bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1593: Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy
Authors: Deronic Adnan , Thagesson Mia , Nilsson Anneli , Ellmark Peter , Fält Anette , Fält Charlotte , Smith Karin Enell 
Published: July 2021

Abstract
Mitazalimab (ADC-1013, JNJ-64457107) is a human CD40 agonistic antibody developed for immunotherapy of cancer. Activation of CD40, expressed on antigen-presenting cells (APC), leads to improved T cell priming and initiation of T cell-dependent anti-tumor responses. There are several CD40 agonists in clinical development with different characteristics, affecting both efficacy and tolerability. Mitazalimab is an FcγR crosslinking-dependent IgG1 antibody, with potential for high efficacy and safety. Immunologically “cold” tumors, such as pancreatic cancer, are defined by low infiltration of immune cells as well as low expression and release of neoantigens. In pancreatic cancer, infiltration of effector CD8+ T cells is blocked by the desmoplastic tumor stroma, which surrounds the tumor and hosts immune-suppressive macrophages that dampen the immune response in the tumor microenvironment (TME). By activating and re-directing the immunosuppressive M2 macrophages into tumoricidal M1 macrophages in the TME, CD40 agonists such as mitazalimab, have the potential to augment the response to chemotherapy and spark an effective immune reaction by i) priming T cells reactive to the tumor neoantigens released by the chemotherapy, and ii) inducing degradation of the stroma surrounding the tumor enhancing the efficacy of chemotherapy. The ability of mitazalimab to augment the response to chemotherapy was demonstrated in mice, transgenic for human CD40 (hCD40tg), inoculated with the syngeneic tumor cell line MB49. Mitazalimab, administered repeatedly together with FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil and folinic acid), synergized effectively with chemotherapy and induced a long-term survival. Further, it was also demonstrated that mitazalimab induced a concentration-dependent activation of tumor-associated macrophages (TAMs), purified from human tumor samples, into a more tumoricidal M1 like phenotype, by upregulation of cell surface markers such as CD83.In conclusion, mitazalimab re-directs human macrophages into a M1 like tumoricidal, less immunosuppressive phenotype, and synergizes effectively with chemotherapy, leading to induction of a long-term survival in a preclinical tumor mouse model. These preclinical data, together with the clinical data of mitazalimab from the phase 1 study (NCT02829099) where mitazalimab was well tolerated up to 1200 μg/kg with manageable side effects, support further clinical development of mitazalimab in combination with chemotherapy in pancreatic cancer.
Citation Format: Adnan Deronic, Mia Thagesson, Anneli Nilsson, Peter Ellmark, Anette Fält, Charlotte Fält, Karin Enell Smith. Mitazalimab, a potent CD40 agonist with potential for combination with chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1593.
Abstract 1611: A novel anti-human CD47 antibody prodrug as cancer therapeutics to lower on-target side effects
Authors: Zhang Richard , Drobenaire Hunter , Li Huey , Pizzarella Veronica , Lin Haishan 
Published: July 2021

Abstract
CD47 is highly expressed in many types of cancers, including human acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and solid tumors such as small-cell lung cancer (SCLC). Binding of CD47 to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. CD47 overexpression is one of the mechanisms cancer cells employ to evade immune surveillance and correlates with poor prognosis in cancers. Several strategies have been used to block CD47 binding to SIRPα, including anti-CD47 blocking antibodies and SIRPα-Fc fusion proteins. However, since CD47 is also expressed on normal cells, a major concern is that anti-CD47 antibodies could also cause on-target side effects, such as red blood cell hemagglutination and anemia. We have identified a panel of high affinity anti-human CD47 blocking antibodies. The lead antibodies bound to human CD47 with sub-nanomolar affinities and displayed a range of activities in blocking CD47:SIRPα interaction. These antibodies showed robust activities in stimulating macrophage-mediated phagocytosis of cancer cells. To minimize the on-target side effects of anti-CD47 antibodies, we have taken an antibody prodrug approach in which the antibody is inactive for normal cells while it becomes functional in the tumor microenvironment enriched with proteases. By screening a phage peptide library, we identified peptides that specifically block the anti-CD47 antibody binding activity. These peptides were fused to the humanized anti-CD47 antibody via a linker containing protease substrate sequences to derive the anti-CD47 antibody prodrug. We demonstrated that the anti-CD47 antibody prodrug lacked CD47 binding activity and was unable to block CD47:SIRPα interaction. Upon cleavage of the anti-CD47 antibody prodrug with proteases, the antibody regained full activities in both CD47 binding and blocking CD47:SIRPα interaction. Importantly, we showed that the anti-CD47 antibody prodrug had minimal hemagglutination and RBC binding activities. These data suggest that the novel anti-CD47 antibody prodrug is a promising candidate for the next generation anti-CD47 therapeutics with improved safety profile.
Citation Format: Richard Zhang, Hunter Drobenaire, Huey Li, Veronica Pizzarella, Haishan Lin. A novel anti-human CD47 antibody prodrug as cancer therapeutics to lower on-target side effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1611.
Abstract 1649: Mechanistic understanding of HPK1 inhibition on enhanced human T cell activation and tumor immunity in a syngeneic model
Authors: Ciccone David , Lazari Vad , Linney Ian , Briggs Michael , Carreiro Samantha , Loh Christine , Tummino Peter , McElwee Joshua , Collis Alan , Kaila Neelu 
Published: July 2021

Abstract
Background: HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in negatively regulating signal transduction cascades in cells of hematopoietic origin. Recent data generated using potent and highly selective HPK1 inhibitors underscores the role of HPK1 in negatively regulating T, B, and dendritic cell activation and thus orchestrating a comprehensive anti-tumor immune response. In the present study, we seek to further understand the biological effects of HPK1 inhibition in primary human T cells and in syngeneic models.
Methods: RNA sequencing and multiplex cytokine analyses were utilized to profile both primary human T cells and the MC38 syngeneic model. In vivo efficacy, target engagement and pharmacodynamic data were generated using murine syngeneic tumor models.
Results: In vitro, HPK1 small molecule inhibition resulted in enhanced cytokine production in primary human T cells. In vivo, HPK1 inhibition abrogated T cell receptor-stimulated phospho-SLP-76, enhanced cytokine production, and mediated robust tumor growth inhibition in a murine syngeneic tumor model.
Conclusion: Pharmacological blockade of HPK1 kinase activity represents a novel and potentially valuable immunomodulatory approach for anti-tumor immunity.
Citation Format: David Ciccone, Vad Lazari, Ian Linney, Michael Briggs, Samantha Carreiro, Christine Loh, Peter Tummino, Joshua McElwee, Alan Collis, Neelu Kaila. Mechanistic understanding of HPK1 inhibition on enhanced human T cell activation and tumor immunity in a syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1649.
Abstract 169: Ephesus - A curated content knowledgebase for the clinical interpretation of genomic variants
Authors: Li Jian , Niu Lili , Kinshuk Fnu , Chu Bernie , Mu John , Greene Nicole , Douglas Vivian , Schartner Caitlin , Kannan Kalpana , Rao Priyanka , Krishna Shuba 
Published: July 2021

Abstract
Accurate and comprehensive interpretation of genomic variants has become a bottleneck in clinical sequencing applications due to the implementation of precision oncology and the growth of biomedical findings. We therefore were motivated to build Ephesus, a framework enabling curation of predictive, prognostic and diagnostic evidence for clinical biomarkers in somatic cancers. Currently Ephesus is the primary content source for Roche NAVIFY Mutation Profiler (RUO). The Ephesus' data model ensures adherence to best practices in the field of clinical genomic content curation. Somatic variant classification followed the AMP guidelines. Approvals and recommendations from regulatory agencies and clinical practice guidelines were applied on a regional basis. The data model is mapped to a set of relational tables. Strategies such as data normalization according to standard ontologies, a submit-review-approval workflow with change logs, and biologically relevant data constraints are adopted to enforce data integrity. Ephesus is deployed as a web application whose UI allows users to conduct edits, sorting, filtering, and bulk operations on entities attributes. In order to minimize the manual effort and maximize content coverage, a number of inference rules are applied before the content is ingested into NMP. Currently Ephesus is developed to guide data collection, browsing and summarizing related to primary entities such as Biomarkers, Evidence items, Genes, Variants, Variant groups, and Drugs. The content from 10/28/20 snapshot contains 233k biomarker profiles (including biomarker combinations), in the context of 17 major cancer types. To evaluate the clinical reporting value of the curated knowledge, ~60k clinical cancer patient samples from the AACR GENIE project were queried against Ephesus. Compared our results against those from 3 other major knowledgebases (snapshotted at the same time as Ephesus), we see the performance of Ephesus/NMP exceeds all these knowledgebases.
Patients% with at least one interpretation (numbers in parenthesis include matching by inferences)KnowledgebaseVariantVariant & diseaseTier I variant & diseaseEphesus53 (91)40 (89)19 (25)CGI3573CIViC402215ClinVar452313
Citation Format: Jian Li, Lili Niu, Fnu Kinshuk, Bernie Chu, John Mu, Nicole Greene, Vivian Douglas, Caitlin Schartner, Kalpana Kannan, Priyanka Rao, Shuba Krishna. Ephesus - A curated content knowledgebase for the clinical interpretation of genomic variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 169.
Abstract 1723: WTX-124 is an IL-2 pro-drug conditionally activated in tumors and able to induce complete regressions in mouse tumor models
Authors: Salmeron Andres , Brodkin Heather , Hicklin Daniel , Ismail Nesreen , Morris Kristin , Nirschl Christopher , Seidel-Dugan Cynthia , Steiner Philipp , Steuert Zoe , Sullivan Jenna , Winston William 
Published: July 2021

Abstract
Cancer Immunotherapy has established itself as the fourth pillar of cancer treatment thanks to the clinical success of checkpoint inhibitors. Despite the durable responses achieved by some patients using these new therapies, the proportion of responders remains low and restricted to some cancer types. Preclinical and clinical studies have demonstrated the promise of cytokine therapy to increase antitumor immunity, however systemic toxicity and poor pharmacokinetic profiles have limited their clinical application. One of these key cytokines, interleukin-2 (IL-2), is approved for clinical use in metastatic melanoma and renal cell carcinoma. Unfortunately, this treatment is linked to serious toxicities which limits its utility. To address these limitations, our approach takes advantage of the dysregulated protease tumor microenvironment (TME) to activate an IL-2 pro-drug (IL-2 INDUKINETM) only at the desired site of activity. Peripheral inactivation is achieved by linking the cytokine to an inactivation domain using a tumor protease-sensitive linker. The INDUKINE is also engineered with a half-life extension element to improve tumor exposure. Once the IL-2 INDUKINETM reaches the tumor, tumor-associated proteases cleave the linker and release the active cytokine. This work presents data summarizing the discovery, biochemical, cellular, and in vivo activity of our lead IL-2 INDUKINETM WTX-124 and reviews the mechanism of action of these molecules. Treatment with WTX-124 results in complete regression of tumors driven by the expansion and activation of CD8+ T cells and NK cells which increases the production of effector cytokines in the tumor. Activity is dependent on the proteolytic processing of the INDUKINE as a non-cleavable control INDUKINE lacks efficacy. PK analysis in mouse models demonstrates a favorable accumulation of free IL-2 in tumors compared to plasma. The animals that rejected the tumors upon IL-2 INDUKINETM treatment were protected against follow up re-challenge with the same tumor cell line. In vitro proteolytic activation by human tumor samples will also be presented. The tumor-selective activation of WTX-124 with reduced peripheral toxicities supports its further clinical development.
Citation Format: Andres Salmeron, Heather Brodkin, Daniel Hicklin, Nesreen Ismail, Kristin Morris, Christopher Nirschl, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, Jenna Sullivan, William Winston. WTX-124 is an IL-2 pro-drug conditionally activated in tumors and able to induce complete regressions in mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1723.
Abstract 1869: Novel TNFR2 antibodies to overcome T cell exhaustion and suppressive tumor microenvironment
Authors: Sum Chi Shing , Danton Makenzie , hu Qii , Pritsker Alla , Lin Ray , Yu Raymond , Chen Kevin , Tang Fangqiang , Pohl Thomas , Wallner Samantha , Hassan Ahmed , Lu Huarui , Huang Haichun , Pei James , Liu Zhong , Li Han , Lei Ming 
Published: July 2021

Abstract
TNFR2 is highly expressed on the surface of activated T effector cells, T regulatory cells and myeloid cells, and it plays essential roles in modulating the tumor microenvironment. In most cancer types, higher TNFR2 expression correlates with increased immune cell infiltration. Furthermore, the TNFR2 gene is differentially expressed in various cancer types, including breast, lung, renal, liver and skin cancers. In cancers such as head and neck cancer and cutaneous melanoma, high TNFR2 expression correlates with better overall survival. The therapeutic potential of antibodies targeting TNFR2 has been demonstrated by agonist antibodies for the T effector cells, and antibodies that antagonize or deplete the T regulatory cells and suppressive myeloid cells. We discovered novel TNFR2 antibodies that demonstrate unique mechanisms to overcome T cell exhaustion and the suppressive tumor microenvironment for more effective immunotherapy. In vitro studies have shown that our antibodies block TNFα ligand binding and potently inhibit TNFR2 signaling in the monocytic cells. Moreover, these antibodies enhance CD8 T cell function to overcome the suppressive effect from the T regulatory cells and can invigorate exhausted CD8 T cells in an FcγR-dependent manner. In a humanized mouse model, our antibodies demonstrate strong anti-tumor efficacy as single agents or in combination with a PD-L1 inhibitor. Therefore, these antibodies offer potential advantages when the tumor microenvironment is enriched in the exhausted T cells, the suppressive myeloid cells, or the regulatory T cells, as found in anti-PD-1/PD-L1 resistant and PD-1 refractory patients. In conclusion, the data obtained indicate that our TNFR2 antibodies are a novel and promising class of drug candidates for cancer immunotherapeutics. Our lead antibody is currently at the IND-enabling stage with the target of entering clinical studies in early 2022.
Citation Format: Chi Shing Sum, Makenzie Danton, Qii hu, Alla Pritsker, Ray Lin, Raymond Yu, Kevin Chen, Fangqiang Tang, Thomas Pohl, Samantha Wallner, Ahmed Hassan, Huarui Lu, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei. Novel TNFR2 antibodies to overcome T cell exhaustion and suppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1869.
Abstract 1905: In vivo CRISPR screen identifies tumor suppressors as drivers of tumor cell-intrinsic immune evasion
Authors: Min Chengyin , Skoulidis Ferdinandos , Zhou Wenrong , Tsoi Jennifer , Huang Alan , Goldstein Matthew J. 
Published: July 2021

Abstract
Cancer cell-intrinsic genetic alterations that allow cancer cells to evade destruction by the immune system remain poorly characterized. Here we performed a pooled CRISPR-Cas9-based in vivo genetic screen targeted to a pre-defined set of tumor suppressor genes to mimic loss-of-function mutations in syngeneic tumor models. CRISPR edited tumor cells were implanted into immune-deficient or immune-competent C57BL/6 mice, a subset of which were treated with anti-PD1 to simulate increased immune pressure. Tumor samples at the endpoint were subjected to next generation sequencing analysis to identify tumor suppressor genes driving immune evasion. The screen confirmed previously identified immunotherapy targets such as CD47 and Adar as well as known drivers of immune resistance in the interferon signaling and antigen presentation pathways. Importantly, we identified loss of STK11/LKB1 and KEAP1 as drivers of immune resistance in syngeneic models. TIL profiling analysis suggests that STK11/LKB1 knockout induces a “cold” tumor microenvironment. STK11/LKB1 and/or KEAP1 genomic alterations are found in ~25% of non-squamous non-small cell lung cancer and have been reported as a major predictor of primary resistance to PD-1 blockade. Together, these data demonstrate that high-throughput in vivo genetic screens can identify tumor cell-intrinsic drivers of immune evasion and establish murine system relevant to the study of primary resistance to PD-1 axis immunotherapy and more generally, tumor cell-intrinsic immune evasion.
Citation Format: Chengyin Min, Ferdinandos Skoulidis, Wenrong Zhou, Jennifer Tsoi, Alan Huang, Matthew J. Goldstein. In vivo CRISPR screen identifies tumor suppressors as drivers of tumor cell-intrinsic immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1905.
Abstract 1920: Armed oncolytic myxoma virus demonstrates transgene production, function, and therapeutic activity xenograft models
Authors: Franco Lina S. , Abrantes Mario , Abdullahi Wazir , de Matos Ana L. , Walker Benjamin S. , Tacner Zachary , Kien Cassandra , Grigaitis Nicole , McFadden Grant , Potts Steven J. , Sharp Leslie L. 
Published: July 2021

Abstract
Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and provide stimulation to the immune system, representing a promising therapeutic option in development to treat cancers that do not respond well to treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Pox family of double stranded DNA viruses. The natural host of MYXV is a subset of rabbits and hares, but MYXV is able to infect cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenic proteins, making it an excellent oncolytic virus for introduction of immunomodulatory proteins. Viral reproduction rates, transgene production, transgene function, and inhibition of cell growth of multi-armed myxoma virus was evaluated in vitro using cell lines representing multiple human cancer indications. Efficacy and mechanism of action of multi-armed myxoma virus was also demonstrated in vivo via xenograft models. Multi-armed myxoma represents a novel, engineerable, oncolytic virus with preclinical characteristics that warrant further investigation as an immunomodulatory cancer therapeutic.
Citation Format: Lina S. Franco, Mario Abrantes, Wazir Abdullahi, Ana L. de Matos, Benjamin S. Walker, Zachary Tacner, Cassandra Kien, Nicole Grigaitis, Grant McFadden, Steven J. Potts, Leslie L. Sharp. Armed oncolytic myxoma virus demonstrates transgene production, function, and therapeutic activity xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1920.
Abstract 1962: Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models
Authors: Wiley Sandra E. , Su Yongwei , Ge Yubin 
Published: July 2021

Abstract
Mutations in KRAS at G12, G13, and Q61 are oncogenic drivers in many cancers, including lung, colorectal, pancreatic, multiple myeloma, and uterine carcinomas. KRAS mutations are frequently accompanied by stabilization of the MYC oncoprotein through increased MYC transcription and decreased protein degradation that is mediated by phosphorylation of MYC on Ser 62 by ERK and CDK9 kinases. Voruciclib is a novel oral inhibitor of CDKs 9, 4, 6, and 1 that is currently being tested in Phase 1B clinical trials for B-cell malignancies and acute myeloid leukemia. Voruciclib inhibition of CDK9 leads to decreased expression of transcriptional targets of RNA Pol II, such as Mcl1 and MYC. To test whether voruciclib could be effective in cancers driven by dysregulated KRAS-MYC signaling, ~20 cancer cell lines with KRAS mutations (G12A, G12C, G12D, G12S, G12V, G13C, G13D, Q61H) were treated in preclinical studies with voruciclib. MTS and Cell Titer Glo assays were used to monitor growth in vitro. Voruciclib decreased viability in all cell lines tested. To investigate MYC protein stability, MIA PACA-2 (G12C) cells were treated with 4 µM voruciclib for 5-240 min, followed by SDS-PAGE and Western Blotting analysis with α-MYC and α-pSer62-MYC antibodies. Voruciclib treatment resulted in a reduction in phosphorylation of MYC on Ser 62. A 60% decrease in pSer62 was observed after 5 min that reached 80% by 60 min. In contrast, there was no decrease in total MYC protein at either 5 or 15 min. A 10% reduction in total MYC was observed at 60 min that reached 50% at 240 min. The ability of voruciclib to inhibit tumor growth in vivo was also tested in murine xenograft models. KRAS mutant human cancer cells HCT-116 (CRC, KRAS G13D), SW-480 (CRC, KRAS G12V), and H-460 (NSCLC, KRAS Q61H) were injected subcutaneously into SCID mice. Once tumors reached 5-10 mm in diameter, voruciclib or vehicle were administered orally at 50, 100, or 200 mg/kg OD for 11-14 days. Tumors were measured every 2-3 days, and growth inhibition relative to control was calculated. Significant tumor growth inhibition (&gt;50%) was observed at all doses of voruciclib tested. Collectively, these data demonstrate that voruciclib inhibition of CDK9 leads to reduced phosphorylation of MYC on Ser 62 followed by a decrease in total MYC protein in MIA PACA-2 cells and inhibition of growth in multiple KRAS mutant cancer cell lines in vivo and in vitro. This suggests that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC.
Citation Format: Sandra E. Wiley, Yongwei Su, Yubin Ge. Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1962.