bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B127: NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders
Authors: Reuveni Hadas , Haviv Izhak , Kupershmidt Lana 
Published: February 2019

Abstract
Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor’s microenvironment, may therefore potentiate immune attack on the tumor. NT219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT219 efficacy was demonstrated in patient-derived tumor xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head and neck when added on to the approved therapies. In these models, NT219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, oxaliplatin). We recently demonstrated that NT219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of cetuximab. FACS analysis showed increased tumor infiltrated lymphocyte population following treatment with NT219 and the combination of NT219 and the immuno-oncology drug.The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs.
Citation Format: Hadas Reuveni, Izhak Haviv, Lana Kupershmidt. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [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 B127.
Abstract B130: Induced lymphangiogenesis enhances antigen-specific T-cell response in anticancer vaccination
Authors: Sasso Maria Stella , Hauert Sylvie , Briquez Priscilla , Wang Yue , Ishihara Jun , Hubbell Jeffrey A. , Swartz Melody A. 
Published: February 2019

Abstract
Tumor-associated lymphatic vessels play multiple and complex roles in the regulation of antitumor immunity. In both mouse and human melanomas, lymphatic markers correlate with increased tumor immune infiltrates and enhanced responsiveness to immunotherapy. Despite the immune-promoting functions of lymphatics in cancer immunotherapy, manipulation of lymphatic vessels directly within the tumor site appears controversial as a therapeutic strategy, due to the correlation of tumor lymphatic growth (lymphangiogenesis) with cancer cell dissemination and metastasis. Here, we sought to manipulate and exploit lymphatic vessels remotely from the tumor by developing and characterizing a lymphangiogenic cancer vaccine. Lymphangiogenic whole-cell vaccines were formulated using lethally irradiated tumor cells overexpressing the pro-lymphangiogenic growth factor VEGF-C in combination with topically retained immune adjuvants (VEGFC vax). In the B16F10 and B16F10-OVA mouse melanoma models, VEGFC vax induced extensive lymphatic growth at the cutaneous injection site, as assessed by both flow cytometry and histologic analysis. Induced lymphangiogenesis increased the rate of fluorescent microbead transport from the skin to the draining lymph nodes, suggesting an enhanced antigen trafficking. In addition, VEGF-C overexpression drove the recruitment in the vaccine injection site of naïve T-cells (responsive to lymphatic-derived CCL21), which could be primed in situ. Compared to a control VEGF-C-free vaccine formulation, VEGFC vax induced a broader T-cell response targeting multiple mouse melanoma antigens (including tumor neoantigens), as assessed by IFNγ ELISPOT following antigen-specific stimulation. In a prophylactic setting, VEGFC vax provided complete protection against B16F10 melanoma challenge, outperforming both the control vaccine and a GM-CSF-secreting whole-cell vaccine (GVAX). Overall this study provides a proof of concept for the use of VEGF-C as an immunostimulatory agent in cancer vaccines, based on its ability to activate and expand lymphatic vessels and consequently promote local immune cell trafficking, antigen transport and T-cell activation. In addition, we here developed and characterized a whole-cell VEGF-C vaccine formulation with potential for clinical translation.
Citation Format: Maria Stella Sasso, Sylvie Hauert, Priscilla Briquez, Yue Wang, Jun Ishihara, Jeffrey A. Hubbell, Melody A. Swartz. Induced lymphangiogenesis enhances antigen-specific T-cell response in anticancer vaccination [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 B130.
Abstract B135: Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells
Authors: Torigoe Toshihiko , Hirohashi Yoshihiko 
Published: February 2019

Abstract
Cancer stem-like cells (CSCs) are small subpopulation of cancer cells that contribute to cancer initiation and progression. These cells have a huge impact in the field of cancer therapy since they are resistant to standard chemoradiotherapy and responsible for disease recurrence. We have studied immunopathologic properties of CSCs derived from colon, breast, and gynecologic cancers to develop a novel CSC-targeted immunotherapy. #1 CSC-specific antigens: CSCs express several germ cell-specific genes. Remarkably, some of them were involved in tumor initiation capacity of CSCs and highly immunogenic since specific cytotoxic T-cells (CTLs) were efficiently induced from peripheral blood lymphocytes. The CTLs exerted specific cytotoxicity against CSCs. Adoptive transfer of the CSC-specific CTLs efficiently protected tumor growth in mouse models. #2 Fibroblastic niche of CSCs: Cancer-associated fibroblasts (CAFs) have important roles in tumor microenvironment. CSCs recruited fibroblasts, which enhanced tumor initiation capacity and immune resistance of CSCs. Gene expression analysis revealed that fibroblast growth factor 4 (FGF4) and FGFR2, a receptor for FGF4 were involved in the fibroblastic niche of CSCs. #3 Innate PD-L1 expression of CSCs: Some CSCs constitutively expressed PD-L1 on the cell surface through activation of PI3K/AKT signaling. Based on these unique properties of CSCs, we propose immunotherapeutic and immunoprophylactic strategy targeting CSCs.
Citation Format: Toshihiko Torigoe, Yoshihiko Hirohashi. Novel immunotherapeutic strategy based on the immunopathologic properties of cancer stem cells [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 B135.
Abstract B139: Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment
Authors: Wang Chuan , Wang Yidao , Allen Alex J. , Jobsri Jantipa , Thomas Gareth J. , Ottensmeier Christian H. , Savelyeva Natalia 
Published: February 2019

Abstract
In order to develop an effective vaccination strategy for cancer, it is necessary to induce robust T-cell responses and to overcome the immunosuppressive tumor microenvironment (TME). To induce anticancer immunity, we focused on a plant viral particle (PVP) that contains-single strand RNA (ssRNA) as a flexible and economical platform to deliver cancer antigens. Initially using PVP loaded with SIINFEKL, we demonstrated the induction of a rapid CD8 T-cell response leading to a significant therapeutic effect in the B16 tumor model. The induction of high levels of CD8 T-cells was also achieved when clinically relevant cancer antigens were used with lysis of human cancer cells expressing these antigens. Further, PVP loaded with whole protein antigen induced CD8 and CD4 T-cell responses against the epitopes delivered through the whole antigen and these cleared established tumors. The mechanisms behind the high immunogenicity of the PVP vaccine revealed that this ssRNA containing vaccine activated the immune mechanisms closely resembling the natural antiviral defence. In a murine model, the immune induction was through the activation of TLR7, leading to release of type I IFN by plasmacytoid dendritic cells and activation of conventional DCs (cDCs) followed with the priming of Th1 immunity. These findings were further supported by experiments using human monocytes derived DCs (moDCs) stimulated in vitro with PVP. The stimulated moDCs released Th1-polarizing cytokines and chemokines, and upregulated CD40 and B7 family surface molecules. Further investigation of the TME demonstrated that cDCs, MHC-II high tumor associated macrophages (TAMs) and tumor-infiltrating neutrophils were recruited into the tumor bed 24 hours after vaccination. While MHC-II low TAMs and myeloid-derived suppressor cells were down-regulated in response to vaccination. This was followed by the increase of tumor-infiltrating lymphocytes (TILs) specific for endogenous tumor antigens. In conclusion, the PVP vaccine is an effective platform to induce T-cells specific to the delivered cancer antigens, and furthermore benefit from its ability to convert an immunosuppressive TME towards an immunostimulatory environment, facilitating the endogenous T-cell epitopes spread.
Citation Format: Chuan Wang, Yidao Wang, Alex J. Allen, Jantipa Jobsri, Gareth J. Thomas, Christian H. Ottensmeier, Natalia Savelyeva. Plant viral particle vaccine induces a potent antitumor response through induction of antigen-specific T-cells and overcoming an immunosuppressive tumor microenvironment [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 B139.
Abstract B142: Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy
Authors: Yin Qian 
Published: February 2019

Abstract
While the human immune system is often able to protect the body from infectious pathogens, it has multiple mechanisms to inhibit mounting an immune system against what it perceives as “self” and thus often fails to eliminate cancer cells since they seem to have the characteristics of “self.” Our lab found that cytotoxic CD8+ T-cells that recognize self antigens in the peripheral blood of healthy humans were present in frequencies similar to those specific for non-self antigens, but these self-specific CD8+ T-cells are resistant to activation and/or expansion. We hypothesized that tumor-infiltrating CD8+ T-cells recognizing self antigens are often in an anergized state but they could be activated with the appropriate immunostimulatory signals to augment antitumor immunity. Thus, we developed a poly(lactide-co-glycolide) nanoparticle (PLGA NP) based immunostimulatory platform that is surface-functionalized with monoclonal anti-CD28 antibody (Ab), and encapsulated interleukin-2 (IL-2), toll-like receptor-2 (TLR2) agonist and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the hydrophobic core. This platform enables the encapsulated immunostimulatory drugs to be continuously released in the tumor microenvironment to activate the tumor infiltrating self-specific CD8+ T-cells in order to enhance antitumor immune response while minimizing the rapid diffusion of these drugs into other parts of the body, greatly reducing the systemic toxicities. Our results demonstrated that the mice bearing melanoma or colon cancers treated with the stimulatory PLGA NP have elicited potent T-cell response, resulting in marked tumor regression and increased overall survival. The developed PLGA NPs are also capable of generating an immunologic memory that prevented tumor growth after rechallenging the survivor mice with the same cancer cell type. Moreover, the developed PLGA NPs can be combined with checkpoint blocking antibodies to achieve the synergistic effect, significantly prolonging the overall survival. We also applied the single-cell TCR sequencing technique to assess both T-cell receptor and phenotypic characteristics of tumor-infiltrating CD8+ T-cells after NP stimulation. The result was further combined with yeast-display libraries of peptide-MHC to identify tumor-specific antigens.
Citation Format: Qian Yin. Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy [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 B142.
Abstract B145: Identification of tumor cell intrinsic immune evasion mechanisms
Authors: Reviriego Carmen Ballesteros , Speak Anneliese O. , Turner Gemma , Iyer Vivek , Parts Leopold , Adams David J. 
Published: February 2019

Abstract
The ability of cells of the immune system, in particular CD8+ cytotoxic T-cells and natural killer (NK) cells, to kill tumor cells in vivo is now being exploited in the clinic with the advent of immunotherapy. While these therapies are effective in a subset of patients the emergence of tumor resistance is now being observed in the clinic. Several studies have investigated tumour evasion from CD8+ cytotoxic T-cell directed killing; however, it is not known if the same mechanisms apply for the tumor cells to evade NK cells. For instance, one major pathway of CD8+ cytotoxic T-cell resistance is via alteration of the MHC class I antigen presentation pathway which could in theory allow the tumor cells to become more sensitive to NK cell mediated killing due to “loss of self.” We have investigated tumor cell intrinsic NK cell resistance and sensitivity pathways using genome-wide CRISPR-Cas9 loss of function in vitro screens. These screens have confirmed the essential role of cell adhesion via ICAM1 in enabling tumor cell killing by NK cells. We have also identified other novel pathways that could be manipulated to enhance tumor cell cytotoxicity and the development of alternative and/or additive therapeutic strategies in the clinic.
Citation Format: Carmen Ballesteros Reviriego, Anneliese O. Speak, Gemma Turner, Vivek Iyer, Leopold Parts, David J. Adams. Identification of tumor cell intrinsic immune evasion mechanisms [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 B145.
Abstract B167: Antigen-presenting cells as coordinators of T-cell responses to gut microbiota
Authors: Kedmi Ranit , Mesa Kai , Littman Dan 
Published: February 2019

Abstract
The immune system in the gut mucosa must balance tolerance to harmless diet and microbial antigens with the ability to mount effective inflammatory responses to diverse invasive pathogens. These requirements are reflected in the functions of distinct subsets of T-cells whose differentiation is guided by diverse cytokines secreted by antigen-presenting cells (APCs). In recent years, different APCs subsets have been proposed to guide CD4+ T-cell polarization and to induce primary T-cell responses in lymph nodes versus secondary responses in tissues. However, the exact roles of APC subsets in mediating T-cell responses to gut microbiota are still under debate and have not been thoroughly addressed. We previously showed that the commensal microbe segmented filamentous bacteria (SFB) induces antigen-specific Th17 cells, while Helicobacter hepaticus (Hh) induces an antigen-specific Treg response. Using those microbial models, I am now studying the contribution of APC subsets to specific T-cell response. I utilize several different approaches to track APC subsets that presents the relevant microbial peptides in the mesenteric lymph node and to characterize their contribution to T-cell priming and polarization. A better understanding of which APCs participate in the differentiation of each category of T-cell will enable in the future to develop better tools to educate T-cells to fight cancer.
Citation Format: Ranit Kedmi, Kai Mesa, Dan Littman. Antigen-presenting cells as coordinators of T-cell responses to gut microbiota [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 B167.
Abstract B169: Engineering phase separation of multivalent signaling proteins through the solubility of folded protein domains
Authors: Kim Jonggul , Ditlev Jonathon , Rosen Michael K. 
Published: February 2019

Abstract
Similar to three-dimensional membraneless organelles, it has been demonstrated that T-cell LAT signaling clusters form through multi-valency driven phase separation. This phase separated cluster was found to promote Arp2/3-complex driven actin assembly in vitro and correlated with increased ERK phosphorylation in cells. However, in this initial study, perturbations used to study phase separation also affect interactions known to be important for T-cell signaling, convoluting the impact of phase separation on signaling with effects due to changes in canonical biochemical interactions. To understand more precisely the role of phase separation in T-cell signaling, I will alter the solubility of folded domains through mutations of surface charged residues to modulate their phase separation propensities, independent of their high-affinity ligand binding interactions. To demonstrate the validity of this approach, I have first applied it to a synthetic system, based on multivalent interactions between the small ubiquitin-like modifier (SUMO) and the SUMO interaction motif (SIM), which will enable us to provide design principles that can be used on T-cell receptor signaling proteins. I demonstrate that it is possible to specifically alter the solubility of folded domains without altering their canonical molecular interactions. The solubility of individual folded domains serves as a predictor of the concentration threshold of phase separation, and phase separation can either be enhanced or abolished with a single mutation. Principles gained from this work on SUMO/SIM will be applied to multivalent proteins involved T-cell receptor signaling, namely Grb2 and Nck1, and the relationship between phase separation and signaling will be firmly established with future implications for rational engineering of T-cells.
Citation Format: Jonggul Kim, Jonathon Ditlev, Michael K. Rosen. Engineering phase separation of multivalent signaling proteins through the solubility of folded protein domains [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 B169.
Abstract B173: G protein coupling signaling as regulators of dendritic cell maintenance and function in immune responses
Authors: Liu Dan , Cyster Jason G. 
Published: February 2019

Abstract
Dendritic cells (DCs) are well known as the professional antigen presenT-cells (APCs), which can scan peripheral tissues where they can recognize, uptake, process and present all kinds of antigens, including pathogens and tumor antigens, to antigen specific naïve T-cells within the lymphoid organs. In these processes, DCs form a remarkable bridge between innate and adaptive immunity by interacting with various lymphoid and myeloid cells. DCs originate from the bone marrow hematopoietic progenitor cells and DC precursors migrate from blood to tissues for developing into immature DCs. Upon activation, DCs migrate to stimulate T-cells and induce immune responses to protect our bodies. However, the mechanism for maintenance and activation of DCs on the local microenvironment is largely unknown. As GPCR signaling has important roles in many cellular process, including cell division, survival, migration and adhesion. Using competitive mixed BM chimaera, I checked some molecules involved in GPCR signal pathways, and found that geneA was required intrinsically in the maintenance of CD4+ conventional DCs (cDCs) in the spleen, as evidenced by observation that geneA-deficient CD4+ DCs were dramatically decreased in spleen but increased in blood. By in vivo 3min CD45-PE labeling assay, cells exposed to the vascular compartment in spleen can be selectively labeled. With this method, I found without geneA, CD4+ DCs had disadvantage to be maintained in the blood-exposed region within the spleens under the shear flow stress. I further showed that geneA-deficient CD4+ DCs had disadvantage to uptake blood-derived Sheep-blood cells (SRBCs). Besides this stimulation, this signal also controlled CD4+ DCs activation in response to different kinds of TLR stimulators. By OT-II adoptive transfer system, geneA-expressing DCs were required to support T-cell proliferation and differentiation efficiently. Therefore, these results demonstrate a key role of G protein-coupled receptor signaling in promoting the maintenance and activation of DCs, and reveal a mechanism in DC positioning in vivo. Thus, it will broaden our understanding of GPCR signaling in DC immunology, which is pivotal for modulating DCs for vaccines and therapies against pathogens, autoimmune diseases and tumors.
Citation Format: Dan Liu, Jason G. Cyster. G protein coupling signaling as regulators of dendritic cell maintenance and function in 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 B173.