Moore, Seung Y. Chu, John R. Desjarlais
Journal: Cancer Research (2020)

Abstract Bispecific antibodies enable therapeutic modalities inaccessible to traditional mAbs, such as T cell engagers that bind both CD3 on T cells and a target antigen on tumor cells. These agents provide synthetic immunity by expanding, activating, and redirecting T cells against a target of interest. While targeting lineage-restricted antigens such as CD19 or CD20 have found clinical success in hematopoietic cancers, targeting solid tumors requires high expressing tumor associated antigens (TAAs) with minimal normal tissue expression. Prostate cancer (PC) is one of the most prevalent cancers in men, and end stage (castration-resistant prostate cancer) has no curative treatment option. Prostate specific membrane antigen (PSMA), a type II transmembrane protein with a large extracellular domain, has long generated interest as a therapeutic target. It is highly overexpressed in PC compared to normal tissue, and its expression has been shown to correlate with malignancy. Previous attempts to target PSMA include antibody-based radiotherapy and antibody drug conjugates, which have shown some success but can be hampered by the inherent toxicity of the modality. Building upon the XmAb® heterodimeric Fc platform, we generated bispecific antibodies in an XmAb 2+1 Fab2-scFv-Fc format that are bivalent for PSMA and monovalent for CD3. Reducing the affinity of both specificities encouraged avid binding and strong activity on high PSMA expressing cell lines while minimizing reactivity on low expressing cell lines, matching PSMA's differential expression pattern. To ensure biologically valid antigen densities were being considered, IHC was conducted on paraffin embedded arrays of tumor tissue, normal tissue, and cell lines. Upon matching the staining intensity between the three sample types, we identified cell lines with corresponding PSMA antigen density that could serve as proxies of tumor and normal tissue. In vitro T cell-dependent cellular cytotoxicity (TDCC) assays on the relevant cell lines confirmed selective potency on high versus low expressing cells. Citation Format: Alex Nisthal, Matthew Dragovich, Erik W. Pong, Veronica Zeng, Michael Hedvat, Christine Bonzon, Kendra Avery, Rumana Rashid, Connie Ardila, Umesh S. Muchhal, Gregory L. Moore, Seung Y. Chu, John R. Desjarlais. Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5663.
Abstract 974: Immune modulation following combination of TAK-164 with checkpoint inhibitors
Authors: Victoria A. Appleman, Michael D. Smith, Michelle Ganno, Tiquella Hatten, Maria Borland, Adnan O. Abu-Yousif
Journal: Cancer Research (2020)

Abstract TAK-164 is an antibody drug conjugate comprised of a full length, fully human IgG1 monoclonal antibody (mAb) directed towards the human extra-cellular domain of guanylyl cyclase C (GCC). The mAb is conjugated using ImmunoGen's peptide-linked indolinobenzodiazepine DNA alkylator DGN549. Previously presented preclinical studies using TAK-164 have demonstrated single agent activity of TAK-164 in a panel of patient derived xenograft models of colorectal cancer grown in immunodeficient mice. With emerging evidence demonstrating the immunostimulatory activity of cytotoxic antibody drug conjugates we sought to explore the potential of TAK-164 in immune competent mice. A CT26 model was engineered to express human GCC, allowing us to test the ability of TAK-164 to modulate the tumor microenvironment, thereby potentiating the activity of checkpoint inhibitors. huGCC-CT26 tumor cells were implanted in the right flank of 6-8 week old BALB/c female mice and randomized when tumors were between 50-150mm3 and treated with a single intravenous administration of TAK-164 alone or in combination with checkpoint inhibition administered Intraperitoneally biweekly for 2 weeks and monitored for tumor growth. To understand if responses observed were driven by a response capable of inducing immunological memory we separated mice with complete responses and rechallenged with CT26 tumor cells on the opposite flank. While memory was observed in the mice that achieved complete response in the single agent groups, both frequency of complete response and tumor rejection was increased in groups treated with a combination of TAK-164 and immune checkpoint inhibition. We performed immunophenotyping studies which revealed broad immunomodulation of lymphoid and myeloid cells by TAK-164 and combination regimens. Collectively these data support further interrogation of immune checkpoint inhibition in combination with TAK-164. Citation Format: Victoria A. Appleman, Michael D. Smith, Michelle Ganno, Tiquella Hatten, Maria Borland, Adnan O. Abu-Yousif. Immune modulation following combination of TAK-164 with checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 974.
Abstract 206: The landscape of oncogenic gene fusions in Chinese colorectal cancer patients
Authors: Zhenhai Lu, Rongfeng Song, Kunsong Li, Ying Cheng, Wenjing Wang, Weifeng Wang
Journal: Cancer Research (2020)

Abstract Background: Oncogenic gene fusions have been reported in patients with colorectal cancer (CRC) as promising actionable targets, but recognition of rare molecular subgroups is a challenge for precision oncology. We aimed to comprehensively characterize the clinical, pathological, and molecular landscape of Chinese CRC patients with oncogenic gene fusions. Methods: A total of 1226 patients with CRC underwent genomic testing between Aug. 2017 and Sep. 2019 using a tissue-based next-generation sequencing (NGS) assay. All the coding exons of 450 cancer-related genes and selected introns were captured by the custom hybridization capture panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed in all patients. Results: Oncogenic gene fusions were found in 1.6% (20/1226) of Chinese CRC tumors, which was higher than that in the western population (0.68%, R. Madison, ESMO 2018 Congress). The most frequently detected fusions were NTRK1 (N = 5, 25%), BRAF (N = 5, 25%), ALK (N = 3, 15%), NTRK3 (N = 2, 10%), and RET (N = 2, 10%). FGFR1, ROS1, and EGFR fusions each occurred in one patient. Compared with patients without fusions, those with fusions were older (median age 69 vs 59 years, respectively, P=0.009), had right-sided CRC (75.0% vs 27.4%, respectively, P&amp;lt;0.001), MSI-high (45.0% vs 8.7%, respectively, P&amp;lt;0.001), and a higher TMB (median TMB of 9.8 vs 5.6 muts/mb, respectively). All MSI-high patients with fusions were TMB-high with a median value of 73.5 muts/Mb (range 51.8-180.3). The most frequently co-mutated genes in fusion cases were TP53 (70%), APC (60%), KMT2D (50%), ACVR2A (45%), RNF43 (45%), and TGFBR2 (40%). KRAS, NRAS, BRAF, POLE, and mismatch repair gene mutations were all mutually exclusive with oncogenic gene fusions. One patient harboring an EGFR-SEPT14 fusion, who had been heavily treated for right colon cancer metastasis, achieved a partial response to erlotinib. Conclusions: This study revealed that oncogenic gene fusions were found in 1.6% of Chinese CRC patients by using a tissue-based NGS assay. As oncogenic gene fusions are mutually exclusive with common oncogenic mutations, using NGS to detect fusions as actionable targets or resistance mechanisms has notable implications for precision therapy. Citation Format: Zhenhai Lu, Rongfeng Song, Kunsong Li, Ying Cheng, Wenjing Wang, Weifeng Wang. The landscape of oncogenic gene fusions in Chinese colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 206.
Long-term survival following initiation of home non-invasive ventilation: a European study
Authors: Maxime Patout, Elodie Lhuillier, Georgios Kaltsakas, Amira Benattia, Johan Dupuis, Gill Arbane, Pierre-Louis Declercq, Michelle Ramsay, Philip Marino, Luis-Carlos Molano, Elise Artaud-Macari, Catherine Viacroze, Joerg Steier, Abdel Douiri, Jean-Francois Muir, Antoine Cuvelier, Patrick Brian Murphy, Nicholas Hart
Journal: Thorax (2020)

Introduction Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. Methods Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. Results Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA &gt;7 years and slowly progressive NMD &gt;7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age &gt;60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence &gt;4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). Conclusion The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.
Abstract 4283: Assessment of the tumor mutational burden in a large cohort of Chinese advanced pan-cancer patients
Authors: Ping Liu, Longgang Cui, Shangli Cai
Journal: Cancer Research (2020)

Abstract Background: Immunotherapy have led to a paradigm shift in cancer treatment, while only a small subset of patients can benefit from the treatment. Recent studies have revealed that tumor mutational burden (TMB) is positively correlated with immunotherapy, however, by far, limited data are available for Chinese tumor patients. Methods: We retrospectively assessed the TMB value with a validated 381-cancer-gene panel across 7,822 patients with advanced cancers, including gastric cancer (n= 457), gallbladder cancer (n=608), colorectal cancer (n=785), breast cancer (n=263), Hepatocellular carcinoma (n=904) and lung cancer (n=2135), Renal cell carcinoma (n=346), Liver cancer (904), NSCLC (2135), Melanoma (110), Ovarian cancer (177), Pancreatic cancer (363), Gastric carcinoma (457), Urinary tract cancer (166) and others. Results: A highest 20% of TMB in each histology was selected as the cut-point. Based on our analysis, the highest and the lowest TMB level was observed in endometrial cancer and RCC, respectively. More specifically, the TMB cut-point was 10.5 for biliary tumor, 9.7 for breast cancer, 15.2 for endometrial cancer, 12.1 for CRC, 49.8 for endometrial cancer, 12.1 for oesophageal cancer, 11.1 for head and neck carcinoma, 7.3 for RCC, 10.1 for HCC, 14.5 for NSCLC, 8.9 for melanoma, 8.1 for ovarian cancer, 7.4 for pancreatic cancer, 11.3 for GC, and 20.1 for urinary tract cancer. Consistent results were observed when the median TMB was applied in the analysis. Conclusion: This is the first study focusing on the distribution of TMB value in a large cohort of Chinese cancer patients. The results showed the varying distributions of TMB across histology and suggested that a high TMB status may not assigned by one universal cut-point across different cancer types. Our findings have provide clues to guide the treatment strategy in clinical practice and shed lights on the future trial design. Citation Format: Ping Liu, Longgang Cui, Shangli Cai. Assessment of the tumor mutational burden in a large cohort of Chinese advanced pan-cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4283.
Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine (vol 48, pg 856, 2016)
Authors: P. Gormley, V. Anttila, B.S. Winsvold, P. Palta, T. Esko, T.H. Pers, K.H. Farh, E. Cuenca-Leon, M. Muona, N.A. Furlotte, T. Kurth, A. Ingason, G. McMahon, L. Ligthart, G.M. Terwindt, M. Kallela, T.M. Freilinger, C. Ran, S.G. Gordon, A.H. Stam, S. Steinberg, G. Borck, M. Koiranen, L. Quaye, H.H.H. Adams, T. Lehtimaki, A.P. Sarin, J. Wedenoja, D.A. Hinds, J.E. Buring, M. Schurks, P.M. Ridker, M.G. Hrafnsdottir, H. Stefansson, S.M. Ring, J.J. Hottenga, B.W.J.H. Penninx, M. Farkkila, V. Artto, M. Kaunisto, S. Vepsalainen, R. Malik, A.C. Heath, P.A.F. Madden, N.G. Martin, G.W. Montgomery, M.I. Kurki, M. Kals, R. Magi, K. Parn, E. Hamalainen, H.L. Huang, A.E. Byrnes, L. Franke, J. Huang, E. Stergiakouli, P.H. Lee, C. Sandor, C. Webber, Z. Cader, B. Muller-Myhsok, S. Schreiber, T. Meitinger, J.G. Eriksson, V. Salomaa, K. Heikkila, E. Loehrer, A.G. Uitterlinden, A. Hofman, C.M. van Duijn, L. Cherkas, L.M. Pedersen, A. Stubhaug, C.S. Nielsen, M. Mannikko, E. Mihailov, L. Milani, H. Gobel, A.L. Esserlind, A.F. Christensen, T.F. Hansen, T. Werge, J. Kaprio, A.J. Aromaa, O. Raitakari, Ikram, T. Spector, M.R. Jarvelin, A. Metspalu, C. Kubisch, D.P. Strachan, Ferrari, A.C. Belin, M. Dichgans, M. Wessman, A.M.J.M. van den Maagdenberg, J.A. Zwart, D.I. Boomsma, G.D. Smith, K. Stefansson, N. Eriksson, M.J. Daly, B.M. Neale, J. Olesen, D.I. Chasman, D.R. Nyholt, A. Palotie
Journal: Nature Genetics (2016)
Abstract 240: Inhibition of glycogen degradation sensitizes glioblastoma cells to ionizing radiation
Authors: Anne M. Hendriks, Christos E. Zois, Syed B. Haider, Elisabete Pires, Dimitra Kalamida, Christoffer Lagerholm, John Morris, James S. McCullagh, Rudolf S. Fehrmann, Wilfred F. den Dunnen, Adrian L. Harris, Mathilde Jalving
Journal: Cancer Research (2020)

Abstract Glycogen storage has been demonstrated in multiple cancer cell lines and is upregulated in response to hypoxia both in vitro and in vivo. Evidence supports a potential role of the “glycogen shunt”, that describes the cycling of glucose through glycogen to subsequently fuel glycolysis, in brain tumors. Glioblastoma (GBM) is the most common and most deadly central nervous system tumor, and is characterized by hypoxia and metabolic reprogramming. We found that inhibition of glycogen degradation by downregulation of glycogen phosphorylase liver isoform (PYGL) in GBM cells led to a decrease in clonogenic growth and sensitization to ionizing radiation (IR) doses of 10-12 Gy. Control cells also showed growth impairment but resumed growth 10 days after IR exposure, while PYGL knockdown cells did not. To understand these different responses to high dose IR, we studied the intra-cellular effects of IR in control and PYGL knockdown GBM cells. Five days after IR exposure of PYGL knockdown cells, mitotic catastrophe and a senescence-like morphology were seen. Dysregulation of autophagy, accumulation of elongated and fragmented mitochondria, decrease in oxygen consumption rate and extracellular acidification rate, and increased pAMPK and pACC expression were shown in irradiated PYGL knockdown cells compared to control cells, suggesting metabolic stress. In human GBMs, PYGL mRNA expression was higher than in normal brain tissue and low PYGL mRNA expression was correlated with improved survival rates (hazard ratio 1.32, 95% confidence interval 1.08 - 1.61, P = 0.006). Immunohistochemical PYGL expression was also increased in human GBM versus normal brain tissue. In conclusion, inhibition of glycogen degradation sensitizes GBM cells to high dose IR, the cornerstone of GBM treatment, and may provide a way forward to improve treatment of primary GBMs. Citation Format: Anne M. Hendriks, Christos E. Zois, Syed B. Haider, Elisabete Pires, Dimitra Kalamida, Christoffer Lagerholm, John Morris, James S. McCullagh, Rudolf S. Fehrmann, Wilfred F. den Dunnen, Adrian L. Harris, Mathilde Jalving. Inhibition of glycogen degradation sensitizes glioblastoma cells to ionizing radiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 240.
NCCN Patient Advocacy Summit: Delivering Value for Patients Across the Oncology Ecosystem
Authors: Terrell Johnson, Lindsey A.M. Bandini, Darryl Mitteldorf, Elizabeth Franklin, Justin E. Bekelman, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2020)

As the oncology ecosystem shifts from service-based care to outcomes and value-based care, stakeholders cite concerns regarding the lack of patient experience data that are important to the patient community. To address the patient perspective and highlight the challenges and opportunities within policy and clinical decision-making to improve patient-centered care, NCCN hosted the NCCN Patient Advocacy Summit: Delivering Value for Patients Across the Oncology Ecosystem on December 11, 2019, in Washington, DC. The summit featured multidisciplinary panel discussions, keynote speakers, and patient advocate presentations exploring the implications for patient-centered care within a shifting health policy landscape. This article encapsulates and expounds upon the discussions and presentations from the summit.
Abstract 4134: Characterization of ATRX loss combined with IDH1 R132H mutation in gliomas
Authors: Jennifer Garbarino, Ranjit Bindra, Ryan Jensen
Journal: Cancer Research (2020)

Abstract Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and is a potential therapeutic target. ATRX functions as a histone chaperone that helps incorporate histone variant H3.3 into the genome. There is some evidence of its involvement in both nonhomologous-end-joining (NHEJ) and replication stress, but a distinct role for ATRX in DNA repair has not been determined. Our lab has found that another common mutation in gliomas in the isocitrate dehydrogenase (IDH1) gene, leads to deficiency in homologous recombination (HR). We hypothesize that modelling these common mutations in glioma cell lines will to confer sensitivity to combinations of DNA repair inhibitor and damaging agents. To test this, we have created multiple cell lines with a CRISPR knockout of ATRX as well as lines that overexpress the IDH1 R132H in the presence of doxycycline. This will allow comparison of the double mutation and each mutation individually in different glioma cell lines for their DNA repair capacity. Currently, we have found a retention of H2AX foci in these cells after hydroxyurea treatment. A luciferase reporter based DNA repair assay has shown a decrease in HR capacity and no change in NHEJ in ATRX KO cells compared to WT. Additionally, we have begun screening DNA repair inhibitors and DNA damaging agents to identify compounds that specifically target ATRX KO cells or the double mutant cell lines. These preliminary screens have shown sensitivity to Chk1 inhibitors and temozolomide, which is currently being validated. We have also performed a focused DNA repair CRISPR screen to assess which DNA repair genes cause sensitivity or resistance ATRX KO cells. We infected both WT and ATRX KO cells with our pooled CRISPR library and harvested genomic DNA at multiple time points. Next generation sequencing was then used to identify sgRNAs that dropped out of the population compared to control guides. Sensitive hits from these screens were underrepresented in the ATRX KO population compared to WT and resistant hits were overrepresented in ATRX KO. These hits are the in the process of being validated. This work is continuing to expand on the hypothesis that ATRX is an important targetable mutation in low and high grade gliomas. Further understanding its mechanism of action as well as its action in combination with IDH1 R132H will help understand these cancers and lead to more targeted treatments for patients. Citation Format: Jennifer Garbarino, Ranjit Bindra, Ryan Jensen. Characterization of ATRX loss combined with IDH1 R132H mutation in gliomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4134.
Abstract 909: The role of checkpoints in Rituximab-mediated NK cell activation
Authors: Zhaoming Wang, George J. Weiner
Journal: Cancer Research (2020)

Abstract Purpose: Despite the remarkable clinical success of anti-CD20 monoclonal antibody (mAb) therapy, the mechanisms of action by which such mAb mediate their anti-tumor effects are not completely understood. This includes a need to better understand the role of various NK cell subtypes and checkpoint molecules in anti-CD20 mAb therapy. Experimental procedures: Raji B cell lymphoma cells and peripheral blood mononuclear cells (PBMCs) from normal donors (n=21) were co-cultured with rituximab (RTX) or trastuzumab as a control mAb for up to 15 days. Analysis included assessment of proliferation, remaining viable cells and phenotype of various cell types. Results: As expected, RTX was superior to trastuzumab in eliminating Raji cells. RTX also induced proliferation of NK cells and a shift of NK cells from a CD56dim to CD56bright population. Both NK cell proliferation and the increase in the CD56bright population occurred at day 5-7 when elimination of Raji cells was largely complete. Addback of additional Raji cells at day 5 delayed proliferation of NK cells and the shift from a CD56dim to CD56bright population suggesting this shift occurs once activation of the NK cell via Fcγ;;R is complete. Evaluation of checkpoint molecule expression by NK cells demonstrated RTX, in the presence of Raji target cells, upregulates NK cell expression of TIGIT and TIM3, but not PD1, CTLA-4, or LAG-3. This upregulation was maintained for the full duration of incubation (up to 15 days). The level of expression of TIGIT and TIM3 on NK cells induced by RTX was dose dependent and peaked at 1-5 ug/ml. NK cells induced by RTX to express TIGIT or TIM3 degranulated (CD107a), produced cytokines (IFNγ, TNFα) and expressed activation markers (CD69 and CD25) to a greater degree than did TIGIT or TIM3 negative NK cells. Anti- TIGIT mAb enhanced CD107a expression and TNFα production by RTX-activated NK cells. Conclusion: NK cells proliferate and shift from CD56dim to CD56bright population after being activated and eliminating RTX-coated target cells. TIGIT and TIM3 are biomarkers for RTX-mediated NK cell activation. Blocking TIGIT can enhance RTX-mediated NK cell degranulation and cytokine production. Citation Format: Zhaoming Wang, George J. Weiner. The role of checkpoints in Rituximab-mediated NK cell activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 909.