Maintenance of Immune Balance: Effects of Targeted and Immune Therapies最新文献

{"title":"Abstract A141: Intratumoral depletion of regulatory T-cells using CD25-targeted photodynamic therapy induces antitumoral immune responses","authors":"H. Lee, D. Oh","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A141","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A141","url":null,"abstract":"Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T-cells, thus providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to deplete Tregs selectively in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs by photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T-cells and the expression of IFN-γ and CD107a, which is cytolytic granule exocytosis marker, in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique. Citation Format: Heung Kyu Lee, Dong Sun Oh. Intratumoral depletion of regulatory T-cells using CD25-targeted photodynamic therapy induces antitumoral immune responses [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 A141.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"188 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83053083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA20: Targeting the immune microenvironment in breast cancer","authors":"S. Loi, P. Savas","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA20","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA20","url":null,"abstract":"Immunotherapy has revolutionized cancer treatment, but the benefits are not ubiquitous or absolute. In breast cancer, higher levels of lymphocytic infiltrate confer significant prognostic advantage, predict response to chemotherapy in early stage disease and are associated with benefit from PD-1 inhibition. To enhance the modest benefits of immunotherapy seen in breast cancer thus far, it is expected that a greater understanding of the immune subpopulations in the tumor microenvironment will be necessary, emphasizing that the quality and quantity of tumor infiltrating lymphocytes are important. We have profiled the T cell infiltrate in primary and metastatic breast cancers, using flow cytometry, single cell mRNASeq, multiplex immunohistochemistry and bulk RNASeq on flow sorted CD8 populations. In this work, we found that CD8 T cells display tissue resident specialization. In particular, we confirmed the presence of a CD8 T cell population with tissue resident memory features. This population was notable for high expression of T cell checkpoint receptors and cytotoxic markers, active proliferation, and a distinct T cell receptor repertoire in contrast to CD8 effector memory T cells. A gene signature derived from this population was found to be prognostic in early stage breast cancer and associated with benefit from PD-1 checkpoint inhibition in melanoma. We find that single cell profiling in human samples is a powerful technique which unveils tissue resident aspects of the anti-cancer immune response. This approach may lead to better immunotherapy biomarkers and optimization of immunotherapeutic strategies. Citation Format: Sherene Loi, Peter Savas. Targeting the immune microenvironment in breast cancer [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 IA20.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"146 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86087727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A123: Skewed CD4 and CD8 T-cell differentiation in pancreatic cancer patients","authors":"Cécile Alanio, B. Bengsch, J. R. Gies, S. Henrickson, N. Weng, Janáe A. Ritz-Romeo, M. O'Hara, J. Melenhorst, S. Lacey, R. Young, C. June, E. Wherry","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A123","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A123","url":null,"abstract":"To understand potential immune system alterations in newly diagnosed, untreated, pancreatic cancer patients and provide a foundation for immunotherapy, we profiled PBMC from pancreatic ductal adenocarcinoma (PDA) patients and age-matched healthy controls using high-dimensional CyTOF analysis. We developed two immune profiling panels: a broad profiling panel that includes 45 phenotypic markers that together permit the identification and enumeration of the main innate and adaptive immune cell subsets in humans, and a deep profiling panel that includes 45 features focusing on T-cell phenotype and biology. We report a 2-fold increase in monocytes, more regulatory T-cells, and more plasmocytes in circulation in pancreatic cancer patients as compared to age-matched controls, as well as a bias towards cytokine-producing NK cells. Using high-dimensional approaches, we observed skewed T-cell differentiation in pancreatic cancer patients, with peripheral blood CD8 T-cells being biased towards more CD45RA-positive CD27-positive CCR7-positive CD95-positive CD49d-positive stem cell memory cells (P=7x10-5), more CD45RA-negative CD27-positive CCR7-negative effector memory cells (P=0.002) and less CD45RA-positive CD27-negative CCR7-negative late effector memory cells (P=0.003) as compared to age-matched controls. Strikingly, when examinating T-cell differentiation in human spleens, we found increased proportions of late effector memory T-cells in the splenic CD8 T-cell compartment of pancreatic cancer patients as compared to age-matched controls. These results suggest an impaired T-cell trafficking in pancreatic cancer patients, with late memory T-cells being retained in the spleen. We are now investigating the mechanisms underlying these observations, as well as their impact on T-cell immunity of the cancer patients. Our goal is to understand the nature of the skewing and how any changes in baseline immune health of the T-cell compartment relate to disease progression and/or response to therapy. These studies should provide a foundation for improving therapy in pancreatic cancer patients. Citation Format: Cecile Alanio, Bertram Bengsch, Josephine R. Gies, Sarah Henrickson, Nan Ping Weng, Janae A Ritz-Romeo, Mark O9Hara, Joseph J Melenhorst, Simon Lacey, Regina M Young, Carl H June, E. John Wherry. Skewed CD4 and CD8 T-cell differentiation in pancreatic cancer patients [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 A123.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"126 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74680997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A159: Agonistic CD40 antibody therapy induces formation of tertiary lymphoid structures in glioma and inhibits the response to immune-checkpoint blockade","authors":"L. Hooren, A. Vaccaro, Maria Georganaki, Mohanraj Ramachandran, Hua Huang, J. Lau, A. Smits, M. Essand, A. Dimberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A159","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A159","url":null,"abstract":"Cancer immunotherapy of glioma, the most common primary brain tumor in adults, is constrained by an immunosuppressive microenvironment. Tertiary lymphoid structures (TLSs) are ectopic lymphoid structures that mediate immune responses and provide a local site for tumor antigen presentation. Here, we show for the first time that TLSs are present in human low-grade glioma and that they can be induced in murine glioma models. Agonistic CD40 antibodies induced lymphotoxin α expression in B cells and enhanced the formation of TLSs in mice bearing orthotopic GL261 or CT-2A gliomas. TLSs consisting of B cells, T-cells and antigen presenting cells formed around CD31+ vessels proximal to the tumor tissue and adjacent to the meninges. Agonistic CD40 antibody treatment improved the CD8+ T-cell / Treg ratio in tumor-bearing mice, but there was no survival benefit. A decreased CD69 activation status on CD8+ T-cells, an increase of B cells with a CD1d+CD5+ regulatory phenotype and a high infiltration of Tregs in TLSs indicate that agonistic CD40 antibodies induce an immunosuppressive microenvironment in glioma. Consistent with this, the efficacy of both PD-1 and CTLA-4 checkpoint blockade was significantly decreased by co-administration of agonistic CD40 antibodies. These results demonstrate that TLSs are present and can be induced in glioma, but that they at least under certain conditions are associated with immunosuppression, shedding light on new mechanisms of immune regulation in the brain microenvironment. Citation Format: Luuk van Hooren, Alessandra Vaccaro, Maria Georganaki, Mohanraj Ramachandran, Hua Huang, Joey Lau, Anja Smits, Magnus Essand, Anna Dimberg. Agonistic CD40 antibody therapy induces formation of tertiary lymphoid structures in glioma and inhibits the response to immune-checkpoint blockade [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 A159.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"122 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82247094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR07: Developing syngeneic NOD tumor models to profile immunotoxicity and antitumor immunity in response to cancer immunotherapies in autoimmune-prone mice","authors":"A. Young, V. Nguyen, J. Kang, Sadaf Mehdizadeh, Amy Mei, K. Sheehan, D. Serreze, Yi-Guang Chen, R. Schreiber, J. Bluestone","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR07","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR07","url":null,"abstract":"With increasing use of cancer immunotherapies, it is evident that some patients develop immunotoxicity, termed immune-related adverse events (irAEs). Many of these irAEs are a consequence of a peripheral breakdown in self-tolerance but the basis, be it genetic, epitope spreading or environment, remains unclear. This highlights an urgent need to develop preclinical models to profile autoimmunity together with antitumor immunity to accurately assess the etiology by which autoimmune pathologies are induced in immunotherapy-treated cancer patients. We generated transplantable syngeneic tumor cell lines in the autoimmune-prone NOD background from spontaneous tumors and methylcholanthrene (MCA)-induced fibrosarcomas. We investigated whether the presence of tumor and level of tumor immunogenicity altered the severity and frequency of autoimmunity in response to cancer immunotherapies. Notably, individual and combination immunotherapies displayed distinct autoimmune pathologies, with induction of certain treatment-associated immunotoxicities, such as type 1 diabetes (T1D), associated with improved tumor control. Following, we investigated genetic and therapeutic strategies to abrogate immunotherapy-induced autoimmunity without impeding antitumor immunity. Multiple loci that control genetic susceptibility to autoimmunity in NOD mice have been identified including a major histocompatibility complex, as well as insulin-dependent diabetes (Idd) susceptibility loci localized to relevant immune checkpoints. Using NOD mice, congenic for individual IDD loci, we determined that NOR- or C57BL/6-derived gene loci provided significant protection from anti-PD-1/PD-L1-induced type 1 diabetes. In some cases, immune tolerance towards autoimmunity limited cancer immune surveillance; however, NOD mice congenic for NOR-Idd9 displayed both superior tumor control and significantly reduced incidence of T1D in comparison to NOD mice. This result suggests that in fact by abrogating the pathogenic autoimmune response, it is possible for improved tumor control to be afforded, representing an exciting area for mechanistic exploration. Together, these preclinical models provide a platform to assess safety profiles for cancer immunotherapies, identifying cellular mechanisms and therapeutic interventions that inhibit the development of autoimmunity while preserving antitumor immunity. Citation Format: Arabella Young, Vinh Nguyen, Jee Hye Kang, Sadaf Mehdizadeh, Amy Mei, Kathleen C. F. Sheehan, David V. Serreze, Yi-Guang Chen, Robert D. Schreiber, Jeffrey A. Bluestone. Developing syngeneic NOD tumor models to profile immunotoxicity and antitumor immunity in response to cancer immunotherapies in autoimmune-prone mice [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 PR07.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83219828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A124: Preclinical characterization of AB154, a fully humanized anti-TIGIT antibody, for use in combination therapies","authors":"A. Anderson, A. Becker, Fangfang Yin, Hema Singh, Xiaoning Zhao, L. Seitz, Rick Stanton, N. Walker, J. Tan","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A124","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A124","url":null,"abstract":"TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that is expressed on natural killer (NK) cells, CD8+ T-cells, and immunosuppressive regulatory T-cells (Treg). DNAM-1 (DNAX Accessory Molecule-1; CD226) is an activating receptor found on NK cells, monocytes and a subset of T-cells. TIGIT and DNAM-1 are paired receptors that compete for shared ligands CD155 (PVR) and CD112 (Nectin-2) expressed by tumor and antigen-presenting cells. TIGIT binding to CD155 or CD112 results in immune suppression, whereas binding of DNAM-1 to the same ligands mediates immune activation. As malignancies progress, high TIGIT expression often occurs alongside the upregulation of other immune checkpoint proteins and markers of T-cell exhaustion such as PD-1 (Programmed Death-1). We have developed AB154 to inhibit TIGIT and shift the balance in the tumor microenvironment towards a more productive anticancer response. Blockade of multiple immune checkpoint proteins can confer effective and durable responses in the treatment of cancer. Data assembled from TCGA (The Cancer Genome Atlas) identified numerous tumor types in which TIGIT is co-expressed with PD-1. In these tumors, TIGIT and PD-1 were significantly upregulated compared to normal adjacent tissue. Immunophenotyping performed on human tumor infiltrating lymphocytes demonstrated a strong correlation between TIGIT and PD-1 co-expression on specific immune cells including CD8+ T-cells and Treg cells. AB154 is a fully humanized antibody that blocks human TIGIT with sub-nanomolar affinity, as determined using a CHO.hTIGIT over-expressing cell line and primary human T-cells. Functional consequences of blocking TIGIT/CD155 interactions in combination with anti-PD-1 or anti-PD-L1 were evaluated using mixed lymphocyte reactions (MLR). Briefly, we show here that co-cultures of GM-CSF/IL-4-differentiated CD155+ PD-L1+ monocytes and TIGIT+ CD4+ T-cells, in the presence of AB154, significantly increased IFN-gamma secretion when combined with anti-PD-1 or anti-PD-L1 blocking antibodies relative to each monotherapy. Understanding pharmacokinetic (PK) and pharmacodynamic (PD) relationships enables the choice of a dosing regimen that provides adequate target coverage. To evaluate the PD effects of AB154 in clinical samples, we developed a multicolor flow cytometry-based assay that utilizes an anti-TIGIT antibody that is competitive with AB154 to determine receptor occupancy. In human whole blood, ex vivo addition of AB154 achieved complete inhibition of TIGIT. Analysis of blood mononuclear cells, including CD8+ and CD4+ T-cells, Treg and NK cells, demonstrated target engagement by AB154 suitable for clinical development. In addition, we examined TIGIT receptor occupancy of AB154 (added to whole blood ex vivo) in a small cohort of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 antibody pembrolizumab. In these samples, TIGIT receptor occupancy by AB154 was comparable to that obtained wi","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84831158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A156: PDA tumor cell death as following combination anti-PD-1 blockade and CXCR4 blockade is a direct effect of CD8+ T-cells","authors":"K. Sullivan, Y. D. Seo, Xiu-yun Jiang, Teresa Kim, R. Yeung, V. Pillarisetty","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A156","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A156","url":null,"abstract":"Introduction: Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States. Despite the fact that the human PDA microenvironment contains a mixture of infiltrating immune cells, including activated effector CD8+ T-cells, attempts to apply immune checkpoint inhibitor therapy have not yet been successful in achieving a clinical response (1). Combining blockade of the immune checkpoint receptor PD-1 with blockade of the chemokine receptor CXCR4 in a mouse model of PDA produced T-cell-mediated tumor cell killing (2). We therefore hypothesized that, in a human PDA slice culture model system that maintains the intact tumor microenvironment (3), combination of CXCR4 blockade with PD-1 blockade would lead to anti-tumor T-cell activation. Methods: Cores (6 mm) were taken from freshly resected, sterile human PDA specimens and cut into 250 µm thick slices using a vibratome. The slices were treated with either IgG antibody isotype control, AMD3100 (a CXCR4 blocking small molecule drug) plus antibody isotype control, anti-PD-1 antibody, or a combination of anti-PD-1 antibody and AMD3100 for two days. The slices were then stained with fluorescently labelled antibodies for CD8 and EpCAM, as well as with SR-FLICA, a reagent that produces a fluorescent signal when bound to activated Caspase 3 and 7 enzymes. Live slices were maintained in a humidified, temperature-controlled CO2 chamber for time-lapse confocal imaging for 1 hour. Similarly, untreated slices were imaged for 90 minutes prior to and following combined anti-PD-1 and AMD3100 drug treatment. Each slice was imaged at 3 different positions to observe CD8+ T-cells, EpCAM+ tumor cells, and SR-FLICA+ apoptotic cells throughout the slice. Each cell type was counted at each position over the entire time course imaged. Results: Compared to antibody isotype control or monotherapy, slices treated with combined PD-1 and CXCR4 blockade contained a greater fraction of EpCAM+ tumor cells that were undergoing apoptosis, indicated by SR-FLICA positivity. This treatment also increased the proportion of EpCAM+ tumor cells with a CD8+ T-cell within 20 µm, and EpCAM+ cells had increased evidence of apoptosis when a CD8+ cell was nearby. When individual slices were imaged before and after combined PD-1 and CXCR4 blockade, a greater proportion of EpCAM+ cells were found to have a CD8+ cell nearby after treatment compared to before treatment, and the tumor cells with a CD8+ cell nearby were more like to be undergoing apoptosis compared to before treatment. Conclusion: Direct visualization of live pancreatic cancer slice cultures demonstrates that combined PD-1 and CXCR4 blockade enhances both the migration of CD8+ T-cells towards epithelial tumor cells and their anti-tumor cytotoxic activity. References: 1. Shibuya KC, Goel VK, Xiong W, Sham JG, Pollack SM, Leahy AM, et al. Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"2003 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87045217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A133: APOBEC3 confers resistance to oncolytic VSV therapy","authors":"Amanda L. Huff, Phonphimon Wongthida, T. Kottke, Jill Thompson, C. Driscoll, M. Schuelke, Kevin G. Shim, R. Harris, Amy M. Molan, J. Pulido, P. Selby, K. Harrington, A. Melcher, Laura Evgin, R. Vile","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A133","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A133","url":null,"abstract":"Tumor cells are able to evade cytotoxic therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor involved in the restriction of vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFNβ-dependent manner, which was responsible for the evolution of virus-resistanT-cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype. ShRNA knockdown of APOBEC3 in B16 cells diminished their capacity to develop resistance to VSV infection in vitro, and enhanced the therapeutic effect of VSV in vivo. Similarly, overexpression of human APOBEC3B promoted the acquisition of resistance to oncolytic VSV in murine melanoma and glioblastoma lines, as well as in a human melanoma cell line in vitro and in vivo. Finally, we demonstrate that progeny virus obtained after passage through APOBEC3B overexpressing cells contained more defective interfering particles, thereby indicating that APOBEC3B directly affected the fitness of VSV, an RNA virus that has not previously been identified to be restricted by APOBEC3B. This research identifies APOBEC3 enzymes as key players to target in order to improve the efficacy of oncolytic viruses as well as broader nucleic acid-based therapeutic platforms. Citation Format: Amanda L. Huff, Phonphimon Wongthida, Timothy Kottke, Jill Thompson, Christopher B. Driscoll, Matthew Schuelke, Kevin G. Shim, Reuben S. Harris, Amy Molan, Jose S. Pulido, Peter J. Selby, Kevin J. Harrington, Alan Melcher, Laura Evgin, Richard Vile. APOBEC3 confers resistance to oncolytic VSV 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 A133.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81212462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A127: Role of macrophage subsets in liver metastasis","authors":"Z. Deng, F. Geissmann","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A127","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A127","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal disease and frequently metastasize to the liver. The presence of macrophages (F4/80+ cells or CD68+ cells) is reported to correlate with tumor progression and metastasis in pancreatic cancer. Emerging evidence has revised the traditional concept of macrophage ontogeny and made it increasingly apparent that there exists functional diversity between resident macrophages originating from yolk sac erythro-myeloid progenitors (EMPs) and hematopoietic stem cells (HSCs)-derived macrophages. Sophisticated therapeutic intervention requires in-depth understanding of these macrophage subsets in the metastasis microenvironment. However, the role and heterogeneity of macrophages in tumor development, in particular in PDAC liver metastasis, remains poorly understood. Here, we utilized murine PDAC model to inidcate that Kupffer cells and tumor associated macrophages (TAMs) are two developmentally and functionally distinct subsets of macrophages. Removal of Kupffer cells by depletion of Id3 in macrophage progenitors or CSF1R blockade increases tumor burden. These findings reveal that Kupffer cells play a key role in restraining PDAC liver metastasis and show the necessity to understand macrophage origin when developing therapeutics for cancer treatment. Citation Format: Zihou Deng, Frederic Geissmann. Role of macrophage subsets in liver metastasis [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 A127.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"61 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90122318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A152: Investigating metabolic basis of neurotoxicity during CAR-T therapies","authors":"Darin Salloum, B. Santomasso, R. Brentjens, H. Wendel","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A152","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A152","url":null,"abstract":"Chimeric antigen receptor T (CAR-T) cell therapies are rapidly becoming first in line therapies for treatment of hematologic malignancies. This is due to the efficacy of the treatment and long-lasting tumor responses. However, CAR-T therapies are associated with unique set of acute toxicities— cytokine release syndrome (CRS) and neurologic toxicities—the cause of which is not clear. As other immune therapies are becoming more widely used, these toxicities are observed in patients undergoing bispecific T-cell engaging antibodies (BiTEs) and checkpoint blockade therapies. Here, we sought to define metabolic changes in patients undergoing chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia. We performed metabolic analysis of amino acids in serum samples, and identified significant up-regulation of tryptophan-kynurenine metabolism in patients with high-grade neurotoxicity. In-depth look at tryptophan-kynurenine pathway in cerebrospinal fluid patient samples determined quinolinic acid up-regulation to correlate with low- and high-grade neurotoxicity, indicating local production of this metabolite. We show that quinolinic acid is produced by activated monocytes and microglia in response to Il1beta and TNF. Importantly, tryptophan metabolite—kynurenine— stimulates Il1beta production and further activation of monocytes, possibly exacerbating CSR and neurotoxicity. This study suggests that inhibition of tryptophan-kynurenine pathway may offer some benefit to manage neurotoxicity and CRS associated with CAR-T-cell therapy treatment. Citation Format: Darin Salloum, Bianca Santomasso, Renier J. Brentjens, Hans-Guido Wendel. Investigating metabolic basis of neurotoxicity during CAR-T therapies [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 A152.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"229 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77222954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}