bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B95: PD-L1-mediated nanotherapeutic targeting of glioma-infiltrating myeloid cells synergizes with radiotherapy for glioblastoma
Authors: Zhang Peng , Miska Jason , Lee-Chang Catalina , Rashidi Aida , Panek Wojciech K. , An Shejuan , Zannikou Markella , Lopez-Rosas Aurora , Han Yu , Xiao Ting , Balyasnikova Irina V. , Lesniak Maciej S. 
Published: March 2020

Abstract
Massive infiltration of tumor-associated myeloid cells (TAMCs), reaching 30-50% of the tumor mass, is a distinctive characteristic of glioblastoma (GBM). These cells are a critical player in generating highly immunosuppressive microenvironment in GBM. Thus, therapeutic targeting of TAMCs might dampen the immunosuppression and improve the outcome of antiglioma therapies. In this work, we developed a novel nano-immunotherapy platform to actively and specifically target glioma-infiltrating TAMCs in vivo. Based on our finding that glioma-infiltrating TAMCs exhibit the highest expression of PD-L1 among all the immune cell infiltrates, we designed a lipid nanoparticle system (LNP) with surface-engineered anti-PD-L1 therapeutic antibody. Decoration of anti-PD-L1 antibody rendered our LNP highly capable of specifically targeting TAMCs and, interestingly, routing PD-L1 to lysosomal degradation. Co-encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into LNP caused a dramatic elimination of TAMCs and inhibition of immunosuppression in glioma. Notably, the targeting efficiency of TAMC-targeted LNP was further increased when combined with radiation therapy (RT), a standard care of GBM. The superior therapeutic efficacy in mice treated by RT+LNP combination over the RT or LNP monotherapy was demonstrated in two syngeneic murine glioma models, GL261 and CT2A. We also demonstrated that our LNP successfully targeted TAMCs harvested from human resection specimens, which further validated the translational potential and clinical relevance of our nano-immunotherapy approach. In conclusion, our work established a new nanotechnology-based immunotherapeutic approach with great potential to improve the clinical outcome in patients with GBM.
Citation Format: Peng Zhang, Jason Miska, Catalina Lee-Chang, Aida Rashidi, Wojciech K. Panek, Shejuan An, Markella Zannikou, Aurora Lopez-Rosas, Yu Han, Ting Xiao, Irina V. Balyasnikova, Maciej S. Lesniak. PD-L1-mediated nanotherapeutic targeting of glioma-infiltrating myeloid cells synergizes with radiotherapy for glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B95.
Abstract B96: Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients
Authors: Truxova Iva , Kasikova Lenka , Salek Cyril , Hensler Michal , Lysak Daniel , Holicek Peter , Bilkova Pavla , Holubova Monika , Chen Xiufen , Mikyskova Romana , Reinis Milan , Kovar Marek , Tomalova Barbora , Kline Justin , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka 
Published: March 2020

Abstract
In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns (DAMPs). Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin (CRT) on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). CRT exposure not only correlated with enhanced T cell-dependent antitumor immunity in this setting but also affected the number of circulating NK cells upon restoration of normal hematopoiesis. Here, we report that CRT exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of CRT to stimulate NK cells relies on CD11c+CD14high cells that, upon exposure to CRT, display higher levels of IL-15Rα, maturation markers (CD86 and HLA-DR), and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferons (IFNs). This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL-15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed CRT favors NK cell activation in AML patients.
Citation Format: Iva Truxova, Lenka Kasikova, Cyril Salek, Michal Hensler, Daniel Lysak, Peter Holicek, Pavla Bilkova, Monika Holubova, Xiufen Chen, Romana Mikyskova, Milan Reinis, Marek Kovar, Barbora Tomalova, Justin Kline, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B96.
Abstract B97: The immunomodulatory roles of tumor-associated lymphatics in triple-negative breast cancer
Authors: Hosseinchi Peyman , Potin Lambert , Mansurov Aslan , Maillat Léa , Hubbell Jeffrey A. , Swartz Melody A. 
Published: March 2020

Abstract
During cancer development, growth and remodeling of lymphatic vessels—termed lymphangiogenesis—is associated with increased metastasis rate. However, our group has recently shown that lymphangiogenesis can also increase tumor immune infiltration and subsequently enhance the responsiveness to immunotherapies in melanoma. However, the role of lymphangiogenesis in antitumor immunity in breast cancer remains unexplored. Moreover, despite the success of immunotherapies in different cancer types, their translation into the treatment of breast cancer has remained challenging. Here, we investigated the role of tumor lymphangiogenesis in immune cell infiltration and responsiveness to immunotherapy in a murine triple-negative breast tumor model. Spontaneously metastatic 4T1 tumor cells were transduced to overexpress the pro-lymphangiogenic growth factor VEGF-C to model tumor lymphangiogensis in vivo. We confirmed that VEGF-C overexpressing tumors were more lymphangiogenic than control ones, as assessed by flow cytometry and immunohistochemistry analyses. As previously reported, tumor VEGF-C signaling also increased the metastatic burden in the lungs. Crucially, lymphangiogenic tumors were infiltrated with increased levels of immune cells, including CD4 T cells and macrophages. Upon treatment with an agonist of the stimulator of interferon genes (STING) pathway, lymphangiogenic 4T1 tumors responded more favorably to the therapy compared to the control tumors, as indicated by a reduced tumor growth in the VEGF-C group. Furthermore, gene expression analysis of human triple-negative breast tumor samples from The Cancer Genome Atlas revealed positive correlations between VEGFC expression and CD4 T-cell and macrophage gene expressions. Taken together, these data suggest that in triple-negative breast cancer, similarly to melanoma, VEGF-C signaling is beneficial to the primary tumor microenvironment upon combination with proper immunotherapy despite promoting metastasis in untreated tumors.
Citation Format: Peyman Hosseinchi, Lambert Potin, Aslan Mansurov, Léa Maillat, Jeffrey A. Hubbell, Melody A. Swartz. The immunomodulatory roles of tumor-associated lymphatics in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B97.
Abstract IA07: Engineering natural killer cells for the treatment of cancer
Authors: Rezvani Katayoun 
Published: March 2020

Abstract
Natural killer (NK) cells play critical roles in host defense against cancer. Our group is exploring a number of avenues to enhance NK cell function against hematologic malignancies and solid tumors. These include novel strategies to expand off-the-shelf cord blood (CB)-derived NK cells based on their coculture with genetically modified feeder cells that express membrane-bound cytokines and costimulatory molecules. To redirect NK cell specificity and enhance their in vivo persistence, we have successfully transduced expanded CB NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15, and inducible caspase-9-based suicide gene (iC9). Data from a first-in-human phase I/II clinical study to test the safety and efficacy of escalating doses of off-the-shelf iC9/CAR.19/IL-15 CB-NK cells in patients with relapsed or refractory B-lymphoid malignancies will be presented.
Citation Format: Katayoun Rezvani. Engineering natural killer cells for the treatment of cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA07.
Abstract IA09: Checkpoint inhibitor-induced autoimmune diabetes and endocrine syndromes
Authors: Herold Kevan 
Published: March 2020

Abstract
Checkpoint inhibitor therapies have had dramatic effects on refractory malignancies but come at a price of autoimmune syndromes. The endocrine organs are frequently targeted. Autoimmune thyroid disease is common, but of particular clinical significance is the development of insulin-deficient diabetes. This talk will review the clinical and pathophysiologic data on this adverse event with consideration of ways in which it may be averted.
Citation Format: Kevan Herold. Checkpoint inhibitor-induced autoimmune diabetes and endocrine syndromes [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA09.
Abstract IA14: Molecular programs defining tumor-specific T-cell dysfunction and reprogrammability
Authors: Schietinger Andrea 
Published: March 2020

Abstract
Tumor-specific T cells in solid tumors are dysfunctional, allowing tumors to progress. The epigenetic regulation determining T-cell dysfunction and therapeutic reprogrammability is not well understood. We recently found that T-cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis: initially, T cells enter a plastic dysfunctional state from which they can be functionally rescued, but with time and continued tumor antigen encounter, they ultimately enter a fixed dysfunctional state that is resistant to reprogramming. We found that plasticity and imprinting of dysfunction is determined by epigenetic programs, and we identified surface markers associated with plastic and fixed chromatin states that demarcated reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T-cell populations. Moreover, we recently identified the nuclear factor Tox as a critical regulator of tumor-specific T-cell differentiation. New insights into the epigenetic and molecular programs underlying tumor-specific T-cell differentiation and dysfunction will be discussed.
Citation Format: Andrea Schietinger. Molecular programs defining tumor-specific T-cell dysfunction and reprogrammability [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA14.
Abstract IA15: Noninvasive imaging of immune responses
Authors: Rashidian Mohammad 
Published: March 2020

Abstract
Immunotherapy has revolutionized cancer treatment. Notwithstanding the encouraging results, responses remain heterogeneous among patients and some face serious side effects. Hence, techniques to noninvasively predict and monitor each patient’s response to immunotherapy are greatly needed. Because the success of immunotherapy hinges on its ability to promote an antitumor immune response, monitoring of the immune response after administration of therapy can be used to evaluate patient response. We have recently developed robust immuno-PET imaging methods to monitor dynamics of immune cells in the tumor microenvironment in real time. These methods have been successful in evaluating the response to immunotherapy in many mouse models of cancer. We will discuss these new advances and their potential to evaluate and predict an ongoing response to cancer treatments, with a focus on checkpoint blockade treatments.
Citation Format: Mohammad Rashidian. Noninvasive imaging of immune responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA15.
Abstract IA19: Myeloid cell control of tumor immunity
Authors: Merad Miriam 
Published: March 2020

Abstract
While the success of T-cell checkpoint-targeted immunotherapies is predicated on the induction of an effector T-cell response against tumor antigens by potent antigen-presenting cells (APC), very little is known about the APC composition in human tumors during immunotherapy. APC form a diverse population of dendritic cells (DCs) and macrophages (macs) that share the capacity to capture and present cell-associated antigens to T cells and instruct the repertoire and effector versus regulatory function of T lymphocytes. Despite the key role of APC in tumor immunotherapy, targeting the APC compartment has proved difficult. This is because little is known about the APC molecular changes during tumor response or resistance to immunotherapy. In order to develop ways to modulate tumor APC and promote cancer immunity, we sought to gain a deeper understanding of the molecular and functional diversity of APC in human NSCLC. Using paired mass cytometry analysis of tumor/adjacent tissues, we recently identified major changes in APC and T-cell composition in early non-small lung cancer (NSCLC) lesions (Lavin et al., Cell 2017). More recently, we used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to further measure APC defects in the tumor lesions. CITE-seq analysis of the tumor lesions revealed profound alterations in tumor APC composition including a reduction of cross-presenting DC at the expense of monocyte-derived cells, which correlated with the presence of dysfunctional T cells compared to the adjacent tissue. Accordingly, we found that DC composition and molecular state controlled CD8+ T-cell accumulation at the tumor site and controlled tumor response to checkpoint blockade in preclinical models. Here, I will discuss the strategies we have developed to enhance DC functionality at the tumor site and the challenges that remain.
Citation Format: Miriam Merad. Myeloid cell control of tumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA19.
Abstract IA21: Colorectal cancer and the microbiota
Authors: Garrett Wendy 
Published: March 2020

Abstract
Increasing scientific and clinical data support a role for the microbiota (the microorganisms associated with the human body) in influencing systemic and tumor microenvironment immunity, promoting tumor growth and spread, and altering the responsiveness and toxicity towards therapeutics. Herein, we discuss both human data from meta’omics analyses and data from mechanistic studies in cell culture and animal models that support that the microbiota influences colonic tumorigenesis.
Citation Format: Wendy Garrett. Colorectal cancer and the microbiota [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA21.
Abstract IA22: The unsuspected role of gut microbiota in cancer therapies: Antigen mimicry between intestinal phage and tumor antigens
Authors: Zitvogel Laurence 
Published: March 2020

Abstract
We recently highlighted the crucial role of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer. Chemotherapeutic agents facilitate the gut permeability and selective translocation of gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic TH17 T-cell responses are primed, facilitating the accumulation of TH1 helper T cells in tumor beds post-chemotherapy as well as tumor regression (Viaud, Science 2013). These findings have been extended to platinum salts as well as to a combination of anti-IL-10R mAb+CpG (Iida et al., Science 2013 Nov). The immune checkpoint blockers (ICB) anti-CTLA4 Ab and anti-PD1/PD-L1 Ab are first-in-class compounds approved for reinstating cancer immunosurveillance and prolonging survival in metastatic patients. Zitvogel’s group showed that antibiotics compromise the efficacy of these ICB in mice and patients and unveiled the immunomodulatory role of distinct commensals from the intestinal ecosystem in mobilizing anticancer immunosurveillance. Vétizou et al. showed that the antitumor effects of CTLA4 blockade, largely dependent upon Toll-like receptor (TLR)2/TLR4 receptors, markedly rely on the regulatory commensal Bacteroides fragilis (in coordination with Burkholderia cenocepacia; Science 2015 Nov). Next, the demonstration of the deleterious role of antibiotics in the clinical efficacy of PD-1 blockade in lung, kidney, and bladder cancer patients was brought up, highlighting the role of Akkermansia muciniphila as the main player in the immunomodulatory effects of pembrolizumab or nivolumab (Routy et al., Science 2017 Nov 2). The mechanisms by which distinct microbes restoring gut dysbiosis can mediate antitumor effects will be uncovered, including the demonstration of antigen mimicry between intestinal phages and tumor antigens. From these findings, we infer that oncomicrobiotics and/or fecal microbial transplantation could be considered as adjuvants to the current oncologic armamentarium in dysbiotic cancer bearers.
Citation Format: Laurence Zitvogel. The unsuspected role of gut microbiota in cancer therapies: Antigen mimicry between intestinal phage and tumor antigens [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA22.
Abstract IA24: T cells as a drug for the personalized immunotherapy of cancer
Authors: Rosenberg Steven 
Published: March 2020

Abstract
Adoptive cell transfer (ACT) immunotherapy using T lymphocytes with antitumor activity is a living therapy that can be highly effective in patients with a variety of metastatic cancers. Naturally occurring tumor-infiltrating lymphocytes (TIL) expanded in vitro and administered following a lymphodepleting preparative regimen mediated objective regression of metastatic melanoma in 56% of 194 patients, including complete regressions in 24% of patients who remain ongoing disease-free 3 to 10 years later. Recent studies have shown that TIL recognized random somatic mutations that served as the targets of treatment, resulting in complete cancer regressions. To extend ACT immunotherapy to additional patients, we developed an approach based on deep exomic sequencing and immunologic testing to generate T cells that recognized immunogenic mutations in a variety of human cancer types, including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian, and lung cancer. 81 of 99 patients with a variety of common epithelial cancers contained T cells that recognized the expressed products of 197 unique cancer mutations. Targeting these unique mutations opens the possibility of using ACT to treat patients with common epithelial cancers. In preliminary studies, we used this approach to treat a patient with metastatic cholangiocarcinoma using autologous mutation-reactive T cells and mediated durable regression of lung and liver metastases ongoing at five years. ACT using T cells that recognized the mutated KRAS oncogene product mediated objective regression of multiple lung metastases in a patient with metastatic colon cancer. Responses have also been seen in patients with metastatic cervical and breast cancer. In addition to the use of naturally occurring mutation-reactive cells, we have genetically engineered autologous lymphocytes to express antitumor T-cell receptors (TCR) or chimeric antigen receptors (CAR) for use in ACT immunotherapy. These cells can mediate durable cancer regressions in heavily pretreated patients with refractory lymphomas, sarcomas, and melanoma. Thus, autologous T cells can potentially be used to provide a highly personalized ACT immunotherapy for cancer patients refractory to conventional cancer treatments.
Citation Format: Steven Rosenberg. T cells as a drug for the personalized immunotherapy of cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA24.
Abstract IA25: Tumor-intrinsic drivers of response and resistance to checkpoint blockade in MRD tumors
Authors: Diaz Luis A. 
Published: March 2020

Abstract
Tumors with mismatch repair deficiency are highly sensitive to checkpoint blockade. We will examine the mechanism of this sensitivity and also discuss mechanisms of treatment failure in tumors with this genotype.
Citation Format: Luis A. Diaz. Tumor-intrinsic drivers of response and resistance to checkpoint blockade in MRD tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA25.