bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1703: Development of NAV-005, a humoral immuno-suppressor antagonist for the treatment of CA125-expressing cancers
Authors: Nicolaides Nicholas C. , Kline Brad , Grasso Luigi 
Published: July 2021

Abstract
Tumors employ a variety of mechanisms to avoid host cellular and humoral immune responses. Recent findings have found that the tumor-produced MUC16/CA125 protein elicits humoral immunosuppressive effects on antibody-mediated tumor cell killing. This effect is facilitated via direct binding to SIGLEC regulatory receptors on natural killer (NK) cells as well as through direct binding to therapeutic antibodies that blocks Fc-γ-receptor and C1q antibody engagement, leading to suppressed antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activities, respectively. We have engineered a human IgG1 Fc fusion protein, called NAV-005, that binds to CA125 with high affinity and blocks its binding to SIGLEC receptors and affected antibodies, thus enabling efficient humoral immune mediated tumor cell killing. NAV-005 is being developed as a novel therapeutic agent to treat humoral immuno-suppressed CA125 expressing cancers.
Citation Format: Nicholas C. Nicolaides, Brad Kline, Luigi Grasso. Development of NAV-005, a humoral immuno-suppressor antagonist for the treatment of CA125-expressing cancers [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 1703.
Abstract 1707: Increasing immune cell infiltration in hepatocellular carcinoma tumors using a novel GPC3-targeting aptamer conjugate
Authors: McGuire Christina , Yuan Jin , Ball Aaron , Sonberg Justin , Wang Yuxun , Thompson Kristin , Zhu Shuhao 
Published: July 2021

Abstract
Glypican 3 (GPC3) is a cell membrane-bound heparin sulfate proteoglycan, expressed at the cell surface of many cancer types. It has emerged as a leading target for hepatocellular carcinoma treatment due to its overexpression in aberrant liver cells and low expression in healthy adult tissues. One of the major challenges in treating hepatocellular carcinoma with current immunotherapies is turning cold tumors into immunogenic ones. Unmethylated CpG oligodeoxynucleotides (ODNs) are known immune stimulators, however their use in combination therapy for cancer treatment is limited due to the requirement of intra tumoral injections to prevent systemic toxicity. Here, we describe a unique GPC3-specific aptamer, able to target GPC3-expressing cancer cells in vivo as a means to deliver the immunostimulatory CpG 7909. Systemic administration through intra peritoneal (i.p.) injection of the GPC3 aptamer-CpG conjugate (GRX51) decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-50% depending on treatment schedule, while also increasing immune cell infiltration. Final tumor volumes of GRX51-treated animals are consistent with tumor volumes of animals treated with the standard of care compound, sorafenib tosylate. Due to its GPC3-targeting capacity, systemic dosing of GRX51 (15 mg/kg) is less toxic than systemic administration with equimolar amounts of CpG 7909 alone (5 mg/kg), with a comparable effect on tumor shrinkage. While both GRX51 and CpG 7909 induce immune cell recruitment, GRX51 treated mice had a final immune:tumor cell ratio of 2.45 ± 0.56, while CpG 7909-treated animals had a ratio of 1.51 ± 0.95 relative to the vehicle control after a 7-day on/7-day off daily dosing schedule. Using the Hep3B xenograft in CD34+ humanized mice, we also showed GRX51 primes tumors for combination treatments with FDA approved checkpoint inhibitors. Mice were treated with GRX51 (7.5 mg/kg daily i.p. dose, 11 days), the PD-1R inhibitor pembrolizumab (10 mg/kg once every 3 days i.p., 11 days), or a combination of the two drugs. The GRX51 treatment alone outperformed pembrolizumab alone, reducing tumor size by 33% and 18% respectively. Notably, the combination of GRX51 with pembrolizumab reduced tumor size by 63%. Together, our data show that GRX51 is a novel GPC3-targeting molecule capable of reducing tumor size and priming GPC3-positive tumors for combination immunotherapy, without inducing major systemic toxicity with i.p. injection.
Citation Format: Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Kristin Thompson, Shuhao Zhu. Increasing immune cell infiltration in hepatocellular carcinoma tumors using a novel GPC3-targeting aptamer conjugate [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 1707.
Abstract 1711: Induction of anti-tumor immunity by intratumoral delivery of mRNA encoding cytokines and TNFRSF agonists
Authors: Gavigan Julie-Ann , Shi Chaomei , Lampa Michael , Malkova Natalia , Yu Qunyan , Qu Hui , Levit Mikhail , Wagenaar Timothy , Hotz Christian , Li Xiangming 
Published: July 2021

Abstract
In the recent decade several immune checkpoint inhibitors, such as anti-PD1/PD-L1 antibodies, have been approved by regulatory authorities and are actively used in oncology clinical practice. However, these antibodies exhibit durable anti-tumor benefits in only a small fraction of cancer patients. A major unmet medical need in immune oncology (IO) is extending the benefits of these therapies to patients who never experience tumor regression (primary resistance) and those who derive initial benefit before experiencing tumor progression (acquired resistance). Novel IO combinations have the potential to both sensitize primary resistant tumors and combat the acquisition of resistance to checkpoint inhibition. Synthetic, in vitro transcribed messenger RNA (mRNA) is an emerging therapeutic modality that offers the ability to express a broad range of therapeutic combinations. In this project, we proposed to ignite anti-tumor immunity locally through intratumoral (i.t.) delivery of a mixture of mRNAs encoding cytokines and a TNF receptor superfamily (TNFRSF) agonist. Using in vitro and in vivo screening, we identified a combination therapy consisting of three cytokines IFNα, IL-7, and a fusion protein of IL-15 with its receptor alpha chain as well as one TNFRSF agonist, an Fc fusion hexameric OX40L for enhanced receptor clustering. The mRNA mixture enhanced human antigen-specific T cell responses in vitro and displayed potent anti-tumor efficacy in syngeneic tumor models when injected i.t., demonstrating the induction of protective immunity. Importantly, in a preclinical dual-flank syngeneic tumor model, we demonstrated that this protective immunity extended beyond tumors injected with the lead mRNA mixture to control growth of distant untreated lesions. Mechanistically, the lead candidate induced anti-tumor immunity by recruiting dendritic cells to the tumor, leading to activation and expansion of tumor specific CD8 T cells. In summary, this mRNA mixture, encoding IFNα, IL-7, IL-15 and OX40L, induced potent anti-tumor immunity in mice and will be further investigated as a combination partner to overcome resistance mechanisms to immune checkpoint inhibition.
Citation Format: Julie-Ann Gavigan, Chaomei Shi, Michael Lampa, Natalia Malkova, Qunyan Yu, Hui Qu, Mikhail Levit, Timothy Wagenaar, Christian Hotz, Xiangming Li. Induction of anti-tumor immunity by intratumoral delivery of mRNA encoding cytokines and TNFRSF agonists [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 1711.
Abstract 1713: Novel, potent and orally bioavailable small molecule CD73 inhibitors for cancer immunotherapy
Authors: Venkateshappa Chandregowda , Narayanan Kishore , Kothandaraman Prasath , Priyadarshani Garima , Nair Rashmi , Goyal Megha , Ahuja Vijay Kamal , Dadhania Sagar , Aravind AB , Samiulla DS , Daginakkatte Girish , Antony Thomas , Nellore Kavitha , Panigrahi Sunil , Chikkanna Dinesh , Samajdar Susanta , Ramachandra Murali 
Published: July 2021

Abstract
CD73 is a cell surface ectoenzyme, which is overexpressed in many types of human and mouse cancers. CD73 is the primary enzymatic producer of immunosuppressive adenosine in the tumor microenvironment, and high CD73 expression is associated with significantly poorer prognosis in several tumor types. Inhibition of either adenosine generation or signaling by inhibiting CD73 have been shown to be effective therapeutic approaches. Here we sought to discover and develop novel and orally bioavailable small molecule inhibitors that target CD73. Aurigene's non-nucleotide small molecule exhibit potent inhibition of CD73 in respective biochemical and cellular assays. High potency translated into rescue of AMP induced repression of IFN-Υ and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties including solubility, Caco2 permeability, lack of CYP inhibition and excellent oral pharmacokinetic exposure. In summary, we have identified small molecule inhibitors with good drug like properties, which showed good in vitro potency and excellent PK. Evaluation of these lead compounds in syngeneic tumor model along with in vivo toxicity studies are currently under way.
Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Prasath Kothandaraman, Garima Priyadarshani, Rashmi Nair, Megha Goyal, Vijay Kamal Ahuja, Sagar Dadhania, AB Aravind, DS Samiulla, Girish Daginakkatte, Thomas Antony, Kavitha Nellore, Sunil Panigrahi, Dinesh Chikkanna, Susanta Samajdar, Murali Ramachandra. Novel, potent and orally bioavailable small molecule CD73 inhibitors for cancer immunotherapy [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 1713.
Abstract 1722: Enhancement of anti-tumor T-cell immunity by means of an oral small molecule targeting the intracellular immune checkpoint MAP4K1
Authors: Leder Gabriele , Carretero Rafael , Mowat Jeffrey , Berndt Sandra , Neuhaus Roland , Font Nuria Aiguabella , Boemer Ulf , von Ahsen Oliver , Eberspaecher Uwe , Guenther Judith , Grees Mareike , Link Corinna , Nicke Barbara , Baumann Daniel , Schaefer Martina , Oezcan-Wahlbrink Mine , Werbeck Nicolas D. , Hartung Ingo , Kreft Bertolt , Offringa Rienk 
Published: July 2021

Abstract
Immune checkpoint blockade using antibodies targeting the cell surface expressed proteins CTLA-4, PD-1 and PD-L1 has revolutionized cancer care and its clinical impact in several indications has prompted a search for complementary immunostimulatory approaches that can further increase the efficacy of these drugs. Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1; HPK1), a serine/threonine kinase expressed exclusively in hematopoietic cell lineages, mediates a negative feedback signal downstream of T-cell receptor stimulation. Its activity is enhanced by PGE2 and TGFβ, factors commonly present in the tumor microenvironment. Mice deficient for MAP4K1 or expressing a kinase-dead variant of MAP4K1 exhibit enhanced T-cell function, including increased anti-tumor immunity. We developed the small molecule inhibitor BAY-405 that displays potent nanomolar MAP4K1 inhibition in biochemical and cellular assays, good kinase selectivity, and in vivo exposure after oral dosing. Pharmacological inhibition of MAP4K1 enhances T-cell immunity and overcomes the suppressive impact of PGE2, TGFβ and CD4+ T-regulatory cells. Single agent treatment of tumor-bearing mice results in suppression of tumor outgrowth in several syngeneic models. This is accompanied by an increase in the anti-tumor T-cell response, dependent on an intact T-cell compartment, while not involving direct anti-tumor cytotoxicity. Inhibition of MAP4K1 in conjunction with PD-L1 blockade results in further suppression of tumor outgrowth. Moreover, we found that MAP4K1 is expressed in both PD-L1-high and PD-L1-low human cancers. In summary, our data show that selective inhibition of MAP4K1 by means of small molecule drugs may be used to expand the patient population responding to immune checkpoint inhibition.
Citation Format: Gabriele Leder, Rafael Carretero, Jeffrey Mowat, Sandra Berndt, Roland Neuhaus, Nuria Aiguabella Font, Ulf Boemer, Oliver von Ahsen, Uwe Eberspaecher, Judith Guenther, Mareike Grees, Corinna Link, Barbara Nicke, Daniel Baumann, Martina Schaefer, Mine Oezcan-Wahlbrink, Nicolas D. Werbeck, Ingo Hartung, Bertolt Kreft, Rienk Offringa. Enhancement of anti-tumor T-cell immunity by means of an oral small molecule targeting the intracellular immune checkpoint MAP4K1 [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 1722.
Abstract 1726: Preclinical evaluation of a novel tumor selectively targeted and activated immunocytokine platform
Authors: Trinh Kham R. , Vasuthaswat Alex , Ayoub George , Morrison Sherie L. , Stover David R. 
Published: July 2021

Abstract
Interferon alpha (IFNα) is a potent cytokine with receptors expressed universally on virtually all cells types. Recombinant versions of IFNα have demonstrated efficacy in multiple tumor indications and have been FDA approved for treatment of various cancers. However, the full anti-tumor potential of IFNα is not realized with these therapies due to dose limiting toxicity, primarily represented by severe flu-like symptoms resulting from systemic activation of immune cells. Antibody-cytokine fusion proteins have been evaluated as an approach to enhance tumor delivery of the cytokine and thereby increase the therapeutic window. While this approach has merit and can increase the efficacy of such constructs, it typically does not reduce the systemic toxicity since the cytokine is still free to interact with its receptor in circulation. We have designed a novel fusion protein in which the IFNα is active only after it has entered the tumor environment, thereby preventing toxicity resulting from systemic activation of IFNα receptors. Direct antitumor efficacy of an anti-CD138-IFNα2 fusion protein with a tumor selectively cleaved peptide mask was seen in models of multiple myeloma and ovarian cancer. The mask was also shown to prevent IFN mediated activation of peripheral blood cells.
Citation Format: Kham R. Trinh, Alex Vasuthaswat, George Ayoub, Sherie L. Morrison, David R. Stover. Preclinical evaluation of a novel tumor selectively targeted and activated immunocytokine platform [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 1726.
Abstract 173: Efficient representations of tumor diversity with paired DNA-RNA aberrations
Authors: Ke Qian , Dinalankara Wikum , Younes Laurent , Geman Donald , Marchionni Luigi 
Published: July 2021

Abstract
In this work we develop a framework which allows for a systematic analysis of joint DNA and putative downstream RNA effects in cancer data cohorts. Using the Reactome database, we extract gene pairs that are linked by known mechanistic connections. Such pairs, which we refer to as 'Source Target Pairs' or STPs, consist of a source gene for which we examine aberrant activity in the DNA profile, and a target gene that is affected by said source gene, for which we examine aberrant activity in the RNA profile.
Using TCGA data for six different cancer types (breast, colon, kidney, liver, lung and prostate), we use mutation and copy number variation information to compile DNA aberrant activity data. For the same cancer cohorts, we use RNASeq gene expression data to quantify RNA aberrant activity via the previous 'divergence' method we have developed. In the divergence framework, normal samples from the same cancer are used to estimate a normal range of expression for target genes of interest and deviation from the normal range is assumed to indicate aberrant activity which may result from upstream DNA aberrations. Then for a given sample, an STP can be represented as a binary variable, indicating presence or absence of joint DNA-RNA aberrant activity.
We utilize integer programming to discover a small set of such STPs for each cancer type such that every sample displays aberrant activity in at least one STP. We refer to these reduced STP configurations as 'minimal coverings' of that cancer. These configurations then allow for the quantification of heterogeneity for that cancer type, as well as for phenotypical groups of interest. This is made possible due to the fact that sample to sample variability can be compared via the entropy of the distribution of the minimal covering, where the small number of STPs in such a configuration makes the computation more tractable.
Our results reveal many known putative drivers of cancer, as well as identify some novel genes of interest for further consideration. Comparison of heterogeneity across phenotypes of interest show higher entropy in more pathological phenotypes, indicating increasing heterogeneity with severity of disease.
Citation Format: Qian Ke, Wikum Dinalankara, Laurent Younes, Donald Geman, Luigi Marchionni. Efficient representations of tumor diversity with paired DNA-RNA aberrations [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 173.
Abstract 1777: Examining dendritic cell heterogeneity in the tumor microenvironment
Authors: To Tsun Ki Jerrick , Devalajara Samir , Folket Ian W. , Haldar Malay 
Published: July 2021

Abstract
Dendritic cells (DCs) are key regulators of anti-tumor immunity with critical roles in priming and stimulating anti-tumor T cells. DCs have heterogeneous phenotype, ontogeny, activation status, and function. However, the distribution of DC subsets within solid tumors remains unclear. Moreover, the study of intratumoral DCs is hampered by their rarity and difficulties associated with distinguishing DCs from other similar cell types in the tumor microenvironment. Using genetically engineered DC reporter mice (ZBTB46-GFP), we performed single-cell RNA-sequencing (scRNA-seq) on DCs from tumors and normal tissue as an unbiased approach for examining DC heterogeneity. Within our scRNA-seq analysis, we identified the major ontological DC subsets (cDC1s and cDC2s) along with two activated DC subsets: one that expressed a migratory signature (mDC) and the other that expressed an interferon-signaling signature (IFN-DC). By comparing DCs in different tumor models and healthy lung tissue, we found that mDCs were present in both tumor and normal tissue, while IFN-DCs were specific to tumors. IFN-DCs were Sca-1high and were selectively enriched for key anti-tumor interferon-stimulated genes such as Cxcl9 and Cxcl10. Additionally, IFN-DCs were further separated into a type I IFN-enriched subcluster (IFN-DC1) and a type II IFN-enriched subcluster (IFN-DC2). IFN-DC2s were lost in tumors of cDC1-deficient Batf3-KO mice as revealed by scRNA-seq of tumor DCs in Batf3-KO mice. Further experiments suggested that this loss of IFN-DC2 was a cell-extrinsic effect due to the dramatic decrease in IFNy in the tumor microenvironment. Specifically, the decrease in IFNy was associated with the absence of cDC1-primed IFNy-producing CD8 T cells in Batf3-KO tumors. In summary, our analysis of tumor DCs using scRNA-seq and DC reporter mice reveals heterogeneous activated DC subsets, including DCs enriched for distinct type I and type II IFN signaling. Further elucidation of the functional relevance of each subset to the tumor immune response can enable more specific targeting of DCs for cancer immunotherapy.
Citation Format: Tsun Ki Jerrick To, Samir Devalajara, Ian W. Folket, Malay Haldar. Examining dendritic cell heterogeneity in the 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 1777.
Abstract 1793: Regional administration of class C CpG Oligodeoxynucleotides results in superior intrahepatic TLR9 activation and immunomodulation compared to systemic infusion
Authors: Ghosh Chandra , Heatherton Kara , O'Connell Kyle , Laporte Jason , Guha Prajna , Jaroch David , Cox Bryan , Katz Steven C. 
Published: July 2021

Abstract
CpG oligodeoxynucleotides (ODNs) are TLR9 agonists (TLR9As) that stimulate pDC and B cells. Yet, multiple other cell types in the liver express TLR9. The effect of TLR9A in reshaping the tumor microenvironment (TME), particularly in the myeloid-derived suppressor cells (MDSC) compartment, is yet to be determined. Clinical success of TLR9As has been limited by toxicity when given systemically and delivery limitations when administered by direct needle injection. Here, we hypothesized that regional intra-vascular infusion of TRL9As would reprogram the liver MDSC compartment to enable immune control of liver metastases (LM). In this study, we evaluated the effect of class C ODN-2395 as TLR9A in inhibiting LM progression and its impact on the liver MDSC population. C57/BL6 mice were challenged with 2.5e6 MC38-CEA-Luc cells via intra-splenic route. After a week, mice were treated with 1, 3, 10 or 30 µg ODN2395 via PV or IV (30 µg). Bioluminescence was measured at 24 and 48 hrs post-ODN administration. CD45+ cells were isolated, and FACS analysis was performed to quantify MDSCs, monocytic MDSCs (M-MDSC), and M1-macrophage subsets, along with downstream signaling. We found that 30 µg ODN2395 delivered via PV compared to IV reduced tumor burden at 24 hrs and persisted up to 48 hrs. Also, 30 µg ODN2395 infused via PV was optimal in controlling MDSC, M-MDSC cells and polarized CD11b+F4/80+ monocytic cells towards pro-inflammatory/anti-tumorigenic M1 macrophage. Using an NFκB-dependent soluble alkaline phosphatase assay (SEAP), we determined that ODN2395 dose-dependently enhanced NFκB transcription factor activity (p&lt;0.001). Western Blot data of tumor lysates show that ODN delivery by PV increased NFκB (pP65) activity and production of IL-6, significantly relative to IV. Overall, our data suggest that the regional delivery of a TLR9A has the potential to provide superior modulation of the TME within the liver.
Table:Readout30µg IV30µg PVP valuenBioluminescence-24 h (photon/s)4e71e7&lt;0.0113Bioluminescence-48h (photon/s)7e72e7&lt;0.0513FACSCD11b+Gr1+ cells/CD45+ NPC (MDSC)29.70 %20.75%&lt;0.0113CD11b+LY6C+ (M-MDSC)60.03%38.98%&lt;0.0113CD11b+F4/80+CD38+EGR2-(M1 macrophage)34.82%58.20%&lt;0.0113Western BlottingpNFκB/NFκB (pP65s276/pP65): Fold change0.862.028&lt;0.016IL6/GAPDH Fold change12.387&lt;0.056
Citation Format: Chandra Ghosh, Kara Heatherton, Kyle O'Connell, Jason Laporte, Prajna Guha, David Jaroch, Bryan Cox, Steven C. Katz. Regional administration of class C CpG Oligodeoxynucleotides results in superior intrahepatic TLR9 activation and immunomodulation compared to systemic infusion [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 1793.