bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3284: HB-201 and HB-202, an arenavirus-based immunotherapy, induces tumor T cell infiltration in patients with HNSCC and other HPV16+ tumors
Authors: Edwards Donna , Schwendinger Michael , Katchar Kia , Schlienger Katia , Orlinger Klaus , Matushansky Igor , Lauterbach Henning 
Published: June 2022

Abstract
Background: Human Papillomavirus 16 (HPV16) is the most common etiologic agent of HPV-associated cancers. Treatment options are limited for patients with HPV16+ recurrent or metastatic cancers. HPV16 E7 and E6 oncogenes constitute attractive immunotherapeutic targets. HB-201 and HB-202 are live-attenuated replicating vectors based on LCMV and PICV arenaviruses, respectively, that express the same non-oncogenic HPV16 E7E6 fusion protein for induction of tumor specific T cell responses.
Methods: A Phase I/II open labelled clinical trial of HB-201 single vector therapy and HB-202/HB-201 alternating two-vector therapy in patients with treatment-refractory HPV16+ cancers is currently ongoing (NCT04180215). To assess circulating E6/E7 specific T cell responses, IFN-γ enzyme-linked immunospot (ELISpot) and intracellular cytokine staining were performed on pre- and post-treatment peripheral blood mononuclear cells (PBMCs). Evaluation of T cell infiltration and PD-L1 status in tumor bed was performed on paired tissue biopsies from a subset of patients by multiplex immunofluorescence.
Results: Single vector therapy (HB-201) and alternating two-vector therapy (HB-202/HB-201) rapidly induce high E6/E7 specific T cell levels, reaching up to ~40% of the circulating CD8+ T cell pool. Alternating two-vector therapy seems to maintain E6/E7 specific T cell responses better in continuous dosing compared to single vector therapy. Furthermore, we demonstrate tumor tissue T cell infiltration in more than 50% of patient samples analyzed. Currently, in depth sequencing of paired biopsies is underway to characterize the tumor microenvironment in response to HB-201 and HB-202/HB-201 treatment.
Conclusion: In this updated dataset, we show that HB-201 and HB-202/HB-201, rapidly induce unprecedented E6/E7 specific T cell levels in circulation following a single dose. Furthermore, these data are seen in conjunction with a pronounced increase of post-treatment CD8+ T cells in tumor, suggesting E6/E7 specific T cell infiltration. Our arenavirus vectors expressing the E7E6 fusion antigen demonstrate an attractive and safe therapy for patients with treatment refractory HPV16+ cancers. The ability of replicating arenavirus vectors to incorporate a broad range of antigens and the potent T cell inducing capacity provide a strong rationale to apply this novel therapy to other cancers.
Citation Format: Donna Edwards, Michael Schwendinger, Kia Katchar, Katia Schlienger, Klaus Orlinger, Igor Matushansky, Henning Lauterbach. HB-201 and HB-202, an arenavirus-based immunotherapy, induces tumor T cell infiltration in patients with HNSCC and other HPV16+ tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3284.
Abstract 3326: Uncovering the molecular mechanisms which predict sensitivity to a novel src kinase inhibitor NXP900 to inform personalized healthcare strategies
Authors: Carragher Neil , Hughes Rebecca , Brunton Valerie , Unciti-broceta Asier , Lanzagorta-Calvillo Iñigo , Temps Carolin , Poradosu Enrique 
Published: June 2022

Abstract
We have previously described the discovery of a highly potent, selective and orally bioavailable Src kinase inhibitor NXP900 with a unique binding mode relative to other Src inhibitors under clinical development or approved (Temps et al 2021). This unique binding mode locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions. Also, in contrast to other Src inhibitors in the clinic, NXP900 exhibits a unique target selectivity profile with 1000 fold selectivity for Src over Abl kinase. The aim of this current study was to perform broad cancer cell line panel screening to inform disease positioning and identify predictive biomarkers of sensitivity for this novel class of Src kinase inhibitor. We describe the results of extensive cancer cell line panel profiling across a suite of 2-dimensional(D) and 3-D in vitro cell viability and high content phenotypic profiling assays that has revealed clear patterns of cell line sensitivity and insensitivity. Among the most sensitive cell line subtypes are, squamous cell carcinoma, Arid1A mutant ovarian clear cell carcinoma and subtypes of breast luminal A and triple negative breast cancer cell lines. HER2+ breast cancer lines appear insensitive to NXP900 indicating HER2 as a potential driver of resistance to NXP900. Further in-depth bioinformatic analysis of genetic and transcriptomic profiles of sensitive cell lines has identified putative biomarkers to support patient selection and personalized healthcare strategies. These studies demonstrate the identification of cancer cell lines which exhibit high sensitivity to NXP900 and which can be grouped into discrete molecular subtypes based on gene mutation status, transcriptomics and histotype. Our result provide an indication of patient subgroups which may exhibit optimal therapeutic response to NXP900 and provide data to guide further preclinical, biomarker and clinical development. Temps C et al., Cancer Res. 2021 Nov 1;81(21):5438-5450. doi: 10.1158/0008-5472.CAN-21-0613.
Citation Format: Neil Carragher, Rebecca Hughes, Valerie Brunton, Asier Unciti-broceta, Iñigo Lanzagorta-Calvillo, Carolin Temps, Enrique Poradosu. Uncovering the molecular mechanisms which predict sensitivity to a novel src kinase inhibitor NXP900 to inform personalized healthcare strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3326.
Abstract 3510: SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy
Authors: Adkins Irena , Antosova Zuzana , Danova Klara , Hladikova Kamila , Augustynkova Katerina , Sajnerova Katerina , Podzimkova Nada , Marasek Pavel , de Martynoff Guy , Bechard David , Moebius Ulrich , Spisek Radek 
Published: June 2022

Abstract
SOT201 is a novel immunocytokine consisting of a monoclonal humanized, Fc silenced antibody against PD-1 fused to a covalent RLI-15 complex of a human IL-15 mutein linked to the high-affinity binding site of the IL-15Rα, the sushi+ domain. SOT201 is developed for immunotherapeutic treatment of various types of cancers. The activity of SOT201 is based on spatiotemporal reinvigorating of anti-tumor immune responses by disrupting co-inhibitory T-cell signaling by blocking PD-1 and synergistically activating adaptive as well as innate immunity by IL-15-mediated signaling via the IL-2/IL-15βγ receptor on T cells, NK, NKT, and γδ T cells. SOT201 showed a superior potentiation of T cell stimulation over pembrolizumab in mixed lymphocyte reaction in vitro. Studies in cynomolgus monkeys showed that decreased affinity of IL-15 mutein in SOT201 for its IL-15Rβγ is well optimized to ensure favorable pharmacokinetic properties while inducing strong CD8+ T cell and NK cell activation and expansion. Synergistic action on CD8+ T cell activation of both anti-PD-1 and RLI-15 moieties was confirmed using mouse surrogate SOT201 molecules in vivo. Strong anti-tumor efficacy after SOT201 treatment was achieved in a human PD-1 transgenic mouse model implanted with the MC38-hPD-L1 cell line. These data represent a promising therapeutic candidate molecule leveraging the synergistic concerted action of anti-PD-1 blockage and simultaneous immune cell activation directed preferentially to the high PD-1+ T cell tumor environment. The therapeutic potential of SOT201 is currently being prepared for evaluation in a Phase I clinical study in metastatic advanced cancer patients as well as for PD-1 resistant/refractory patients as our clinical stage IL-2/IL-15Rβγ agonist SOT101 already showed a clinical benefit in these patients in its ongoing Phase I study.
Citation Format: Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3510.
Abstract 357: Characterization of KRas pathway inhibitors in 2D and 3D screening formats
Authors: Schaich Katharina , Feger Daniel , Siedentopf Oliver , Ulrich Sarah , Ehlert Jan Erik 
Published: June 2022

Abstract
The KRas/Raf/MEK signalling axis has been identified to play a critical role in the formation of cancer, resulting in several investigational new drugs targeting this pathway. Identification of appropriate drugs is hampered, however, by the assumption that a three-dimensional setting may be required to observe significant inhibitory effects, possibly due to alternate gene expression and protein activity in such a “closer-to-physiology” setting. In order to explore that topic, in the current study we have made use of our 140 cell lines (CL)-2D proliferation panel (3 days incubation) and our 100CL-3D soft agar panel (&gt; 7 days incubation). On these platforms, we have compared inhibitors targeting the KRas/Raf/MEK pathway via either KRas:SOS interaction (e.g. BI3406), the KRas mutation at G12C (e.g. AMG510), or Raf-kinase (e.g. AZ628) and MEK1/2-kinase activity (e.g. AZD6244). It showed that especially the Raf- and MEK kinase inhibitors exhibited significantly enhanced potency in the 3D soft agar setting in the majority of the cell lines tested. The other inhibitors also showed an increased potency under soft agar conditions, however, on clearly fewer cell lines and usually not as strongly. For all kinds of inhibitors tested, the most significant changes in potency were associated with enhanced efficacy as observed by stronger cell death induction. Differences may be attributable to three-dimensional growth, but also to the elongated duration of the soft agar assay. For selected conditions, we addressed this topic by analyzing the inhibitor impact on 3D spheroid growth after shorter incubation times. Our results show that 3D growth analysis either in the soft agar or spheroid setting clearly supports the development of KRas/Raf/MEK pathway inhibitors.
Citation Format: Katharina Schaich, Daniel Feger, Oliver Siedentopf, Sarah Ulrich, Jan Erik Ehlert. Characterization of KRas pathway inhibitors in 2D and 3D screening formats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 357.
Abstract 3573: DNA immunotherapy targeting BARF1 demonstrates therapeutic impact in novel murine carcinoma models expressing EBV latent antigens
Authors: Zhu Xizhou , Perales-Puchalt Alfredo , Wojtak Krzysztof , Xu Ziyang , Yun Kun , Bhojnagarwala Pratik S. , Bordoloi Devivasha , Park Daniel H. , Liaw Kevin , Bah Mamadou A. , Lieberman Paul M. , Gary Ebony N. , Patel Ami , Weiner David B. 
Published: June 2022

Abstract
Epstein Barr Virus (EBV) latent infection is associated with multiple types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV+ malignancies, suggesting additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV-associated gastric carcinoma (EBVaGC) and EBV+ nasopharyngeal carcinoma (NPC) and has not been evaluated as an antigen in the context of therapeutic immunization. Here, we developed a synthetic DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and polyfunctional effector T cell responses in vivo. We observed significant antigen-specific increases of IFN-γ+, IFN-γ+ TNF-α+, and IFN-γ+ TNF-α+ IL-2+ populations in CD8+ T cells from the pBARF1 immunized animals in both C57BL/6 and BALB/c mice. Novel BARF1 expressing carcinoma lines that grow in immune-competent animals were developed as surrogates for human EBV+ tumors. We confirmed that BARF1 expression in these new cancer cell lines, MC38-BARF1 and CT26-BARF1, was within the range of human EBV+ cancer cell lines, SNU719 and C666-1. Immunization with pBARF1 plasmid demonstrated impact of tumor progression through induction of CD8+ T cell in these BARF1+ carcinoma models. We also observed long-term antitumor immunity, at least up to 446 days, against BARF1 in a CT26-BARF1 rechallenge study. Using IVIS in vivo imaging, we observed that pBARF1 immunized animals rapidly controlled and cleared cancer cells. These studies demonstrate the potential for pBARF1 immunity to induce antigen-specific immune responses impacting tumor progression. Further study of this immune target and these EBV+ tumor models is likely important as part of therapeutic approaches for EBV+ malignancies.
Citation Format: Xizhou Zhu, Alfredo Perales-Puchalt, Krzysztof Wojtak, Ziyang Xu, Kun Yun, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Daniel H. Park, Kevin Liaw, Mamadou A. Bah, Paul M. Lieberman, Ebony N. Gary, Ami Patel, David B. Weiner. DNA immunotherapy targeting BARF1 demonstrates therapeutic impact in novel murine carcinoma models expressing EBV latent antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3573.
Abstract 3583: Identifying and testing cancer-derived synthetic-lethal anti-SARS-CoV-2 targets
Authors: Pal Lipika R. , Cheng Kuoyuan , Nair Nishanth Ulhas , Martin-Sancho Laura , Sinha Sanju , Pu Yuan , Riva Laura , Yin Xin , Schischlik Fiorella , Lee Joo Sang , Chanda Sumit , Ruppin Eytan 
Published: June 2022

Abstract
Introduction: Despite the development of two mRNA vaccines, there is an urgent unmet need of finding new antiviral strategies. One such potential antiviral strategy is to target the synthetic lethal (SL) partners of transcriptionally altered genes in infected host cells, thereby selectively killing them to halt the infection at its heels (Mast FD, JCB, 2020).
Methods: Here we conduct a first proof-of-concept SL inference approach to predict anti-SARS-CoV-2 targets in a systematic genome-wide manner. This effort capitalizes on our recently published pipeline for inferring clinically relevant SL interactions in cancer (Lee et al, Cell, 2021). Based on the latter, we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict candidate antiviral targets that are SL with altered host genes. Importantly, as our predictions are fine-tuned based on the analysis of patients’ data, they are more likely to be of translational value.
Results: Our key results are twofold:1) The predicted SL-based targets are highly enriched for genes that are reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens to inhibit growth of infected cells. 2) A subset of top predicted 26 genes were experimentally tested in a targeted siRNA screen conducted in both infected and non-infected human Caco-2 cells. Remarkably, as expected given that these targets were predicted to be SL specific with genes upregulated in infected cells, indeed, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells.
Conclusion: In summary, this study is the first to demonstrate the potential of a synthetic lethality approach to identify viral (specifically anti-SARS-CoV-2) targets. Importantly, as both single cell and bulk transcriptomics patients’ data is considered from both infected people and controls, they are more likely to be of clinical relevance. Targeting host genes identified via an SL-based approach is probably more suitable when the infection is at the early stage and host can still tolerate the loss of infected host cells.
Citation Format: Lipika R. Pal, Kuoyuan Cheng, Nishanth Ulhas Nair, Laura Martin-Sancho, Sanju Sinha, Yuan Pu, Laura Riva, Xin Yin, Fiorella Schischlik, Joo Sang Lee, Sumit Chanda, Eytan Ruppin. Identifying and testing cancer-derived synthetic-lethal anti-SARS-CoV-2 targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3583.
Abstract 3607: A novel adjunctive LAT-activating CAR T (ALA-CART) cell platform demonstrates enhanced antigen sensitivity and eradication of antigen-low leukemia
Authors: Pham-Danis Catherine , Leach Lillie , Ebmeier Christopher , Kohler M. Eric 
Published: June 2022

Abstract
CAR T cells have demonstrated clinical success in malignancies that are refractory to standard therapies; however, preclinical and clinical studies have demonstrated that CAR T cell efficacy is greatly reduced in settings of low levels of target antigen. This was exemplified in a clinical trial of CD22-directed CAR T cells where despite inducing complete remissions in &gt;70% of patients, post-CAR relapses occurred in the majority of patients, driven by decreased expression of CD22 below the threshold required for adequate CAR T cell activation. To address this limitation of CAR T cells, we investigated the mechanism underlying suboptimal CAR responses to low levels of antigen. Using a SILAC/mass spectrometry approach, we performed global phosphoproteomics to examine CAR T cell signal transduction in response to high- and low-levels of CD22 antigen. Low levels of CD22 antigen resulted in decreased utilization of several canonical T cell signaling pathways in CAR T cells. We hypothesized that LAT, a scaffolding protein integral to the T cell signalosome, was inefficiently utilized in response to low levels of antigen. Indeed, while signaling events proximal to LAT, such as Zap70, were unaffected by CD22 antigen density, phosphorylation of LAT at multiple activating residues decreased in response to stimulation with CD22-low leukemia cells. To overcome the inefficient LAT activation by low levels of antigen, we designed a bicistronic construct consisting of a clinically active 2nd generation CD22-BBz CAR along with a novel Adjunctive LAT Activating CAR incorporating the intracellular signaling domain of LAT (ALA-CART). ALA-CART cells expressed both CARs on the surface and demonstrated enhanced phosphorylation of LAT and PLCγ in response to CD22-low leukemia cells. In xenograft models, ALA-CART cells completely eradicated CD22-low leukemia, significantly extending survival of mice in comparison to the standard CD22-BBz CAR which only modestly slowed leukemia progression. Additionally, in mice engrafted with leukemia expressing WT-levels of CD22, we found the persistence of ALA-CART cell was significantly enhanced relative to standard CD22-BBz CAR T cells. Thus, by identifying deficits in CAR signaling, we rationally designed the ALA-CART platform to target antigen-low cells, overcoming a mechanism of resistance to standard CAR therapies with the potential to improve outcomes of patients receiving CAR therapies.
Citation Format: Catherine Pham-Danis, Lillie Leach, Christopher Ebmeier, M. Eric Kohler. A novel adjunctive LAT-activating CAR T (ALA-CART) cell platform demonstrates enhanced antigen sensitivity and eradication of antigen-low leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3607.
Abstract 3618: Loss of SETD2 sensitizes kidney cancer cells to DNA methylation inhibitors by inducing viral mimicry and RNA mis-splicing
Authors: Li Hong-Tao , Jang Hyo Sik , Rohena-Rivera Krizia , Gujar Hemant , Liu Minmin , Kulchycki Justin , Zhou Xinyi , Zhao Shuqing , Jones Peter , Bhowmick Neil , Liang Gangning 
Published: June 2022

Abstract
Large-scale sequencing efforts of human cancers have identified recurrent mutations and deletions in a variety of chromatin-regulating proteins that modulate DNA methylation, histone modifications, and nucleosome positioning. The dysregulation of histone H3 lysine 36 (H3K36) methyltransferase, SETD2, through transcriptional or genetic aberrations is associated with worse clinical outcomes and metastasis in kidney cancer. Limited targeted therapeutic interventions are available for aggressive SETD2-mutant ccRCC tumors. Here, we reveal that kidney cancer cells displaying diminished H3K36 trimethylation levels, a consequence of SETD2 deficiency, show increased sensitivity of anti-tumor effects to DNA hypomethylating agent (HMA). We discovered that HMA treatment induced stronger viral mimicry activation and immune upregulation, which is potentiated by higher transposable element (TE) expression in SETD2-mutant cancer cells. Mechanistically, we provide evidence that substantial number of the HMA-induced TE expression is a consequence of mis-splicing, which is associated deficient in slicing in SETD2-loss content along with rapid gain of H3K9me3 across exons. These all suggested HMA could turn immune-cold tumor to immune-hot tumor and sensitize tumors to immune therapy. Then we performed in vivo assay in immune competent mice. Indeed, SETD2 deficient tumors were extremely sensitive to combination treatment of HMA and immune checkpoint inhibitor. Our finding provides one of the first preclinical and in vivo evidence that demonstrates the SETD2 dysregulation can be an epigenetic therapeutic target in ccRCC, especially in combination with immune checkpoint inhibitors, for future clinical trials.
Citation Format: Hong-Tao Li, Hyo Sik Jang, Krizia Rohena-Rivera, Hemant Gujar, Minmin Liu, Justin Kulchycki, Xinyi Zhou, Shuqing Zhao, Peter Jones, Neil Bhowmick, Gangning Liang. Loss of SETD2 sensitizes kidney cancer cells to DNA methylation inhibitors by inducing viral mimicry and RNA mis-splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3618.