bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A142: An in vivo functional genomics screen identifies molecular determinants of adaptive immune rejection
Authors: Shuptrine Casey W. , Fertig Elana J. , Salcie-Gautreaux Marsha , Weiner Louis M. 
Published: May 2016

Abstract
The complex cross-talk occurring among cells in the tumor microenvironment influences the anti-cancer immune response. Here we employed an RNAi screen of a murine cancer cell line syngeneic to C57Bl/6 mice to parse out the ability of the immune system to identify and eliminate malignant cells. To identify rate-limiting immune modulators, the EO771 mammary cancer cell line was transduced with a barcoded genome-wide shRNA library and engrafted in immune-competent as well as immune-deficient mice. Analysis of tumors grown in the presence of a functional adaptive immune system compared to those grown in immune-deficient mice, revealed cancer cell autonomous genes that modulate immune recognition. Pathway analysis identified enrichment of shRNAs targeting previously identified immune regulators including the TGF-BR pathway and MHC class I antigen processing. Among the candidates, we selected CD47, Tex9, Yif1a, EMP2, Pex14, and Sgpl1 for validation based on consistency between independent screens and known association with immune regulation. The roles of CD47, Tex9, Pex14, and Sgpl1 were validated for T cell-dependent recognition and elimination of EO771 tumors. CD47, a known inhibitor of target cell phagocytosis by macrophages, also regulated the adaptive immune response in this novel system. Two previously understudied molecules, Pex14 and Sgpl1, have immune inhibitory functions, as their respective knockdown suppressed EO771 tumor growth and increased survival in immunocompetent mice. Tex9 serves as a potential tumor antigen or immune stimulant, as reduction of expression enhances tumor growth when EO771 tumors are grown in immunocompetent mice. Therefore, this functional in vivo screening approach enabled the discovery of CD47, Pex14, Sgpl1, and Tex9 as novel tumor-based modulators of anti-tumor adaptive immunity. To the best of our knowledge, we are the first to report the successful utilization of an in vivo functional genomics approach to identify novel tumor cell-based mediators of immune regulation.
Note:This abstract was not presented at the conference.
Citation Format: Casey W. Shuptrine, Elana J. Fertig, Marsha Salcie-Gautreaux, Louis M. Weiner. An in vivo functional genomics screen identifies molecular determinants of adaptive immune rejection. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A142.
Abstract A147: Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma
Authors: Liu Xian-De , Hoang Anh , Sun Mianen , Lijun Zhou , Ding Zhiyong , Zhang Xuesong , Bai Shanshan , Tannir Nizar , Jonasch Eric 
Published: May 2016

Abstract
Antiangiogenic therapy is the current mainstay of treatment for renal cell carcinoma (RCC). Recently we reported that antiangiogenic therapy-treated primary tumors demonstrated both increased infiltration of CD4 and CD8 T cells and higher expression of the immune checkpoint ligand PD-L1, all of which were associated with therapy resistance. The underlying mechanism remains unknown. IFNγ-STAT1 signaling pathway drives the expression of both immunosuppressive PD-L1, and immunostimulatory chemoattractants, adhesion molecules and class I antigen presentation components. We studied the effects of sunitinib on the IFNγ-STAT1 signaling pathway. We found that sunitinib treatment magnified IFNγ-induced STAT1 activity. Sunitinib not only increased the activity of janus kinase (JAK) and the tyrosine phosphorylation of STAT1, but also decreased the protein level of PIAS and SOCS, negative regulators of STAT1 signaling. These results indicate that sunitinib treatment potently activates IFNγ-mediated STAT1 signaling by modulating both activators and inhibitors of STAT1. Further investigation is underway into the precise signaling pathways involved in sunitinib mediated regulation of upstream regulators of STAT1, and on the effect of sunitinib mediated STAT1 signaling on other immunostimulatory molecules in the tumor cell. Understanding the impact of STAT1 activation on target proteins after stimulation by antiangiogenic therapy will guide us to develop predictive biomarkers for combination antiangiogenic and immunomodulatory therapy, and devise precise interventions to overcome tumor cell specific immunosuppressive signaling.
Citation Format: Xian-De Liu, Anh Hoang, Mianen Sun, Zhou Lijun, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Nizar Tannir, Eric Jonasch. Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A147.
Abstract A173: Inhibition of the STING pathway by the AIM2 inflammasome
Authors: Corrales Leticia , Woo Seng-Ryong , Gajewski Thomas F. 
Published: May 2016

Abstract
Recognition of tumor-derived DNA by the cGAS/STING pathway in the cytosol of antigen-presenting cells leads to production of type I IFN, facilitating adaptive immunity against tumors. But cytosolic DNA is also recognized by AIM2, leading to the assembly of the AIM2 inflammasome and the production of mature IL-1 and IL-18. As stimulation of the STING pathway by endogenous tumor-derived DNA or exogenous therapeutic agonists have shown to trigger an immune response against tumors, a key question was whether the AIM2 inflammasome would have a positive or negative regulatory role, given the sharing of the same ligand by both pathways. In vivo, sorted CD45+ cells from implanted B16 tumors in AIM2-/- animals showed a higher IFN-β expression than the same cells sorted from WT mice, suggesting that AIM2 plays a negative role in the induction of type I IFN in vivo. Experiments in vitro confirmed that macrophages and dendritic cells from AIM2-, ASC-, or caspase-1-deficient mice produced substantially higher IFN-β in response to tumor-derived DNA. Biochemical analysis revealed that all steps in the STING pathway were enhanced in the inflammasome deficient cells: generation of cGAMP, aggregation of STING, and phosphorylation of TBK1 and IRF3. Studies investigating the biological mechanism by which activation of the AIM2 inflammasome inhibits the STING pathway revealed that pyroptosis induced by activation of the AIM2 inflammasome was critically involved. Pre-incubation with a caspase-1 inhibitor abolished cell death, and recovered a significant proportion of phosphorylation of TBK1/IRF3 and production of IFN-β. Our data suggest that the activation of AIM2 inflammasome inhibits the STING pathway mainly by cell death derived from the activation of the inflammasome. This crosstalk may have potential consequences for anti-tumor immunity which should be explored in vivo.
Citation Format: Leticia Corrales, Seng-Ryong Woo, Thomas F. Gajewski. Inhibition of the STING pathway by the AIM2 inflammasome. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A173.
Abstract A174: Mechanistic elucidation of activation-induced deaminase (AID) in immunity and cancer
Authors: Qiao Qi , Wang Li , Meng Feilong , Wu Hao 
Published: May 2016

Abstract
Activation-induced cytidine deaminase (AID) plays a critical role in human immune system. It initiates both somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes and possibly performs destructive mutations on non-Ig genes, related in cancer generation and development. Due to the aggregation behavior and extremely low activity of AID protein in vitro, the molecular basis of its function is still unclear. Using protein engineer approach, we successfully produced fully functional monomeric human AID mutants with dramatically elevated activity in vitro and intact CSR ability in vivo. Biochemistry data showed structured DNA with single strands joint feature, like G-quadruplex or partially branched DNA, can provide 10-20 fold AID affinity and 50-100 fold deaminase activity, suggests such structure can perform as direct AID recruiters in vivo. AID self-assembly upon DNA binding was observed and likely to be important for CSR. Stable AID-DNA complexes were purified in constant stoichiometry. Using crystallography method, we solved structures of AID alone and in complex with different DNA components in atomic resolution. Analyze on substrate binding interface and potential self-oligomerization interface together with abundant assay results support a structure based AID targeting and processing model during CSR and potential AID recruiting mechanism in causing off-target mutations. For the first time, our study reveals a closer look at this mystery protein, and provides solid basis for further investigation in AID function in antibody production and related diseases.
Citation Format: Qi Qiao, Li Wang, Feilong Meng, Hao Wu. Mechanistic elucidation of activation-induced deaminase (AID) in immunity and cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A174.
Abstract A182: Zbtb7b is involved in the association of EBF1 enhancer to the nuclear lamina during early B cell commitment
Authors: Zhu Yina , Murre Cornelis 
Published: May 2016

Abstract
It is well established that E2A proteins activate the expression of tumor suppressors, EBF1, PAX5 and FOXO1, to promote the B cell fate. E2A and EBF1 are frequently mutated either by chromosomal translocations, point mutations or gene deletions in B-cell precursor acute lymphoblastic leukemia. However, it remains an enigma why EBF1 is not transcribed in multipotent progenitors, in which E2A is expressed at high levels. It has been shown that, by HiC and 3D-fluorescence in situ hybridization (3D-FISH), in multipotent progenitors the EBF1 locus was located at the nuclear lamina, in pro-B cells the EBF1 locus was located away from the lamina. In this study, using gain-of-function approaches, we show that enforced Zbtb7b expression inhibited B cell differentiation and caused rapid loss of EBF1 and Pax5 mRNA. Notably, Using 3D-FISH, we found enforced expression of Zbtb7b sequestered EBF1 locus to the nuclear lamina, and using live cell imaging, we show that, Zbtb7b primarily localized at nuclear lamina. We are now investigating whether and how the nuclear envelope and its interaction with the genome change during early B cell commitment using Damseq; and anti-Zbtb7b ChIP-seq provide fine mapping of potential interaction regions with nuclear lamina. These data indicate a novel role of Zbtb7b in B cell lineage commitment and potentially link EBF1 and Zbtb7b into a common pathway. Experiments are ongoing to further examine how sequestration of genes to the nuclear lamina relates to the development of lymphoid cells.
Citation Format: Yina Zhu, Cornelis Murre. Zbtb7b is involved in the association of EBF1 enhancer to the nuclear lamina during early B cell commitment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A182.
Abstract B004: The importance of quality standards to support test performance for the purpose of treatment decision making
Authors: Midha Anita , Walker Jill , Rebelatto Marlon C. , Sabalos Costi , Mistry Amita , Schechter Nicole 
Published: May 2016

Abstract
The role of PD-L1 as a patient selection biomarker is emerging, with clinical outcome data from numerous studies demonstrating enrichment of responders. PD-L1 expression as a continuous variable measured via IHC presents a number of challenges to the clinical community including: 1) the relevant expression levels for treatment decision making 2) how well the cut-off can be deployed routinely in the clinical setting and 3) the lack of a ‘gold standard’ that establishes PD-L1 truth, and against which assays in development can compare.
To fully determine the clinical utility of PD-L1 as a predictor of response, it is critical to first remove concerns that relate to test performance. During companion diagnostic development, the assay undergoes a comprehensive analysis of performance and evaluation in the population of intended use. Prior to pre market approval (PMA), the assay must demonstrate that it meets the criteria for safe and effective use as determined through statistically relevant acceptance criteria established by the sponsor.
Following commercialisation of the assay, performance is assessed in the real world setting through various external quality assurance schemes with the goal of reducing inter-laboratory variation and establishing assay standardisation. The latter is critical to the maintenance of test quality and ensuring patient care.
We will present a detailed overview of the quality standards observed for IHC-based companion diagnostic approvals. Previously approved PMA and cleared 510(k) assay summaries of safety and effectiveness data (SSED) will be reviewed. Published EQA Quality assessments will be compared to data obtained from SSED. Set against this is the quality level that has been achieved with the Ventana SP263 PD-L1 assay.
Citation Format: Anita Midha, Jill Walker, Marlon C. Rebelatto, Costi Sabalos, Amita Mistry, Nicole Schechter. The importance of quality standards to support test performance for the purpose of treatment decision making. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B004.
Abstract B008: Design and development of a novel series of PI3K-p110beta/delta-selective inhibitors with combined tumor immunotherapeutic, growth inhibition, and anti-metastatic activity
Authors: Shuttleworth Stephen J. 
Published: May 2016

Abstract
The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. In solid tumor therapy, the majority of clinical activity has centered on pan-class I (p110alpha, beta, delta and gamma) inhibitors of limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110delta and p110gamma has been the main focus for hematological cancer treatment. Our research at Karus has focused on the emerging role of p110beta and p110delta in both cancer types, though increasingly in solid tumors, in which overexpression, mutation and PTEN-defectiveness have been shown to be key features in disease pathogenesis and progression. We have designed and developed a uniquely-selective series of orally-active molecules that inhibit the p110beta/delta isoforms, and which display extremely high specificity in the human kinome. The design of such molecules has enabled us to interrogate the function of p110delta in solid tumor immunotherapy and p110beta in primary tumor growth and metastasis, with our lead compounds showing promising oral activity in syngeneic models, in which they inhibit tumor growth and metastatic spread whilst also impacting on downstream biomarker levels. Additionally, through our ability to tune selectivity over p110alpha and p110gamma, elimination of the mechanism-related toxicities associated with those isoforms can be realized, making selective dual p110beta/delta inhibition, described herein for our lead compound, KA2237, potentially more conducive to combination therapy than for pan-inhibitors, including with signal transduction pathway inhibitors and other immunotherapeutics. KA2237, an orally-active, potent and selective small molecule p110beta/delta inhibitor, has completed GLP toxicology and will enter Phase I studies in 2015.
Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of PI3K-p110beta/delta-selective inhibitors with combined tumor immunotherapeutic, growth inhibition, and anti-metastatic activity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B008.
Abstract B014: BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy
Authors: Gausdal Gro , Davidsen Kjersti , Wnuk-Lipinska Katarzyna , Wiertel Kathleen , Hellesøy Monica , Blø Magnus , Ahmed Lavina , Hodneland Linn , Kiprijanov Sergej , Brekken Rolf A , Lorens James B 
Published: May 2016

Abstract
Signaling via the AXL receptor tyrosine kinase is a key suppressor of anti-tumor innate immune response. AXL is expressed on several cells associated with the suppressive tumor immune microenvironment including natural killer cells, dendritic cells and tumor-associated macrophages. AXL is also an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) that contributes to anti-tumor immune evasion. Hence AXL signaling contributes uniquely to tumor intrinsic and microenvironmental immune suppression in tumors. We therefore evaluated whether blocking AXL signaling with BGB324, a selective clinical-stage small molecule Axl kinase inhibitor, enhances the effect of immune checkpoint blockade in syngeneic cancer mouse models that display limited immunogenicity.
We measured the effect of BGB324 in combination with anti-CTLA-4 and anti-PD-1 in the mammary adenocarcinoma 4T1/Balb/C syngeneic mouse model. BGB324 (50 mg/kg bid) significantly enhanced responsiveness to anti-CTLA-4/anti-PD-1 treatment (10 mg/kg of each, 4 doses) in Balb/C mice bearing 4T1 tumors. The combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in complete tumor clearance in 46.1 % of mice versus complete tumor clearance in 11.7 % of the mice treated with anti-CTLA-4/anti-PD-1 (p = 0.0087). BGB324 + anti-CTLA-4/anti-PD-1 treated tumors displayed enhanced CD8+ T cell tumor infiltration. Combination of BGB324 with immune checkpoint inhibitors is being evaluated in additional models, and detailed interrogation of AXL-dependent immune effector cell activity in tumors is in progress.
In conclusion, AXL inhibition represents a unique opportunity to target anti-tumor immune suppressive mechanisms and supports clinical translation of BGB324 in combination with cancer immunotherapy in human cancer.
Citation Format: Gro Gausdal, Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Kathleen Wiertel, Monica Hellesøy, Magnus Blø, Lavina Ahmed, Linn Hodneland, Sergej Kiprijanov, Rolf A Brekken, James B Lorens. BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B014.
Abstract B016: Allogenic CAR T-cells for adoptive immunotherapy
Authors: Galetto Roman , Lebuhotel Celine , Chion-Sotinel Isabelle , Francon Patricia , Gouble Agnes , Smith Julianne 
Published: May 2016

Abstract
Chimeric antigen receptor (CAR)-redirected T-cells have given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. A limitation of the current autologous approach is that CAR T-cells must be manufactured on a “per patient basis”. We have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic “off-the-shelf” engineered CAR+ T-cell–based frozen products. This platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRα constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR's to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, obtaining up to 80% of TCRβα negative cells. This allows us to efficiently produce TCR-deficient T-cells that have been shown to no longer mediate alloreactivity in a xeno-GvHD mouse model. We have adapted this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed in tumor cells of patients with Acute Myeloid Leukemia as well as CS1 a glycoprotein highly expressed on tumor cells of patients with multiple myeloma. We will present both in vitro and in vivo data demonstrating specific anti-tumor activity of engineered CAR T cells against cell lines expressing the targeted antigen.
Citation Format: Roman Galetto, Celine Lebuhotel, Isabelle Chion-Sotinel, Patricia Francon, Agnes Gouble, Julianne Smith. Allogenic CAR T-cells for adoptive immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B016.