tbuckley/cabot-search huggingface dataset:
Abstract 3091: Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions
Authors: Priyanka Sharma, Brenda Diergaarde, Soldano Ferrone, John M. Kirkwood, Theresa L. Whiteside
Journal: Cancer Research (2019)

Abstract Background: Exosomes are a subset of small (30-150nm) extracellular vesicles (EVs) of the endocytic origin that mediate intercellular communication in health and disease. Exosomes are actively produced by tumor cells, circulate freely in body fluids and carry messages that alter functions of normal cells in the tumor microenvironment (TME), including immune cell functions. The ability of melanoma exosomes to reprogram immune cell functions might contribute to disease progression. Methods: To evaluate effects of melanoma cell-derived exosomes (MTEX) on human immune cell subsets, we isolated exosomes from plasma of 12 patients with melanoma and separated MTEX from non-MTEX by immune capture using anti-CSPG4 mAb on beads. These exosome fractions, and exosomes from plasma of 6 normal donors used as controls (NC), were studied by on-bead flow cytometry to quantify their surface protein profiles and in co-incubation assays with immune cell subsets for functional attributes. Phenotypic and functional profiles of MTEX and non-MTEX were compared. Results &amp; Conclusion: MTEX were enriched (p&amp;lt;0.005)( in FasL and TRAIL, induced apoptosis of CD8+T cells, down-regulated CD69 expression levels on T cells and inhibited their proliferation (all p&amp;lt;0.0005). MTEX also interfered with NK cell functions (p&amp;lt;0.001). Non-MTEX were enriched (P&amp;lt;0.005) in co-stimulatory proteins, CD40L, OX40L, OX40 and, similar to exosomes of NC, were not immunosuppressive. Thus, MTEX, present in excess in plasma of patients with metastatic melanoma, mediate immune suppression and contribute to immune escape of the tumor. Citation Format: Priyanka Sharma, Brenda Diergaarde, Soldano Ferrone, John M. Kirkwood, Theresa L. Whiteside. Effects of melanoma cell-derived exosomes in melanoma patients’ plasma on immune cell functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3091.
Abstract 4442: CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination
Authors: Yanjie Kong, Zehua Wang, Zhongmei Zhou, Xiaoyu Mao, Ceshi Chen
Journal: Cancer Research (2019)

Abstract The Cullin 7 (CUL7) gene encodes a member of the cullin family of E3 ubiquitin ligases. Accumulated evidence suggests that CUL7 is oncogenic. However, the mechanism by which CUL7 improves cancer cell survival has not been fully elucidated. Here, we reported that CUL7 confers anti-apoptotic functions by interacting with Caspase-8. CUL7 prevents Caspase-8 activation by promoting Caspase-8 modification with non-degradative polyubiquitin chains at K215. CUL7 knockdown sensitized cancer cells to TRAIL-induced apoptosis in vitro and in nude mice. These results suggest that CUL7 limits extrinsic apoptotic signaling by promoting Caspase-8 ubiquitination. Citation Format: Yanjie Kong, Zehua Wang, Zhongmei Zhou, Xiaoyu Mao, Ceshi Chen. CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4442.
Abstract 1490: Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling
Authors: Dhwani Haria, Helena Kiefel, Yuliya Katlinskaya, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham
Journal: Cancer Research (2019)

Abstract The gut microbiome is a key contributor to the maintenance of host physiology. At the same time, increasing evidence implicates microbiome dysbiosis as a key determinant of numerous metabolic and inflammatory disorders. It is, therefore, of paramount importance to understand the interactions between the host and gut microbiota. Second Genome has developed a proprietary, bioinformatics-driven discovery platform to identify novel microbiome-derived peptides with the potential to modulate host immune responses. We have leveraged this platform to evaluate immunomodulatory functions of novel, secreted peptides derived from gut-resident bacterial species Bifidobacterium longum and Bifidobacterium breve. Previously, the microbial genus Bifidobacterium (‘Bifido’) has been shown to be associated with enhanced dendritic cell functions and antitumor effects. Here, we identify Bifido-derived peptides that are putative agonists of certain murine and human Toll-like receptors (TLRs). These peptides induce secretion of pro-inflammatory cytokines such as TNF-α and IL-6 by in vitro-generated mouse dendritic cells and peritoneal macrophages in a TLR4 and CD14-dependent manner. One of the peptides, SG-A, also induces secretion of Th1-type cytokines and chemokines such as IL-21, GRO-α, and IP-10 by human monocytes and monocyte-derived dendritic cells. Moreover, in vivo administration of SG-A in mice elicited a systemic pro-inflammatory immune response in the absence of any secondary stimulus. Collectively, our results demonstrate the ability of a novel bacterial-derived peptide to engage the host innate immune system. Moreover, our findings validate the potential of the Second Genome discovery platform for identification of novel microbiome-derived agents that: i) have the ability to modulate host cell functions; and ii) may be developed into therapeutic agents for immune and inflammatory disorders. Citation Format: Dhwani Haria, Helena Kiefel, Yuliya Katlinskaya, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. Novel microbiome-derived peptides activate the host innate immune system by regulation of TLR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1490.
Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons
Authors: Samuele G. Marro, Soham Chanda, Nan Yang, Justyna A. Janas, Giulio Valperga, Justin Trotter, Bo Zhou, Sean Merrill, Issa Yousif, Hannah Shelby, Hannes Vogel, M. Yashar S. Kalani, Thomas C. Südhof, Marius Wernig
Journal: Neuron (2019)
Abstract 2209: Novel therapeutic agents for RET-driven cancers, which is highly potent and selective inhibitor to RET kinase
Authors: Hua Li, SeoHyun Jo, Woomi Do, Hyunkyung Kim, Hwan Kim, Kyung-ah Seo, Ji-hoon Oh, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim
Journal: Cancer Research (2019)

Abstract The rearranged during transfection (RET) tyrosine kinase is mostly altered by fusion and it makes RET as a attractive therapeutic target for medullary thyroid cancer and non-small cell lung cancer (NSCLC). Multi-kinase inhibitors (mKIs) such as cabozantinib and vandetanib expressed poor tolerability and limited efficacy due to off-target kinase inhibitory activity in academia and clinical cases. As for selective RET inhibitor, compounds such as BLU-667 and LOXO-292 are under development, currently in clinical trials. We are currently developing potent and selective RET inhibitors to address unmet medical needs for RET-driven cancers. Our team has validated its high potency and selectivity via kinase profiling and in-vitro assay results. We also anticipate our compound to overcome certain mutation, such as V804M. Our compounds strongly suppress phosphorylation of RET in tumor cells with various RET fusions and mutations by inhibiting proliferation at below 10 nM. This potency result is higher than those of other mKIs with RET inhibitory activity. The inhibitory concentration of our compounds to VEGFR2 is more than dozens of fold compared with RET. In addition, our compounds reveal low cytotoxicity in Ba/F3 naïve cells in the 1 µM concentration. These findings lead us to conclude that our compounds can be potent and highly selective inhibitors of RET kinase, a potential novel therapeutic agents for RET-driven cancers. Citation Format: Hua Li, SeoHyun Jo, Woomi Do, Hyunkyung Kim, Hwan Kim, Kyung-ah Seo, Ji-hoon Oh, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim. Novel therapeutic agents for RET-driven cancers, which is highly potent and selective inhibitor to RET kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2209.
Abstract 4899: The impact of the <i>EGFR</i>-T790M mutation detection by re-biopsy in EGFR mutant NSCLC patients in the retrospective analysis
Authors: Akihiro Yoshimura, Tadaaki Yamada, Naoko Okura, Junji Uchino, Koichi Takayama
Journal: Cancer Research (2019)

Abstract Background: EGFR-TKIs show a good anticancer effect in to most of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, it ultimately acquires resistance to EGFR-TKIs. We currently attempt to detect EGFR-T790M mutation by re-biopsy after disease progression, because the third generation EGFR-TKI osimertinib was effective against the refractory tumors with EGFR-T790M mutation. However, the re-biopsy from tumors is relatively invasive and some cases are impossible to biopsy. Therefore, it is a beneficial if we predict the EGFR-T790M mutation before re-biopsy. In this study, we analyzed the patients with disease progression after initial EGFR-TKIs to address the issues. Methods: 78 advanced NSCLC patients with EGFR mutations were enrolled from five institutions in Japan. In all patients, re-biopsy samples were obtained successfully after the resistance to initial EGFR-TKI treatment We analyzed the relationship between the emergence of EGFR-T790M mutation and clinical parameters including clinical outcomes with EGFR-TKI treatment and EGFR activating mutation status. Results: Of 78 advanced NSCLC patients with EGFR mutations, 39 patients were EGFR-T790M positive and 39 were negative based on the re-biopsy samples. Of 39 EGFR-T790M positive patients, 2 patients achieved complete response (CR), 33 partial response (PR), and 4 stable disease (SD) by initial EGFR-TKI treatment. In contrast, 1 patient experienced a CR, 19 a PR, 18 SD, and 1 progressive disease (PD) in 39 T790M negative patients. The objective response rate was higher in patients with T790M positive mutations than those with T790M negative mutations (89.7% versus 51.2%, p&amp;lt; 0.01). There was no statistically significant difference in progression free survival and time to failure treated with initial EGFR-TKIs between both groups. Conclusion: The response to initial EGFR-TKIs treatment might be one of good predictors for emerging of refractory tumors with EGFR-T790M mutation. Citation Format: Akihiro Yoshimura, Tadaaki Yamada, Naoko Okura, Junji Uchino, Koichi Takayama. The impact of the EGFR-T790M mutation detection by re-biopsy in EGFR mutant NSCLC patients in the retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4899.
Abstract 4042: Longitudinal monitoring of neoepitope-specific T cell repertoires in patient blood following cancer immunotherapy
Authors: Songming Peng, Benjamin Yuen, Joanne Tan, Fangfang Yin, Robert Bao, Zheng Pan, Olivier Dalmas, Duo An, Boi Quach, Michael Yi, Michael Bethune, Stefanie Mandl, Matt Walters, Juan Jaen, Alex Franzusoff
Journal: Cancer Research (2019)

Abstract T cells targeting neoepitopes derived from mutations exclusive to the tumor are one of the main drivers of cancer immunotherapy efficacy. Tracking these neoepitope-specific T cells during cancer immunotherapy has been hampered by the impracticality of repeated sampling from the tumor, and by the low frequency of neoepitope-specific T cells in peripheral blood. An ultra-sensitive and high-throughput technology (imPACT) has been developed for the identification and isolation of neoepitope-specific T cells from peripheral blood. Subjects with colorectal cancer, endometrial adenocarcinoma, nasopharyngeal carcinoma and other solid tumors were treated with AB122 (anti-PD-1 antibody) as part of an ongoing dose-escalation clinical trial. Pre-treatment blood samples were analyzed to identify the basal repertoire of neoepitope-specific T cells. Evolution of this repertoire during AB122 treatment was monitored to enable immune phenotyping and correlation with clinical outcomes. In addition, transcriptional profile changes were monitored at the single-cell level for each neoepitope-specific T cell. These data will enable us to analyze T cells targeting neoepitopes and identify driver mutations that correlate with and may be responsible for therapeutic benefit. More broadly, this platform technology promises to significantly advance our understanding of T cell-mediated mechanisms of cancer immunotherapy. Citation Format: Songming Peng, Benjamin Yuen, Joanne Tan, Fangfang Yin, Robert Bao, Zheng Pan, Olivier Dalmas, Duo An, Boi Quach, Michael Yi, Michael Bethune, Stefanie Mandl, Matt Walters, Juan Jaen, Alex Franzusoff. Longitudinal monitoring of neoepitope-specific T cell repertoires in patient blood following cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4042.
Abstract 4141: The induction of iNKT cells and CIK cells toward anti-tumor phenotypes
Authors: Adisak Wongkajornsilp, Khin Su Su Htwe, Nathawadee Sawatpiboon, Sunisa Duangsa-ard, Kanda Kasetsinsombat
Journal: Cancer Research (2019)

Abstract Natural killer T (NKT) cells and cytokine-induced killer (CIK) cells contain features of both T cells and NK cells that occasionally brought confusion to several studies. These cells have been reported to possess either anti-tumor or immunosuppressive properties. NKT cells could be directly isolated from the peripheral blood, while CIK cells require ex vivo culture of peripheral blood lymphocytes for 2-3 weeks with IFN-γ, IL2 and anti-CD3. NKT type I cells carry invariant TCRαβ recognizing α-Galcer loaded CD1d on antigen-presenting cells. We investigated whether NKT type I cells, as well as CIK cells, could be induced toward Th1 phenotype that should elicit anti-tumor activity. The inducers included ODN, checkpoint inhibitors and CDKi. We observed the tipping toward Th1 phenotype in both cell types, especially on CIK cells. It is concluded that both NKT type I cells and CIK cells could be induced toward the anti-tumor Th1 phenotype. Citation Format: Adisak Wongkajornsilp, Khin Su Su Htwe, Nathawadee Sawatpiboon, Sunisa Duangsa-ard, Kanda Kasetsinsombat. The induction of iNKT cells and CIK cells toward anti-tumor phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4141.
Validity and reliability of itch assessment scales for chronic pruritus in adults: A prospective multicenter study
Authors: Yong Hyun Jang, Seok Min Kim, Dong Hyuk Eun, Kyung Duck Park, Gyeong-Hun Park, Byung-Soo Kim, Kapsok Li, Chang Ook Park, Hye One Kim, Hei Sung Kim, Min Soo Jang, Eun Jin Doh, Dong Hun Lee, Yang Won Lee, Do Won Kim, Seong-Jin Kim
Journal: Journal of the American Academy of Dermatology (2019)
Abstract LB-202: Immunotherapy with TMV vaccine inhibits metastatic tumor growth in an immune checkpoint resistant murine lung cancer model
Authors: Haley Lei Huang, Ramireddy Bommireddy, Luis E. Munoz, Ashwathi P. Menon, Suresh Ramalingam, Periasamy Selvaraj
Journal: Cancer Research (2019)

Abstract Lung cancer is the second most common cancer among men and women and the leading cause of cancer deaths in the world. Despite the advancements in diagnostic technologies and the development of novel treatments in the recent years such as immune checkpoint inhibitor (ICI) therapy, the prognosis of lung cancer patients is still poor, and the survival rate is low. The patient-to-patient heterogeneity is the major problem in treating lung cancer, which results in differential responses to ICI therapy. In this study, we investigated the efficacy of a vaccine immunotherapy prepared by modification of tumor membrane vesicles (TMVs) prepared from the tumors to express immunostimulatory molecules in combination with ICI therapy in a partially ICI resistant murine lung cancer model. We demonstrate that prophylactic vaccination of TMV adjuvanted with immunostimulatory molecules prevents the CMT-167 tumor growth in mice and helps the mice develop immunological memory to the tumor cell challenge. In a therapeutic setting, the TMV vaccine inhibited tumor growth and induced primary tumor regression in 40% of mice and significantly reduced the metastatic tumor burden. However, the combination of TMV vaccination with anti-PD-1 mAb doesn’t have a synergistic or additive effect on the primary or metastatic tumor growth. Overall, these studies provide insight into using the TMV vaccine immunotherapy for treating lung cancer. Funding: Supported by the Lung Cancer seed grant from the Winship Cancer Institute of Emory University Citation Format: Lei Huang, Dr. Selvaraj's lab. Immunotherapy with TMV vaccine inhibits metastatic tumor growth in an immune checkpoint resistant murine lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-202.
Abstract 1020: p300 and CBP targeting in castration therapy resistant prostate cancer
Authors: Tobias Furlan, Natalie Sampson, Frédéric R. Santer, Zoran Culig
Journal: Cancer Research (2019)

Abstract p300 and CBP interact with transcription factors and other proteins via their histone acetyltransferase domain (HAT) and a bromodomain (Bd). In prostate cancer, p300 and CBP act as oncogenes and are commonly upregulated. p300 and CBP are valid targets for therapy due to their function as androgen receptor (AR) coactivators and involvement in castration resistance. Revealing downstream pathways and their function in cancer cell proliferation and resistance should further identify potential novel therapeutic targets. The effect of the p300/CBP HAT inhibitor C646 and the Bd inhibitor ICBP-112 on viability was tested. To this end several human PCa cell lines with different AR expression levels and resistance status were used. The resistant cells were derived from DUCaP, LAPC4 and LNCaP cells chronically treated with Enzalutamide (DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA). Resistance was verified by viability assay. Regulation of AR downstream targets was studied by qRT-PCR and Western blot. Gene expression in the different DUCaP and LNCaP sublines after inhibitor treatment was analyzed with RNAseq. Both inhibitors exhibited IC50 values on viability at micromolar concentrations with a significantly lesser effect on androgen-insensitive PC3 cells compared to AR sensitive cells. Significantly increased sensitivity to inhibitors was observed in enzalutamide-resistant DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA cell lines relative to parental cells: respectively 1.83- (*), 2- (*) and 2.7-fold (*) for C646 and not significant, 1.8- (p&amp;lt;0.1) and 1.56-fold (*) for ICBP-112. Moreover, ICBP-112 treatment of DUCaP cells significantly reduced expression of the AR target genes FKBP5, PSA and TMPRSS2 0.6- (**), 0.57- (**) and 0.37-fold (***) respectively. Similar results were obtained with DUCaP ENZA cells 0.46- (*), 0.45- (*) and 0.57-fold (ns) for FKBP5, PSA and TMPRSS2, respectively. Whilst less pronounced, this regulation was also observed at the protein level. Similar results were obtained with C646. RNAseq results suggest multiple changes in sublines after chronic enzalutamide treatment in DUCaP and LNCaP cells. Inhibition of p300 and CBP reduced androgen-, myc- and parts of an EMT-signature, which are likely involved in the development of enzalutamide resistance. Taken together, C646 and ICBP-112 are effective inhibitors of AR dependent PCa. Furthermore, differences between cell lines suggest that the AR background and other factors influence the inhibitor effectivity. A significantly increased effect of the HAT and Bd inhibitors in CRPC suggests an important role for p300/CBP in CRPC. Citation Format: Tobias Furlan, Natalie Sampson, Frédéric R. Santer, Zoran Culig. p300 and CBP targeting in castration therapy resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1020.
Abstract 4077: ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells
Authors: Sara Fritzell, Mattias Levin, Ida Åberg, Maria Johansson, Magnus Winnerstam, Karin Enell Smith, Peter Ellmark, Christina Furebring, Per Norlén, Anne Kvarnhammar
Journal: Cancer Research (2019)

Abstract ATOR-1144 is a human CTLA-4 x GITR bispecific IgG1 antibody generated by fusing a high affinity CTLA-4 binder, derived by FIND® optimization of the CTLA-4 binding domain of CD86, to an agonistic GITR antibody isolated from the human antibody library ALLIGATOR-GOLD®. CTLA-4 and GITR are highly expressed on Tregs in the tumor microenvironment, and GITR is also expressed on NK cells and certain tumor cells. ATOR-1144 was designed to induce a tumor-directed immune activation for treatment of solid tumors and hematological malignancies. The in vitro activity of ATOR-1144 in terms of Treg depletion and activation of T cells and NK cells was investigated using purified cells from healthy human donors. ATOR-1144 induced depletion of primary Tregs in an ADCC assay with NK cells. T-cell activation in terms of IL-2 and IFN-γ release was demonstrated in the presence of CTLA-4 and Fcγ receptor crosslinking. NK cells treated with ATOR-1144 released IFN-γ, perforin and granzyme B, and displayed enhanced cytolytic killing of tumor cells. Moreover, NK cell-mediated depletion of CTLA-4-expressing cells was significantly improved upon stimulation with ATOR-1144 compared to monospecific anti-CTLA-4, indicating that NK cells activated via GITR acquire an enhanced capacity to induce ADCC. In conclusion, ATOR-1144 is a first-in-class bispecific tumor directed antibody targeting CTLA-4 and GITR. ATOR-1144 acts through several mechanisms, including depletion of Tregs, activation of effector T cells and activation of NK cells for enhanced Treg depletion and tumor cell killing. Citation Format: Sara Fritzell, Mattias Levin, Ida Åberg, Maria Johansson, Magnus Winnerstam, Karin Enell Smith, Peter Ellmark, Christina Furebring, Per Norlén, Anne Kvarnhammar. ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4077.