bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4235: A combination of CAR-NK and CAR-T cells results in rapid and persistent anti-tumor efficacy while reducing CAR-T cell mediated cytokine release and T-cell proliferation
Authors: Li Guangnan , Wu Xiumin , Chan Ivan H. , Trager James B. 
Published: September 2020

Abstract
CAR-NK cells show rapid and potent anti-tumor cytotoxic activity even at very low effector-to-target ratios, however, they do not typically expand upon encounter with antigen and lack long term persistence commonly associated with CAR-T cells. Conversely, CAR-T cells generally exhibit persistent killing activity, even though they are activated somewhat more slowly. In addition, the explosive expansion of CAR-T cells is frequently associated with a variety of toxicities (e.g. CRS, CRES, etc.). To address these shortcomings, Nkarta has developed a novel platform to combine both CAR-NK and CAR-T cells as a novel cancer therapeutic. To evaluate the overall outcomes of combining CAR-NK and CAR-T cells as an anti-tumor therapy, we have developed two novel in vitro assays: (a) IncuCyte-based matrixed cytotoxicity assay, which allows direct assessment of tumor killing kinetically with different E:T and NK:T ratios; (b) IncuCyte-based tumor re-challenge assay, which provides a convenient and quick assessment of anti-tumor persistence. For proof-of-concept studies, a CD19 directed CAR (CAR19) was retrovirally engineered into NK and T cells. Our newly developed assays revealed that the combination of CAR-NK and CAR-T cells clearly outperformed CAR19-NK or CAR19-T cells alone in anti-tumor efficacy and persistence. Additionally, the combination also showed an improved cytokine profile. To further investigate the cellular mechanism(s) underlying the beneficial effects of combining CAR-NK and CAR-T cells, we performed FACS-based phenotyping and a Violet Cell Trace based proliferation assay. When challenged with tumor cells, the presence of CAR19-NK cells reduced the proliferation of CAR19-T cells. Surprisingly, the presence of CAR19-T cells could trigger the proliferation of CAR19-NK cells. Finally, we evaluated the NK plus T platform in vivo with a Nalm6 xenograft model. Treatment with CAR19-NK cells combined with a low dose of CAR19-T cells (5e5 cells/animal) delayed tumor progression. Combined treatment with a medium dose of CAR19-T cells (2.5e6 cells/animal) largely prevented tumor relapse, and consequently enhanced the overall survival of the animals. In summary, our in vitro and in vivo studies strongly demonstrate that the NK plus T platform can harness the advantages of both CAR-NK and CAR-T cells, allowing for both rapid and persistent killing while potentially minimizing the toxicities associated with CAR-T cells.
Citation Format: Guangnan Li, Xiumin Wu, Ivan H. Chan, James B. Trager. A combination of CAR-NK and CAR-T cells results in rapid and persistent anti-tumor efficacy while reducing CAR-T cell mediated cytokine release and T-cell proliferation [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 4235.
Abstract 4286: TGF-β signature is a therapeutic biomarker for combination immunotherapy for hepatocellular carcinoma
Authors: Chen Jian , Su Xiaoping 
Published: September 2020

Abstract
Background: Several immune checkpoint inhibitors have recently shown promising results in patients with advanced hepatocellular carcinoma (HCC). However, tumor response rates ranged from 14% to 17%. Thus, there remains a large unmet medical need for novel and effective immunotherapeutic strategies against HCC. Dysregulated signaling in the transforming growth factor (TGF)-β pathway plays a central role in immunomodulation, inflammation, and fibrogenesis in the HCC microenvironment. We therefore used The Cancer Genome Atlas database to analyze potential therapeutic approaches combining TGF-β inhibition and immunotherapies for HCC.
Methods: Transcriptomic analyses were performed in 193 HCC cases. Pathway analyses were performed by correlating 70 published signatures with TGF-β signatures.
Results: 1. Unsupervised hierarchical clustering of TGF-β genes in HCC revealed four distinct clusters with unique TGF-β signatures: highly activated (14.5%), activated (45.0%), normal (30.6%), and inactivated (9.9%). 2. Highly activated TGF-β signatures were significantly associated with fibrosis and activated stromal signatures. 3. TGF-β signature subtypes were significantly associated with immune cell infiltration, T cell exhaustion, and checkpoint blockade response subclasses. 4. Potentially targetable genes were associated with specific TGF-β signatures. 5. TGF-β signatures provide potential combination therapeutic options for HCC.
Conclusion: We demonstrated a specific immunosuppressive role of TGF-β in mediating immunotherapy resistance in HCC, highlighting the TGF-β signature as a potential biomarker in individualized immunotherapeutic approaches in HCC.
Citation Format: Jian Chen, Xiaoping Su. TGF-β signature is a therapeutic biomarker for combination immunotherapy for hepatocellular carcinoma [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 4286.
Abstract 4414: Single-cell analysis on the Cancer Genomics Cloud reveals changes in the transcriptome profiles of endothelial tumor cells over time - novel insights from a public dataset of a mouse model of melanoma
Authors: Vucic Nemanja , Ray Manisha , Veljkovic Dalibor , Cidilko Stefan , Davis-Dusenbery Brandi 
Published: September 2020

Abstract
The Cancer Genomics Cloud (CGC) powered by Seven Bridges makes the analysis of large datasets accessible from any environment, which is critical as the volume of datasets continues to expand. This expansion of the size, complexity, and location of datasets has been prominent in the field of single-cell genomics, which can present challenges for data analysis. Here we combined the rich datasets available through the Human Cell Atlas (HCA) with the tools and computational resources available on the CGC to provide a path for any scientist to explore complex biological questions. To demonstrate these capabilities, we processed a single-cell dataset of immune and stromal cells isolated from the tumor and lymph nodes of a mouse model of melanoma using an optimized version of the SmartSeq2 pipeline recommended by the HCA. This dataset contains 13.3k paired-end sequencing files for 6.6k estimated cells, with a total size of 371.60 GB. The entire dataset was transferred from Human Cell Atlas Data Portal to the CGC, where it is accessible to all users.
The goal of this study was to process a single-cell dataset on the tumor microenvironment with the SmartSeq2 pipeline and to investigate changes in transcriptome profiles of endothelial tumor cells over time. We used an alternative approach than authors in the original study, which aimed to analyze the immune and stromal cells (Davidson et al. bioRxiv 2018). To perform alignment and quantification of raw sequencing reads using the CGC execution environment, we created an implementation of the SmartSeq2 pipeline in Common Workflow Language. Quantification results were used to perform cell clustering, followed by a pseudotime analysis on the endothelial tumor cells. For the cell clustering and pseudotime analyses, we created interactive notebooks in the RMarkdown format that can be executed within the RStudio environment on the CGC. In summary, this work demonstrates the importance of developing reproducible workflows that can run on multiple environments as well as data sharing that can bring to light new insights from the existing data.
Citation Format: Nemanja Vucic, Manisha Ray, Dalibor Veljkovic, Stefan Cidilko, Brandi Davis-Dusenbery. Single-cell analysis on the Cancer Genomics Cloud reveals changes in the transcriptome profiles of endothelial tumor cells over time - novel insights from a public dataset of a mouse model of melanoma [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 4414.
Abstract 4441: CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy
Authors: Li Zhenhu , Ren Zhaoxiang , Ma Jingshu , Tang Liang , Lu Liang , Zhu Ying , Wu Yunfei , Liu Tiancheng , Zhang Juan , Bao Yuanwu , Zhang Kangyu , Wei Changqing , Chen Shuhui , Wang Xinzhong Jon 
Published: September 2020

Abstract
Background: Histone deacetylases (HDACs) are involved in diverse cellular regulatory function including histone modification and non-histone modification. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor growth and immunogenicity. In particular, the selective inhibition of HDAC6 has function of inhibiting tumor growth in several malignancies. However, the mechanism of this effect is still not clear.
Methods: In this study, we evaluated CS3003, a selective HDAC6 inhibitor, inhibition profile using cell-based free assays. In vivo anti-tumor efficacy was evaluated in MM.1S xenograft mouse model. CS3003 and PD-1 blockade combination effect was evaluated in CT26 syngeneic mouse model. RNA-seq method was used to explore the transcription regulation by CS3003 compared to other pan-HDAC, Class I HDAC inhibitor and selective HDAC6 inhibitors.
Results: CS3003 has distinct inhibition profile in HDAC family members. Combination of CS3003 and proteasome inhibitor synergistically enhanced anti-tumor function in human multiple myeloma mouse model (coefficient of drug interaction, CDI=0.69). In addition, CS3003 improves the anti-tumor activity of anti-PD-1 immune checkpoint blockade in solid tumor model (CDI=0.62 and 0.88 when the dosage of CS3003 was 30 and 70mg/kg, respectively). Transcriptome analysis demonstrated a unique gene expression pattern of CS3003 from other pan-HDAC and selective HDAC6 inhibitors.
Conclusions: These data provide a comprehensive pre-clinical characterization of CS3003 that supports its unique HDAC inhibition profile and its capability of improving anti-PD-1 immune checkpoint blockade therapy efficacy.
Citation Format: Zhenhu Li, Zhaoxiang Ren, Jingshu Ma, Liang Tang, Liang Lu, Ying Zhu, Yunfei Wu, Tiancheng Liu, Juan Zhang, Yuanwu Bao, Kangyu Zhang, Changqing Wei, Shuhui Chen, Xinzhong Jon Wang. CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy [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 4441.
Abstract 4791: Metabolic switch from glycolysis to oxidative phosphorylation (ox-phos) provides survival advantage to anti-androgen-treated prostate cancer cells and make them vulnerable to mitochondrial metabolism inhibitors IACS-010759 and CB-839
Authors: Basu Hirak S. , Wilganowski Nathaniel , Robertson Samantha , Ramachandran Sumankalai , Zurita-Saavedra Amado , Titus Mark , Cohen Evan , Reuben James , Wilding George 
Published: September 2020

Abstract
Background: Most cancer cells depend more on glycolysis for their energy need compared with their normal counterparts incubated under identical condition. In addition to glycolysis, tumor cells also engage mitochondrial ox-phos to support growth. Here, we show that PCa cells surviving under anti-androgen enzalutamide (ENZA) treatment switch from glycolysis to ox-phos for their energy need and are more vulnerable to mitochondria-targeted metabolic inhibitors. We have also standardized a high-resolution quantitative fluorescence microscopic method to detect this metabolic switch in patient circulating tumor cells (CTCs).
Methods: Seahorse assay has been used to compare mitochondrial metabolism in ENZA treated anti-androgen-sensitive LNCaP and -resistant C4-2 and PCa2b cells. The Seahorse data were supported by mass spectroscopic analysis of corresponding metabolites and metabolic fluxes. An ex vivo fluorescence staining for the CTC mitochondria with high ox-phos followed by high-resolution quantitative microscopic image analysis method has been standardized to follow such changes in cultured cells and patient CTCs.
Results: Seahorse, mass spectroscopy and high-resolution microscopy of mitochondrial ox-phos showed that ENZA significantly decreases glycolysis and increases ox-phos in all surviving PCa cells within 24h of treatment. These cells are more vulnerable to treatment with mitochondrial ox-phos inhibitor IACS-010759 and a glutaminase inhibitor CB-839. High-resolution microscopic analysis of CTCs has thus far been performed in 18 patient blood samples. Six out of the 18 patients developed resistance to anti-androgen therapy within 0-6 months of sample collection. CTCs from all six patients showed a relatively higher average fluorescence due to high mitochondrial ox-phos as compared with the rest of the patients.
Discussion: The data presented here may lead to informed combination therapy for selected PCa patients developing resistance to anti-androgen therapy for better clinical outcome.
Citation Format: Hirak S. Basu, Nathaniel Wilganowski, Samantha Robertson, Sumankalai Ramachandran, Amado Zurita-Saavedra, Mark Titus, Evan Cohen, James Reuben, George Wilding. Metabolic switch from glycolysis to oxidative phosphorylation (ox-phos) provides survival advantage to anti-androgen-treated prostate cancer cells and make them vulnerable to mitochondrial metabolism inhibitors IACS-010759 and CB-839 [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 4791.
Abstract 525: A novel anti-PD1-IL15 immunocytokine potentiates anti-tumor T cell activity of PD-1 checkpoint inhibition and IL-2R-beta-gamma agonism
Authors: Lu Dan , Polonskaya Zhanna , Chang Tzi-Pei , Martomo Stella , Luna Xenia , Zhang Zhikai , Miyara Faical , Patel Jeedar 
Published: September 2020

Abstract
Therapeutic antibodies targeting immune checkpoint inhibitors (ICI) such as PD-1/PD-L1 effectively expand and reactivate T cells in patients, leading to long-lasting response in multiple tumor types. However, only a fraction of patients responded to approved ICIs, majority are either resistant or quickly become refractory. Other immunotherapy modalities including immunostimulatory cytokines IL-2, IL-12 and IL-15 demonstrated clinical benefits as monotherapy or in combination with ICIs. Cytokines exhibit in general a short half-life and systemic toxicities that limit their use as the optimal doses in treating cancer. An antibody-based immunocytokine fusion such as Kadmon lead candidate KD033 (anti-PDL1/IL15) and Roche anti-PD1/CEA/FAP-IL2v can extend the half-life of cytokine and reduce systemic toxicities. In this study, a fully human single-chain variable fragment (scFv) antibody against mouse PD1 (mPD1) have been isolated from the phage display library. The variable domains of these antibodies were fused to either human IgG1a or mouse IgG2a constant domain first, and then fused to either human IL15 receptor alpha sushi domain-hIL15 complex (hSD15) or mouse IL15 receptor alpha sushi domain-mIL15 complex (mSD15). These variations of fusion have been tested in in vitro binding and functional assays, and in vivo in PD1/PDL1 resistant mouse syngeneic model LL2 (Lewis Lung Carcinoma). We demonstrated that hSD15 fusion antibody can stimulate both IL2 dependent human and murine cells growth, surprisingly, mSD15 fusion antibody can only stimulate murine cell growth. Although mSD15 fusion antibody EC50 was 10 folds better than hSD15 fusion antibody in stimulating mouse spleen cell growth in vitro, it did not show a better efficacy than hSD15 fusion antibody in LL2 model. In vivo, mSD15 fusion antibody had higher maximum tolerate dose than hSD15 fusion antibody (up to 12mg/kg). In addition, anti-mPD1/mSD15 showed better efficacy than either the mIL15 and anti-mPD1 alone or the combination of anti-mPD1 plus mIL15 in vitro and in vivo. Together these preclinical data have confirmed that PD1-IL15 could be a promising next generation IL-15 fusion for cancer immunotherapy.
Citation Format: Dan Lu, Zhanna Polonskaya, Tzi-Pei Chang, Stella Martomo, Xenia Luna, Zhikai Zhang, Faical Miyara, Jeedar Patel. A novel anti-PD1-IL15 immunocytokine potentiates anti-tumor T cell activity of PD-1 checkpoint inhibition and IL-2R-beta-gamma agonism [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 525.
Abstract 528: EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy
Authors: Ren Fang , Wu Xuan , Yang Dandan , Wu Danqing , Gong Shiyong , Zhang Yingxi , Lensky Stephan , Wu Chengbin 
Published: September 2020

Abstract
Interruption of EGFR signaling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumors. EGFR tyrosine kinase inhibitors (TKIs) provide a favorable treatment outcome in EGFR mutation positive NSCLC patients. However, many patients eventually develop progressive disease after treatment. Such acquired resistance limits the long-term efficacy of these EGFR TKIs in the clinic. The mechanisms of acquired resistance include a variety of mutations of the EGFR and crosstalk with the adjacent cMet receptors that allow the tumor to partially compensate the EGFR activity. EMB-01 is an innovative bispecific antibody developed based on EpimAb's proprietary FIT-Ig® platform to target EGFR and cMET on tumor cells simultaneously. The anti-EGFR and anti-cMet Fab-domains in each EMB-01 arm are fused directly in-tandem in a unique crisscross orientation without any mutations or use of peptide linkers to form a final tetravalent binding complex with the corresponding receptors on cell surface. We have demonstrated that EMB-01 can maintain all the biological activity from parental monoclonal antibody (mAb) to block ligand binding and the downstream signal pathway. In addition, such tetravalent binding feature is found to induce significant co-degradation of EGFR and cMET in various tumor cells, and such effect is unattainable by either mAb alone or in combination, demonstrating a unique synergistic function of EMB-01. At equivalent doses, EMB-01 induces significantly stronger anti-tumor activity in PDX and CDX tumor models than that of anti-EGFR mAb or anti-cMet mAb alone. Furthermore, EMB-01 shows significant anti-tumor activity in anti-EGFR mAb resistant tumor model. These results demonstrate the potential benefit of EMB-01 in treating EGFR and/or cMET driven cancers, particularly in cases where patients develop acquired resistance due to secondary EGFR mutations in the kinase domain or cMET activation. Currently, EMB-01 has initiated a Phase I/II clinical trial with advanced/metastatic solid tumors.
Citation Format: Fang Ren, Xuan Wu, Dandan Yang, Danqing Wu, Shiyong Gong, Yingxi Zhang, Stephan Lensky, Chengbin Wu. EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy [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 528.
Abstract 539: Novel engineered toxin bodies targeting SLAMF7 (CS1)
Authors: Iberg Aimee , Cornelison Garrett L. , Howard Caleigh , Robinson Garrett L. , Zhao Jay , Ramos Hilario J. , Willert Erin K. 
Published: September 2020

Abstract
Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Three ETBs are in clinical development (MT-3724 targeting CD20, MT-5111 targeting HER2, and TAK-169 targeting CD38). The novel mechanism of action has potential benefit in different indications including in the relapsed setting, when disease has progressed after chemotherapies and other targeted therapies, and additionally may be able to be combined with standard of care. Additional ETBs are being developed that target other cell surface receptors for solid and hematological malignancies, including SLAMF7 (CS1). SLAMF7 is a clinically validated target of monoclonal antibody therapy. Although clinical responses to the monotherapy were not observed, patients treated with combination therapy using standard of care agents that are known to stimulate immune effector cell activity have improved responses. Thus, a SLAMF7 targeted agent that can act independent of effector cells by directly killing tumor cells has the potential to provide broader benefit to patients. ETBs targeting SLAMF7 harbor the catalytic activity of the SLTA subunit and can effectively and specifically kill multiple myeloma cell lines expressing the target protein in vitro. The coupling of specific targeting to myeloma cells with potent and direct cell kill activity has the potential to deplete malignant cells without reliance on effector functions of the patient immune system, such as antibody or complement dependent cellular cytotoxicity or phagocytosis, and could be beneficial when disease progresses post antibody therapy. Additionally, the novel mechanism of action of an ETB also has potential to be combined with standard of care therapies and/ or to be effective in the relapsed or refractory setting.
Citation Format: Aimee Iberg, Garrett L. Cornelison, Caleigh Howard, Garrett L. Robinson, Jay Zhao, Hilario J. Ramos, Erin K. Willert. Novel engineered toxin bodies targeting SLAMF7 (CS1) [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 539.