bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4419: Subtyping of HNSCC single-cell RNA-seq identifies transcriptional programs characterized by suppression of Mtorc1 and Wnt signaling pathways and better patient prognosis
Authors: Reed Eric , Owa Takashi , Nomoto Kenichi , Varelas Xaralabos , Kukuruzinska Maria , Monti Stefano 
Published: September 2020

Abstract
Single-cell RNA-seq (scRNA-seq) is an emerging platform for high-throughput profiling of individual cells in a sample and is routinely employed to investigate the transcriptional landscapes of the cellular constituents of tumors. To this end, many scRNA-seq specific clustering algorithms have emerged to analytically partition cells into modules of comparatively similar profiles. To facilitate data driven molecular subtyping of such scRNA-seq clustering results and other large-scale-omics studies, we have developed K2 Taxonomer. K2 Taxonomer is an R package built around a novel top-down hierarchical clustering algorithm, utilizing repeated perturbations of the data to generate robust taxonomical partitions of observations. The software runs additional analyses to define gene co-expression signatures of these modules, as well as to integrate user-input annotations of genes and/or observations. An interactive web portal has been generated to assist in the interrogation of the full compendium of results.
We applied K2 Taxonomer to publicly available HNSCC scRNA-seq data, identifying pertinent tumor cell subtypes, distinguished by cell cycle and epithelial-to-mesenchymal transition, and with analytical projection of this signature onto TCGA-HNSCC bulk RNA-seq data exhibiting association with worse survival in TCGA-HNSCC patients. A transcriptional signature corresponding to suppression of Mtorc1 and Wnt/β-catenin signaling was also identified in a sub-population of HNSCCs, and shown to be associated with improved patient survival. Of notice, highly ranked markers of this signature are significantly associated with gene expression changes altered by E7386 - a novel β-catenin/CBP modulator with an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values - suggesting a role for this signaling axis in subsets of HNSCC. In conclusion, taxonomical subtyping with K2 Taxonomer provides a novel framework to expand the scope of applicability of scRNA-seq clustering results, and has revealed potentially novel HNSCC subtypes that offer directions for future studies.
Citation Format: Eric Reed, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti. Subtyping of HNSCC single-cell RNA-seq identifies transcriptional programs characterized by suppression of Mtorc1 and Wnt signaling pathways and better patient prognosis [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 4419.
Abstract 4437: Anti-tumor immunotherapeutic strategy for uveal melanoma by combining photodynamic therapy with ROCK inhibitor
Authors: Kim Seohyun , Kim In-San 
Published: September 2020

Abstract
Uveal melanoma (UM) is the most frequent intraocular malignant tumor among adults. Although UM is a rare disease, the prognosis of patients with UM is poor since nearly 50% of patients develop metastatic disease, and the overall survival outcome is dismal. Here, we suggest a novel and optimal treatment regime for UM not only offering lower burden to patients with high applicability but also preventing lethal metastatic disease by empowering the immune system through the combination of local Photodynamic therapy (PDT) and ROCK inhibitor. PDT is a topical treatment modality with the minimally invasive therapeutic method and now broadly used in a treatment option for the eyes. PDT with chlorin e6 based formulated FIC elicits immunogenic cell death (ICD) of cancer cells, and hallmarks of ICD stimulate antigen-presenting cells (APCs). Furthermore, ripasudil, one of the ROCK inhibitors, is clinically approved for the treatment of glaucoma and ocular hypertension in the form of an eye drop solution. Ripasudil is repurposed as an anticancer compound based on the immuno-stimulatory effect of ROCK inhibition. A combination of FIC-PDT with ripasudil mediated stimulation of APCs leads primed cytotoxic T cell infiltration into the tumor microenvironment (TME) and eventually augment anti-tumor immunity. Moreover, the combinational strategy sensitizes PD-1/PD-L1 immune checkpoint blockade (ICB) therapy to improve survival rates over time and inhibit tumor growth of the distant tumor by generating a systemic anti-tumor immune response. Collectively, our therapeutic strategy may lead to a new treatment option for UM by suppressing the primary tumor effectively and preventing the metastatic disease.
Citation Format: Seohyun Kim, In-San Kim. Anti-tumor immunotherapeutic strategy for uveal melanoma by combining photodynamic therapy with ROCK inhibitor [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 4437.
Abstract 4438: A bispecific antibody targeting CD28H and PDL-1 is a novel and potent immunomodulator of T cell responses
Authors: Ramaswamy Madhu , Kim Taeil , Jones Desmond , Ghadially Hormas , Mahmoud Tamer , Garcia Andrew , Wilson Susan , Riggs Jeffrey , Schofield Darren , Carlesso GIanluca 
Published: September 2020

Abstract
The success of immune checkpoint inhibitors CTLA4 and PD-1 monoclonal antibody, both FDA approved cancer therapies, specifically counteracts inhibitory pathways to activate antigen-specific T cells. However, their success is limited by the fact that not all patients respond to immunotherapy and a variety of adverse events due to non specific and systemic T cell activation limits their administration.
A newly identified B7 family receptor, CD28H/TMIGD2, is constitutively expressed on T, pDCs and innate lymphoid cells including NK and ILCs. CD28H is also detected in TILs including the CD8+ tissue resident memory T cells (TRM), a T cell subset that correlates with better prognosis and response to immune checkpoint inhibitor therapy. Functionally, CD28H provides costimulatory function to T cells in the context of TCR signaling events during activation.
We engineered a bispecific antibody (Bis mAb) targeting CD28H and PDL1 aimed to augment T cell costimulation and NK activation. The CD28H-PDL1 Bis mAb potentiates T cell proliferative and cytokine responses in antigen-specific human T cell assays and induces human NK -mediated redirected killing of PDL1+ tumor cells. In T cells, the mechanism of action of the Bis mAb requires intracellular signaling domain of the CD28H which downmodulates SHP phosphorylation upon CD3 activation. Intriguingly, we found that the Bis mAb increases induction of CD8 TRM cells in vitro. In human TILs, where CD28H is mostly expressed on CD8 TRM in tumors, the Bis mAb enables higher cytokine responses over PDL1 mAb alone. Given the recent relevance of TRM cells as an important pool of anti-tumor T cell immunity, the rationale for targeting this population via CD28H in the context of blocking PDL1 may prove to be a therapeutic tool for enhancing responses to checkpoint inhibitor therapy.
Citation Format: Madhu Ramaswamy, Taeil Kim, Desmond Jones, Hormas Ghadially, Tamer Mahmoud, Andrew Garcia, Susan Wilson, Jeffrey Riggs, Darren Schofield, GIanluca Carlesso. A bispecific antibody targeting CD28H and PDL-1 is a novel and potent immunomodulator of T cell responses [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 4438.
Abstract 4449: Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy
Authors: Neri Shinya 
Published: September 2020

Abstract
There are theoretical benefits of combining immune checkpoint blockade with radiotherapy, however, there are few indications that such combinations have translated to significant clinical benefit to patients. There is an unmet need to further enhance the effectiveness of these “immunoradiotherapy” combinations. We hypothesize that enhancing antigen presentation through augmenting dendritic cell (DC) activation could potentially improve the effectiveness of immunoradiotherapy. Towards this end, we have investigated the potential for combining the microtubule destabilizing first-in-class agent Plinabulin as the candidate DC activator, with radiotherapy and anti-PD1 immunotherapy (αPD1). First, we investigated how DCs could be affected by Plinabulin and irradiation in in vitro assays. We irradiated SP37A3 and XS106 DC lines with 10Gy and added Plinabulin to those cells. With the addition of Plinabulin, the phosphorylation of JNK and NFκB was upregulated and DC maturation was promoted with high MHC-II, CD86, CD80 and CD40 surface expressions (p&lt;0.05, Dunnett's test). Combining Plinabulin and radiotherapy further augmented the response, particularly in sequence with plinabulin but not in combination. In in vivo models. TSA syngeneic breast cancer cells were implanted to the flank of BALB/c mice, irradiated with 24Gy/3fr, and treated with αPD1 and Plinabulin. There were no anti-tumoral effects with αPD1 alone, Plinabulin alone, and αPD1+Plinabulin groups. However, triple therapy showed much stronger tumor regression than the double therapy of irradiation and αPD1. Tumors were collected from the mice at 2.5-3 weeks after the irradiation and dissociated tumor cells were analyzed for DC activation and immune repertoire using flow cytometry. The percentage of CD8 T cells and CD86+ DCs in the tumor were significantly increased in the triple therapy group that were not seen for the monotherapy or bimodal therapy groups (p&lt;0.05, Dunnett's test). Our findings may serve as a rationale for establishing clinical trial designs of synergistic combinational approaches to enhance immunoradiotherapy.
Citation Format: Shinya Neri. Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy [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 4449.
Abstract 4458: New HDAC inhibitor (M166) has a synergistic effect with immune checkpoint inhibitor in lung cancer treatment
Authors: Lee Sung Yong , Shin Hyun-Seock , Choi Juwhan 
Published: September 2020

Abstract
Recently, Immune checkpoint inhibitor (ICI) has been widely applied to various types of cancer therapies and it is used as a treatment in clinical application. ICI has a higher effect on lung cancer than other cancers; however, the treatment efficiency is only about 25%. Therefore, many research groups are making efforts to improve treatment efficiency with co-treatment therapy using chemical medications and ICIs. We evaluated the efficacy of a new PAN-HDAC inhibitor (M166) and ICI. M166 showed growth inhibition in mouse lung cancer cell (TC-1) line, mouse lung carcinoma (LLC) and human lung cancer cell (A549) line compared with normal epithelial cell lines (NIH3T3 and HEK293. Also, we checked ten kinds of immune-related cytokines and chemokines in mRNA level by treated with M166 using RT-PCR methods. CCL2 and CXCL10 chemokines are significantly increased by dose-dependently. These results indicate that M166 regulates immune response by CCL2 and CXCL10 chemokine related pathways. In order to check the synergistic effect of ICI plus HDACi co-treatment, we explored the employment of M166 in combination with ICI in a preclinical mouse model. For in vivo experiment, the mice were divided into four groups: group 1 received no treatment after the E7-expressing TC-1 tumor challenge, group 2 was treated with M166, group 3 was treated with mouse PD-1 antibody, and group 4 was both treated with M166 and mouse PD-1 antibody. The combination therapy of M166 and mouse PD-1 antibody significantly inhibited tumor growth. These results indicate that ICI plus HDACi treatment induces tumor growth inhibition through an immune response. These findings have important implications for future clinical translation.
Citation Format: Sung Yong Lee, Hyun-Seock Shin, Juwhan Choi. New HDAC inhibitor (M166) has a synergistic effect with immune checkpoint inhibitor in lung cancer treatment [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 4458.
Abstract 4479: Immune exhaustion of tumor microenvironment mediates crizotinib resistance in ALK rearranged advanced non small cell lung cancer
Authors: Zhang Yongchang 
Published: September 2020

Abstract
Introduction: Previous study showed the correlation between immune tumor microenvironment and the efficacy of checkpoint inhibitor in non-small cell lung cancer (NSCLC). This study evaluated whether biomarkers for immune tumor microenvironment including programmed death ligand 1 (PD-L1), cluster of differentiation 8 (CD8), Granzyme B (GZMB) and T cell receptor (TCR) could predict the treatment response to the first-line crizotinib of patients with ALK-rearranged non-small cell lung cancer (NSCLC).
Methods: We retrospectively evaluated patients with advanced NSCLC who received crizotinib at Hunan Cancer Hospital between January 2016 and December 2018. The patients' baseline expression of PD-L1, CD8 and GZMB was evaluated in one slide using immunofluorescence. TCR was also evaluated with paired blood samples simultaneously.
Results: All the 108 eligible patients were stratified according to their expression profile into PD-L1+/CD8+/GZMB+ (n=21), PD-L1-/CD8+/GZMB+ (n=42), PD-L1+/CD8-/GZMB- (n=23), and PD-L1-/CD8-/GZMB- (n=22) group. Patients with strong PD-L1 expression have a significantly inferior objective response rate (36.5% versus 72.2%, p = 0.002), and shorter progression-free survival (PFS) (5.6 versus 16.5 months, p &lt; 0.001) as compared to patients with weak or negative PD-L1 expression. Among the four groups, we found patients with PD-L1-/CD8+/GZMB+ had the best response (85.7% versus 26%, p=?), while PD-L1+/CD8-/GZMB- showed primary resistance to crizotinib had the worse outcomes (4.6 versus 18 months, p &lt; 0.001). Furthermore, for TCR analysis, the counts of TCR and Shannon index was strongly correlated with longer PFS for crizotinib treatment (20.6 versus 8.2months, p &lt; 0.001; 19.3 versus 6.1 months, p &lt; 0.001, respectively). However, the clonality acts as poor predictive marker with worse PFS (6.8 versus 18.2 months, p &lt; 0.001). Finally, three patients with de novo resistance to crizotinib experienced a favorable response to anti-PD-1 therapy.
Conclusions: This study revealed immune exhaustion for tumor microenvironment as a poor predictive marker in first-line crizotinib-treated ALK-rearranged non-small cell lung cancer. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1, CD8, GZMB, and TCR expression and suggest potential therapeutic sensitivity to PD-1 blockade.
Citation Format: Yongchang Zhang. Immune exhaustion of tumor microenvironment mediates crizotinib resistance in ALK rearranged advanced non small cell lung cancer [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 4479.
Abstract 4484: ScRNA-seq of patients with immune-related adverse events and checkpoint inhibitor therapy
Authors: Khan Shaheen , Gerber David E. 
Published: September 2020

Abstract
Despite the remarkable success of immune checkpoint inhibitor (ICI) therapy, a significant number of patients develop severe and unpredictable immune-related adverse events (irAEs) affecting a wide variety of organs. Concerns over irAE have led to the exclusion of patients with autoimmune disease from ICI clinical trials. Role of host genetic and immune factors in mediating irAEs remain unclear and it is not clear if the manifestations of irAEs is associated with response to therapy. In this study, we used single cell RNA sequencing (ScRNA-seq) to study the peripheral immune repertoire at a single cell level to identify blood-based signatures predictive of irAEs and response to ICI therapy. We characterized changes in host immune system in 40 patients receiving ICI therapy by performing ScRNA-seq on peripheral blood mononuclear cells (PBMCs) at baseline and post-immunotherapy. In addition, we evaluated serum levels of 40 cytokines/chemokines, antinuclear autoantibodies (ANA) and 124 autoantibodies and performed bulk RNA sequencing on PBMCs at baseline and post immunotherapy in these patients. Our preliminary data analysis identified signatures of autoantibodies and cytokines correlating with response and toxicity. ScRNA-seq data revealed changes in distinct immune cell subsets and gene expression signatures in patient developing irAEs. In this meeting, we will present preliminary ScRNA-seq data combined with immune and genetic correlates of irAEs and response to therapy in our patient cohort. We hope that our studies can help identify blood-based biomarker signatures predictive of irAEs and/or response and reveal novel insights into the mechanisms underlying irAE. Our current genetic data suggests further expanding the genetic studies in larger patient population to identify the role of underlying genetic predisposition to autoimmunity in mediating irAEs. We hope our findings may ultimately help customize therapy, expand use of immunotherapy and prevent toxicities.
Citation Format: Shaheen Khan, David E. Gerber. ScRNA-seq of patients with immune-related adverse events and checkpoint inhibitor therapy [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 4484.
Abstract 4508: Modulating the release rate of polyethylene glycol (PEG) polymers from interleukin-2 (IL-2) PEG conjugates to optimize anti-tumor efficacy
Authors: Li Hui , Song Yuntao , Zhou Haiping , Liao Chuan , Xu Meng , Li Chuang 
Published: September 2020

Abstract
The cytokine interleukin-2 (IL-2) is an endogenous agonist of the IL-2 pathway that activates and expands tumor killing lymphocytes. High doses of IL-2 are needed to activate CD8 T cells and NK cells, through binding on low-affinity IL-2 receptor beta gamma subunits (IL-2Rβγ). Severe toxic side effects associated with high doses, as well as the poor PK profile of IL-2, have limited its clinical usage. In addition of the toxicities, IL-2 also stimulates proliferation and activation of regulatory T cells (Tregs) through binding on the high-affinity heterotrimeric IL-2 receptor alpha beta gamma subunits (IL-2Rαβγ), which may antagonize the intended anti-tumor immunity. We report on an IL-2 PEGylation strategy to improve the pharmacokinetic properties of IL-2. Utilizing our proprietary PEGylation technology, IL-2 was covalently connected with multiple polyethylene glycol (PEG) polymers through releasable linkers. Our technology enabled the conjugation of IL-2 with average of 5-6 polyethylene glycol (PEG) polymers in high efficiency and 80-90% isolated yield. Anti-tumor efficacy of IL-2 was optimized by modulating the hydrolysis rate of the releasable linkers connecting IL-2 and polymers. The releasable linkers used in the study had the hydrolysis rate in the range of 15 to 120 hours to release one PEG polymer from the conjugates. The conjugates with hydrolysis rate of 20-60 h showed the optimal anti-tumor efficacy in B16F10 animal model. These results suggest that our novel approach of IL-2 PEGylation may optimize IL-2 biological activity and anti-tumor efficacy. Modulating the releasable rate of the PEG polymer would optimize the pharmacokinetic properties of the released active IL-2 species and enable the optimized anti-tumor efficacy. We are currently exploring the usage of our technology platform to further engineer IL-2 as a non-IL2Rα binding conjugate for improved toxicity profile.
Citation Format: Hui Li, Yuntao Song, Haiping Zhou, Chuan Liao, Meng Xu, Chuang Li. Modulating the release rate of polyethylene glycol (PEG) polymers from interleukin-2 (IL-2) PEG conjugates to optimize 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 4508.
Abstract 4518: Pre-clinical development of NL-201: A de novo α-independent IL-2/IL-15 agonist
Authors: Walkey Carl D. , Hara Paul , Tatalick Laurie , Ulge Umut , Drachman Jonathan , Silva Daniel-Adriano 
Published: September 2020

Abstract
Interleukin-2 (IL-2) and interleukin-15 (IL-15) promote anti-tumor immune activity by stimulating effector T and NK cells expressing the β and γ subunits of the IL-2 and IL-15 receptors. However, preferential activation of off-target cell populations expressing the high-affinity α subunit (including regulatory T cells, eosinophils, and endothelial cells) has limited the safety, therapeutic benefit, and widespread clinical use of these cytokines. Recently, we used sophisticated computational methods to create Neoleukin-2/15 (Neo-2/15), an entirely de novo α-independent agonist of both the IL-2 and IL-15 receptors. Unlike strategies that attempt to sterically inhibit or mutate the α-binding region of IL-2 or IL-15, Neo-2/15 was computationally designed to have no α-binding interface, while also having increased affinity for the β and γ signaling subunits. As a result, Neo-2/15 stimulates effector T and NK cells more potently and selectively than IL-2 or IL-15. Here, we report on the preclinical development and pharmacology of NL-201, a long-circulating variant of Neo-2/15 that is intended for clinical applications. NL-201 was derived from Neo-2/15 via the site-specific conjugation of a single PEG molecule and is manufactured using a simple and scalable process. NL-201 has a prolonged blood half-life and a sustained pharmacodynamic effect while retaining the high potency, selectivity, and thermodynamic stability of Neo-2/15. Preclinical studies demonstrate the robust antitumor activity of NL-201 as a single agent across a wide range of syngeneic murine tumor models, including those that do not respond well to checkpoint inhibitors. Due to its stability, high potency, and selectivity, NL-201 may overcome the long-standing challenges associated with the clinical use of IL-2 and IL-15 for cancer immunotherapy.
Citation Format: Carl D. Walkey, Paul Hara, Laurie Tatalick, Umut Ulge, Jonathan Drachman, Daniel-Adriano Silva. Pre-clinical development of NL-201: A de novo α-independent IL-2/IL-15 agonist [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 4518.