bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy
Authors: Padmanee Sharma 
Published: February 2019

Abstract
Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1 and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted pre-surgical and tissue-based clinical trials, which permit access to tumor tissues for laboratory studies. To compare and contrast data, we chose one tumor type that responds well to immune checkpoint therapy and one that does not. The first pre-surgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. The second pre-surgical trial was conducted with anti-CTLA-4 (ipilimumab) in patients with localized prostate cancer. In addition, we evaluated data from patients with melanoma who received immune checkpoint therapy. These data enabled us to identify the ICOS/ICOSL pathway as relevant for anti-tumor immune responses in the setting of anti-CTLA-4 therapy. We also identified resistance mechanisms including expression of other immune inhibitory pathways, such as VISTA, and loss of the IFNg signaling pathway in tumor cells. These data will be discussed in greater details.
Citation Format: Sharma Padmanee. From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA05.
Abstract IA11: The immunotherapy faces of Interleukin-8 and CD137
Authors: Melero Ignacio 
Published: February 2019

Abstract
IL-8(CXCL-8) is a chemoattractant factor for myeloid leukocytes, that is produced in large quantities by many solid tumors. Interestingly its concentration in serum is a negative prognostic and is predictive of lack of response to the anti-PD-1 mAb nivolumab, as confirmed in large series of patients. As a neuthrophil chemoattractant, IL-8 produced in cancer tissue attracts myeloid-derived suppressor cells and correlates with poor T-cell infiltration and weak gamma-interferon gene signatures. An IL-8 blocking mAb is being developed in combination with PD-1 blockade for cancer therapy focusing on cases with high circulating levels of IL-8. CD137 (4-1BB) is a costimulatory receptor expressed on primed NK and T cells whose activation with agonists antibodies invigorates CTL responses to fight cancer. CD137 agonists are highly synergistic with adoptive T-cell therapy. Recent evidence shows that CD137-costimulation reprograms chromatin, modifying DNA methylation in the loci of immune –relevant genes and potently enhances the size and respiratory functions of mitochondria in human and mouse CD8 T cells. Metabolic and epigenetic effects of CD137 agonists are critical for the antitumor therapeutic effects. In combination immunotherapy, strategies of CD137 costimulation can be used to potentiate radiotherapy in a synergistic fashion. Multiple constructs based on CD137 agonists are being developed clinically by the pharmaceutical and biotech industries.
Citation Format: Ignacio Melero. The immunotherapy faces of Interleukin-8 and CD137 [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA11.
Abstract PR04: A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
Authors: Barry Kevin C. , Krummel Matthew F. 
Published: February 2019

Abstract
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T-cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 “checkpoint” immunotherapy for cancer largely targets T-cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T-cell–directed immunotherapy and that these innate cells are necessary for enhanced T-cell tumor responses, suggesting this axis as a target for new therapies.
Citation Format: Kevin C. Barry, Matthew F. Krummel. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR04.
Abstract PR13: A new high-performance HLA ligand identification strategy enables prediction of T-cell tolerance to neoepitopes
Authors: Klatt Martin G. , Gejman Ron S. , Moon Sung S. , Korontsvit Tatyana S. , Dao Tao , Scheinberg David A. 
Published: February 2019

Abstract
T-cell responses against neoepitopes presented by human leukocyte antigen (HLA) complexes represent a critical effector of anticancer immunity. However, detection of neoepitopes by mass spectrometry is still challenging as is identification of the fraction of neoepitopes that elicit immune responses in vitro and in vivo. To address these problems, we developed a strategy to identify HLA ligands combining the peptide identification algorithm Byonic with the epitope binding predictor netMHCpan. We obtained up to 4-fold increases in unique HLA ligand identifications compared to standard approaches, false discovery rates below 0.6% and over 17,000 unique HLA ligand identifications in a single experiment. Even with only 10 million cancer cells we were able to detect over 5,000 unique HLA ligands, which allows our approach to be applied to small tumor samples in a clinical setting. Of note, phosphorylated as well as glycosylated HLA ligands were identified with the same accuracy and allowed a better characterization of the rules for presentation of post-translationally modified HLA ligands. Furthermore, by reanalyzing mass spectrometry samples with our novel approach, we confirmed high-confidence, rejected low-confidence and identified additional neoepitopes including the first-time detection of a phosphorylated neoepitope. Finally, we used our broadened knowledge of the immunopeptidome to create rules for prediction of non-immunogenicity of neoepitopes based on high biochemical similarity with unmutated HLA ligands, which showed high specificity and positive predictive value when validated with two datasets derived from neoepitope-based clinical studies. Altogether, our methods substantially improved sensitivity and specificity for detection of native, modified and mutated HLA ligands, propose an explanation for tolerance to neoepitopes, and should in combination facilitate the design of neoepitope-based therapies.
Citation Format: Martin G. Klatt, Ron S. Gejman, Sung S. Moon, Tatyana S. Korontsvit, Tao Dao, David A. Scheinberg. A new high-performance HLA ligand identification strategy enables prediction of T-cell tolerance to neoepitopes [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR13.
Abstract A23: Anti-PD-1 antibody scFv producing recombinant Bifidobacterium exerts antitumor effect in a larger fraction of the treated mice compared to full-length anti-PD-1 antibody
Authors: Shioya Koichiro , Wang Li , Matsumura Tomio , Shimizu Hitomi , Kanari Yasuyoshi , Seki Yuji , Shimatani Yuko , Taniguchi Shun’ichiro , Kataoka Shiro 
Published: February 2019

Abstract
Anti-PD-1 therapy has improved therapeutic outcomes of patients in multiple cancer types. However, the therapy has demonstrated clinical benefits in only a small fraction of patients. The reason of the limited response in clinical practice is not fully understood.
In an aim to improve anti-cancer drug delivery and potency, we have been developing in situ delivery and production system (i-DPS) by modifying a non-pathogenic anaerobic bacterium, Bifidobacterium, which localizes and proliferates only in the hypoxic environment like solid tumors after intravenous administration, produces anticancer proteins, enzymes or other pharmacologically active molecules selectively at the tumor site. Here we present anti-human PD-1 antibody scFv producing i-DPS in cancer immunotherapy, which could be specifically delivered to and amplified only at the hypoxic sites of solid tumors. A series of in vitro assays has been performed to confirm the stable expression and secretion of anti-human PD-1 scFv by recombinant Bifidobacterium, the binding inhibition of PD-1/PD-L1 interaction and elevated IFN gamma production in mixed lymphocyte culture by anti-human PD-1 scFv secreted from recombinant Bifidobacterium.
Anti-murine PD-1 scFv producing Bifidobacterium as surrogate systemically administered to the syngeneic mice model demonstrated significant tumor growth inhibition. Of particular interest, the suppression of tumor growth was observed in a larger fraction of the treated mice while the control anti-PD-1 antibody showed the effect on only a few mice. The analysis of tumor infiltrating lymphocytes and myeloid cells will be presented as well. Taken together, i-DPS for anti-PD-1 antibody provides a new promising immune-therapeutic modality to target hypoxic solid tumors and also provides a unique insight for antibody drug delivery in cancer immunotherapy.
Citation Format: Koichiro Shioya, Li Wang, Tomio Matsumura, Hitomi Shimizu, Yasuyoshi Kanari, Yuji Seki, Yuko Shimatani, Shun’ichiro Taniguchi, Shiro Kataoka. Anti-PD-1 antibody scFv producing recombinant Bifidobacterium exerts antitumor effect in a larger fraction of the treated mice compared to full-length anti-PD-1 antibody [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A23.
Abstract A52: Vaccine cells derived from cancer stem cells expressing interleukin-15 and its receptor inhibit tumor growth
Authors: Toukam Donatien Kamdem , Steel Jason C. , Carwell Christian , Eldessouki Ihab , Morris John C. 
Published: February 2019

Abstract
Background: Interleukin-15 (IL-15) is a powerful activator and inducer of NK cells and cytolytic CD8+ T cells. IL-15 also activates and expands CD8+ memory T cells without stimulating immunosuppressive CD4+CD25+ T regulatory cells. As such, IL-15 may be useful as an immunotherapy for cancer. In an effort to enhance antitumor activity and reduce systemic side effects, we studied an approach using a tumor vaccine enriched for cancer stem cells (CSCs) expressing murine (m) IL-15 and its receptor (mIL-15Rα).
Methods: Lentiviral vectors expressing the wild type or optimized (opt) cDNA sequences for mIL-15 and/or mIL-15Rα under the control of the human EF-1 promoter were generated and used to transduce TC1 mouse lung cancer cells. The TC1 cells were cultured under low serum conditions to generate tumor spheroids enriched for CSCs.
Results: The transduced TC1 cells demonstrated the expected mRNA transcripts. On flow cytometry only the cells transduced with mIL15Rα in combination with mIL-15 showed surface expression of mIL-15, while cells transduced with mIL-15 or mIL-15Rα constructs did not. When co-cultured with the transduced tumor spheroids or incubated with supernatants from these TC1 cells, CTLL-2 murine T cells demonstrated proliferation indicating that the cloned cDNAs expressed functional proteins. The vector demonstrating the greatest stimulation of CTLL-2 cells expressed both the mIL-15Rα and mIL-15opt sequences and demonstrated suppressed TC1 tumor growth in vivo.
Conclusion: CSCs expressing mIL-15Rα and mIL-15 stimulated proliferation of T cells in vitro and demonstrated inhibited tumor growth in mice. In vivo tumor vaccination studies are in progress.
Citation Format: Donatien Kamdem Toukam, Jason C. Steel, Christian Carwell, Ihab Eldessouki, John C. Morris. Vaccine cells derived from cancer stem cells expressing interleukin-15 and its receptor inhibit tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A52.
Abstract B06: Enhancement of checkpoint inhibitor efficacy by combination treatment with a novel COX2/sEH dual inhibitor
Authors: Zimmermann Maike , Hwang Sung Hee , Hammock Bruce D. , Cimino George , Henderson Paul T. 
Published: February 2019

Abstract
It has been shown that the COX2/PGE2 pathway is involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells, and that angiogenesis inhibitors alter tumor stroma in a pro-immunogenic fashion. We recently developed Oomnicoxib, a compound that concurrently inhibits COX2 and soluble epoxide hydrolase (sEH), which work together to modulate expression a variety of prostaglandins of importance to inflammation and cancer. Oomnicoxib potently inhibits tumor angiogenesis in several tumor types via this mechanism of action that is unique compared to approved anti-angiogenesis drugs, which includes downregulation of COX2 and PGE2. Importantly, the compound is nontoxic to human PBMC. Accordingly, we hypothesize that Oomnicoxib modulates tumor stroma to favor immune cell infiltration and can potentiate immune activation of check point inhibitors. Progress towards comprehensive Oomnicoxib immune profiling and efficacy enhancement of a checkpoint inhibitor in mice will be presented.
Note: This abstract was not presented at the conference.
Citation Format: Maike Zimmermann, Sung Hee Hwang, Bruce D. Hammock, George Cimino, Paul T. Henderson. Enhancement of checkpoint inhibitor efficacy by combination treatment with a novel COX2/sEH dual inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B06.
Abstract B19: Modulation of cytotoxic effects of vemurafenib by chloroquine in malignant melanoma cells G-361: Role of dermcidin
Authors: Neyra Jennifer Montoya , Belizario Jose 
Published: February 2019

Abstract
Dermcidin (DCD) is a candidate oncogene localized at 12q13.1 and co-amplified with multiple oncogenes in many tumor cells, including breast carcinomas and melanomas. DCD is one of the 100 gene signature for melanomas. To further understand the role of DCD on growth, survival and progression of melanoma cells, we selected G-361 melanoma cell clones expressing shRNA to DCD and established in vitro and in vivo models. In this study we evaluated the pharmacologic effects of vemurafenib (BRAFV600E inhibitor) and chloroquine (autophagy inhibitor) in cell viability and tumor growth of two melanoma cell lines identified as G-361 pLKO, which expresses DCD and BRAFV600E, and G-361 IBC I which express shRNA to silence DCD constitutively. Vemurafenib induces features of stress-induced senescence in addition to apoptosis. G-361 melanoma cells responded to vemurafenib (1-2 μM) alone or combined with chloroquine (50-100 μM) which increased apoptosis rates, while decreasing senescent cells expressing β-galactosidase enzyme. Vemurafenib (50 mg/kg / 21 days) inhibited melanoma growth in immunodeficient mice dependent on DCD expression. Chloroquine (30 mg/kg) in combination with vemurafenib, accelerated (given at 24-hour interval), and reduced (given at 72 hours interval), melanoma growth. Tumor cells resistant to vemurafenib and chloroquine displayed atypical cell morphology and nuclear histological patterns and diferential expression of melanocytic differentiation biomarkers S100, HMB-45, Melan-A and pancytokeratins. This work confirms the efficacy of vemurafenib and suggests potential adjuvant effects of chloroquine. It also confirms the role of dermcidin as growth factor and oncogene for melanoma cells.
Citation Format: Jennifer Montoya Neyra, Jose Belizario. Modulation of cytotoxic effects of vemurafenib by chloroquine in malignant melanoma cells G-361: Role of dermcidin [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B19.
Abstract B28: Validation and characterization of MiXeno humanized mouse models for immuno-oncology
Authors: Zhang Lan , Zhang Juan , Qiao Meng , Yan Xuefei , Ding Jian , Chen Fei , An Xiaoyu , Yang WenQing , Shi Qian 
Published: February 2019

Abstract
Despite the unprecedented success of immune checkpoint blockade therapy in patients with various cancer types, a lack of effective preclinical mouse models remains a major challenge for the development of novel immunotherapeutics. Different strategies to humanize immunodeficient mouse model systems have been reported, including replenishment with human hematopoietic stem cells (HSC) or human PBMC, as well as the development of chimeric models harboring human immune checkpoint targets in immunocompetent mice. CrownBio has successfully established a number of human PBMC-humanized xenograft models known as MiXeno for in vivo immunotherapy evaluation. Our MiXeno platform is a rapid and simple strategy for model humanization. However, aspects such as the optimal PBMC injection route and cell number, the PBMC donor dependence and specificity, and the impact of donor HLA type on the engraftment of immune or tumor cells, etc., require fine tuning. After comparative studies for cell titration and immune cell reconstitution, the optimal inoculation conditions and protocols were established for each model. Immune cell constitution and tumor cell engraftment were synchronized so that graft versus host disease (GvHD) can be managed. Models were also characterized by immunophenotyping. MiXeno is proven as a valid alternative to other humanized mouse models, and has a broad spectrum of applications in immuno-oncology including the evaluation of human specific immuno-modulatory drugs in vivo.
Citation Format: Lan Zhang, Juan Zhang, Meng Qiao, Xuefei Yan, Jian Ding, Fei Chen, Xiaoyu An, WenQing Yang, Qian Shi. Validation and characterization of MiXeno humanized mouse models for immuno-oncology [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B28.
Abstract B31: Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration
Authors: Heaster Tiffany M. , Yu Jiaquan , Beebe David J. , Skala Melissa C. 
Published: February 2019

Abstract
Macrophages are key regulators of tumor progression, and can be targeted for cancer treatment. However, reprogramming macrophages for anti-tumor activity is challenging due to their plasticity. Standard assessment of macrophage function (e.g., ELISA) lacks the sensitivity to capture cell-level heterogeneity in living macrophages. Therefore, single cell imaging and analysis tools are needed to study heterogeneous macrophage behavior within the tumor microenvironment. Macrophages adapt their metabolism to alter both phenotype and function. Thus, we propose the combination of optical metabolic imaging (OMI) and microdevice co-culture to observe cellular level macrophage heterogeneity in response to tumor stimuli. OMI enables noninvasive, dynamic imaging of intact, living samples by measuring autofluorescence from the metabolic co-enzymes NAD(P)H and FAD. Cellular level redox balance is evaluated with the optical redox ratio, defined as the ratio of NAD(P)H to FAD intensity. Additionally, NAD(P)H and FAD fluorescence lifetimes report on metabolic enzyme binding activities. Three-layer microdevices consisting of murine PyVMT breast carcinoma cells, collagen (200 micron thickness), and RAW 264.7 macrophages, respectively, were designed to monitor tumor-mediated macrophage polarization and migration. Metabolic changes with macrophage migration were measured with OMI at 24, 48, and 72 hours after culture. Redox ratio and NAD(P)H mean lifetime increased over time in co-cultured macrophages (p &lt;0.05). Macrophage mono-cultures exhibited lower redox ratio and NAD(P)H lifetime (p&lt;0.05) than in co-culture, consistent with the metabolism of naïve and cytokine-stimulated M2-like macrophages, respectively. Phenotype and function of co-cultured macrophages were confirmed with polymerase chain reaction (PCR) gene expression analysis and immunostaining. Furthermore, volumetric imaging visualized macrophage migration distance-dependent changes in NAD(P)H autofluorescence intensity. These results demonstrate that OMI and microdevice co-culture can capture dynamic changes in macrophage metabolism throughout 3D tumor-stimulated polarization and migration. Overall, this approach could enhance our understanding of macrophage metabolism and function, thus revealing novel therapeutic targets within the tumor microenvironment.
Citation Format: Tiffany M. Heaster, Jiaquan Yu, David J. Beebe, Melissa C. Skala. Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B31.
Abstract B44: Regulation of macrophage activation by vascular niche in glioblastoma
Authors: Wang Qirui , Gong Yanqing Anna , Fan Yi 
Published: February 2019

Abstract
Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as a major source for interleukin (IL)-6 expression in GBM microenvironment. Furthermore, we reveal that colony stimulating factor-1 (CSF-1) and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor (PPAR)-γ-dependent transcriptional activation of hypoxia-inducible factor (HIF)-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors.
Note: This abstract was not presented at the conference.
Citation Format: Qirui Wang, Yanqing Anna Gong, Yi Fan. Regulation of macrophage activation by vascular niche in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B44.