bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B02: Targeting CSK kinase activity to enhance antitumor immunity
Authors: Wang Cindy , Cao Carolyn , Berman-Booty Lisa , Eraslan Ruki , Sanjuan Miguel , Vite Gregory , Hunt Jack , Fink Brian , Wee Susan
Published: February 2019

To mount an effective tumor immune response, a T cell receptor (TCR) must first recognize a cognate antigen presented by the malignant cells. This antigen-TCR engagement at the cell surface initiates an intracellular signaling cascade that leads to the upregulation of pro-inflammatory and cytolytic cytokines. Successful effector T cell activation in turn results in the elimination of antigen-presenting diseased cells. A key regulator of this signaling cascade is the C-terminal Src (CSK) kinase. In lymphocytes CSK inhibits T cell activation by phosphorylating the SRC kinase family member LCK at tyrosine 505 and thereby terminates the signaling cascade. To assess whether relieving an intracellular blockade of TCR signaling will lead to a more robust T cell response, and hence improved tumor immunity, we developed both genetic and pharmacologic approaches to inhibit CSK activity. A tamoxifen-inducible transgenic CSK knock-out mice was engineered to bypass the embryonic lethality observed with constitutive systemic CSK depletion. As expected loss of CSK enhanced cytokine production and increased anti-tumor immune response in the MC38 syngeneic tumor mouse model. Potent and selective CSK small molecule inhibitors, in the presence of TCR stimulation, similarly activated the proximal TCR signaling pathway and increased cytokine production and proliferation. In an in vivo efficacy study, however, the CSK inhibitor as monotherapy or in combination with aPD1 did not improve anti-tumor immune response at the dose levels tested. This seemingly discrepant finding in tumor response observed in the tamoxifen-inducible KO mice and mice treated with the CSK inhibitor may reflect the need for further optimization in target coverage and dosing regimen. In this poster, we will present our findings on the role of CSK inhibition in tumor immunity.

Citation Format: Cindy Wang, Carolyn Cao, Lisa Berman-Booty, Ruki Eraslan, Miguel Sanjuan, Gregory Vite, Jack Hunt, Brian Fink, Susan Wee. Targeting CSK kinase activity to enhance antitumor immunity [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 B02.
Abstract B09: TLR1/2 ligand promotes Fc gamma RIV mediated depletion of tumor-infiltrating treg by anti-CTLA-4 antibody and its anti-tumor efficacy
Authors: Sharma Naveen , Allison James P.
Published: February 2019

Many cancer patients either do not respond or become resistant to immunotherapy with checkpoint inhibitors. To determine whether activating both the innate and adaptive immune pathways improve the tumor reduction and survival outcomes achieved with immunotherapy, we treated a mouse model of melanoma with intratumoral injections of TLR1/2 ligand plus intraperitoneal injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively, and its efficacy depended on CD4 T cells, CD8 T cells, Fc gamma receptor IV and macrophages. Interestingly, our results suggest a unique and novel mechanism by which TLR1/2 ligand enhances the anti-tumor efficacy of anti-CTLA-4 antibody by increasing Fc gamma receptor IV expression on macrophages and increasing the density of these macrophages in tumor, which in turn enhances the depletion of tumor-infiltrating regulatory T cells. This mechanism could be harnessed to modulate the clinical outcome of other antibody-based immunotherapies.

Citation Format: Naveen Sharma, James P. Allison. TLR1/2 ligand promotes Fc gamma RIV mediated depletion of tumor-infiltrating treg by anti-CTLA-4 antibody and its anti-tumor efficacy [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 B09.
Abstract B13: New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen
Authors: Tsuno Takaya , Kanno Shohei , Ryoichi Iwata , Tanigawa Noboru , Ueba Tetsuya
Published: February 2019

Purpose: Chemotherapy and radiation therapy (RT) are frequently selected for cancer treatment regimens, however they have limitations. Further regimens should be considered to overcome difficulties in cancer treatments. We have reported that interferon (IFN)-alpha induces in vitro cell death mediated by BH3-interacting domain death agonist (BID). However, low-dose pegyrated (PEG)-IFN-alpha, which suggests the possibilities of better adherence and fewer side effects, is clinically approved for treatment of hepatitis C, but not for that of any tumors. RT may also induce cell death. Here we assessed in vivo antitumor effects of pIRES-hBID (BID) transfection followed by low-dose PEG-IFN-alpha and RT (BID+IFN+RT).

Experimental Procedures: A549 human lung carcinoma cells are resistant to both IFN-alpha and RT. In the present study, BID and low-dose PEG-IFN-alpha were administered into nude mice bearing subcutaneous A549 xenografts. The mice were then irradiated with 3 Gy gamma ray. These treatments were performed once a week for 4 weeks.

Results: No body weight-loss was observed following any treatments. Immunohistochemistry demonstrated significantly less intranuclear localization of BID protein induced by BID alone and BID+IFN compared to mock alone and BID alone, respectively. These results suggest that each of BID and low-dose PEG-IFN-alpha affected BID translocation. Assessment of tumor volume indicated synergistic effects of growth inhibition induced by BID+IFN+RT. Electron microscopic examination of tumors on Day 56 demonstrated not only fragmented plasma membranes and nuclei but also cytoplasmic vesicles with degraded contents induced by BID+IFN+RT, indicating that low-dose PEG-IFN-alpha and RT following BID may induce both apoptotic and non-apoptotic cell death including autophagy and/or necrosis.

Conclusions: Even low-dose PEG-IFN-alpha likely had antitumor effects when combined with BID and RT, suggesting the possibility of new drug repositioning of PEG-IFN-alpha. Consequently, BID+IFN+RT may be a promising regimen for treating tumors that are resistant to both IFN-alpha and RT.

Citation Format: Takaya Tsuno, Shohei Kanno, Iwata Ryoichi, Noboru Tanigawa, Tetsuya Ueba. New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen [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 B13.
Abstract B33: Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry
Authors: Ziello Jennifer , Klein Sarah , Crosby Katherine
Published: February 2019

Antibody blockade of the PD-1/PD-L1 axis is approved for clinical use in multiple tumor types in an effort to block tumor immune evasion. The high number of emerging cancer immunotherapy agents indicates that there is an increased importance in assessing and understanding the immunosuppressive tumor microenvironment. In this study, we applied a 7-color multiplex immunohistochemistry panel to a lung tumor tissue microarray consisting of FFPE adenocarcinoma and squamous cell carcinoma cores. The panel was composed of immune checkpoint receptors PD-1 and TIM-3; PD-L1, a PD-1 ligand; CD68 and CD8, macrophage and cytotoxic T cell markers, respectively; as well as cytokeratin as the tumor mask and DAPI as the nuclear counterstain. The array included three cores per patient, and the concordance between fields was analyzed. Additionally, the frequency and co-localization of these markers and checkpoint proteins in the tumor and tumor microenvironment were quantified. TIM-3 expression was found not only on CD8+ T cells, but also on CD68+ macrophages, where it is thought to have a distinct function involved in phagocytosis of tumor cells. Furthermore, the significant role that macrophages play in tumor progression via promoting angiogenesis and inhibiting antitumor immunity makes these data increasingly relevant. These data demonstrate how antibody-based multiplex analysis in tissue can provide insight into the various cell types involved in tumor-mediated immune evasion. Multiplex IHC with highly specific antibodies will serve to improve our understanding of how immunotherapies can be used to affect the innate and adaptive branches of the immune system in the course of cancer treatment.

Citation Format: Jennifer Ziello, Sarah Klein, Katherine Crosby. Coexpression and frequency of immune checkpoint proteins in the tumor microenvironment analyzed via multiplex immunohistochemistry [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 B33.
Abstract B41: Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung cancer
Authors: Rayes Roni F. , Tinfow Alexandra , Antonatos Dorothy , Bourdeau France , Giannias Betty , Spicer Jonathan D.
Published: February 2019

Immunotherapy using checkpoint inhibitors has shown success in the treatment of late-stage non-small cell lung carcinomas (NSCLC). Indeed, nivolumab (anti-PD1 antibody) increased overall response by 9 % and overall survival by 3 months compared to chemotherapy (docetaxel). Combining Ipilimumab (anti-CTLA-4 antibody), another immune checkpoint inhibitor, with nivolumab was shown to improve response rates and survivals in NSCLC patients compared to nivolumab alone (phase 1/2 study). Despite these advances, there are still many patients that are non-responsive to available immunotherapies. We hypothesize that the immune system can overtake the inhibition of immune suppression via other mechanisms leading to a more immune suppressive tumor microenvironment. Neutrophils, being amongst the first cells of our innate immune system to be recruited to the tumor microenvironment, are key players in modulating other immune cells. Indeed, we and others have demonstrated that neutrophils play a critical role during cancer progression and from a clinical standpoint elevated neutrophil counts both in circulation and within growing lesions have been associated with poor oncologic outcomes. Therefore, neutrophil could well be the immunosuppressive switch in the tumor microenvironment. To test our hypothesis, we injected liver metastatic lung carcinoma cells into mice treated with daily injection of neutrophil elastase inhibitor (NEi, Sivelestat) and into untreated (control) mice. We then collected the livers of those mice at multiple time points post-tumor inoculation and analyzed the immune profile of these mice. As expected, NEi-treated mice had significantly less liver metastases than control mice (p < 0.05) indicating that neutrophils play a pro-tumor role in cancer progression. Furthermore, NEi-treated mice had a significant decrease in the number of tumor infiltrating granulocytes (GR1+ cells, p <0.05) and tumor associated neutrophils (TANs, Ly6G-1A8 + cells) (p<0.0005). This significant decrease in TANs correlated with a significant decrease in CD3+ T-cells (p<0.05) in NEi-treated mice compared to control mice 1-week post-tumor injection. The number of tumor associated macrophages (F4/80+ cells) was the same in both groups (p=0.65) and thus not affected by the significant decrease in TANs. These findings show that neutrophils play a role in T-cell recruitment in liver metastases of lung cancer cells and thus neutrophil can be an important target for new immunotherapies.

Citation Format: Roni F. Rayes, Alexandra Tinfow, Dorothy Antonatos, France Bourdeau, Betty Giannias, Jonathan D. Spicer. Neutrophils modulate T-cell recruitment and promote hepatic metastases in lung cancer [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 B41.
Abstract B68: Targeted inhibition of Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts, suppresses Stat3 activation in pancreatic cancer cells and reverses immunosuppression
Authors: Huang Huocong , Hagopian Moriah , Du Wenting , Zhang Yuqing , Driscoll Kyla E. , Brekken Rolf A.
Published: February 2019

Pancreatic cancer is characterized by dense stroma consisting of myofibroblasts, abundant extracellular matrix (ECM) and inflammatory/immune cells. Elevated levels of transforming growth factor β (TGFβ), a prominent driver of stromal accumulation, is a negative prognostic indicator for pancreatic cancer patients. However, inhibition of TGFβ has been challenging due to the context-dependent tumor suppressor function of TGFβ in pancreatic cancer. We reported previously that neutralizing the activity of murine TGFβ receptor 2 (Tgfβr2) using a monoclonal antibody (2G8), has potent antitumor activity in orthotopic human pancreatic tumor xenografts. The findings in xenografts highlight that TGFβ induction of stromal cell function is critical for its impact on tumor cell behavior and PDA progression and supports that inhibition of TGFβ-dependent effector functions on stromal cells has potential efficacy in PDA. Herein we demonstrate that inhibition of murine Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts (CAFs), resulting in a reduction of Stat3 activation in tumor cells and reversion of the immunosuppressive landscape of murine models of PDA. Moreover, the reduction of stromal IL-6 results in activation of NK cells. In summary, we found TGFβ induced IL-6 secretion from CAFs in PDA contributes to tumorigenesis and immunosuppression and can be abrogated by inhibition of stromal Tgfβr2.

Citation Format: Huocong Huang, Moriah Hagopian, Wenting Du, Yuqing Zhang, Kyla E. Driscoll, Rolf A. Brekken. Targeted inhibition of Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts, suppresses Stat3 activation in pancreatic cancer cells and reverses immunosuppression [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 B68.
Abstract B75: Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses
Authors: Caronni Nicoletta , Simoncello Francesca , Cervantes-Luevano Karla , Collavin Licio , Benvenuti Federica
Published: February 2019

Recent studies highlighted the essential role of tissue-resident dendritic cells (DCs) for T cells priming and immune checkpoint therapy, however the mechanism leading to DCs suppression during tumor growth are still poorly understood. Here we have isolated CD103 (DC1) and Cd11b (DC2) from orthotopic Kras/Trp53 adenocarcinomas to study their function and gene expression profiles. At early stages of tumor progression (day 14-21) DC1 effectively cross-presented tumor antigens acquired in vivo and this was paralleled by the presence of IFN-γ; secreting tumor specific CD8+ T cells in the lung. Starting from day 28 post tumor inoculation, despite minor changes in tumor burden, DC1 were no longer able to cross present tumor associated antigens and CD8+ T cell responses were concomitantly shut-off. DC1 isolated from tumor bearing lungs and fed with antigen ex-vivo confirmed a selective loss in cross-presentation. In parallel, DC2 skewed their cytokine profile and acquired a Th17 promoting phenotype mediated by high production of IL-23. In order to identify factors causing the sudden loss in DC1 activity we analyzed gene expression profiles in total lung tissues. At day 21 we observed a peak in T cell attracting chemokines together with expression of inhibitory pathways. This signature was dramatically modified at day 28, with a decrease in T cell associated genes and an increase in neutrophils related transcripts. Gene expression profiles in de-activated DC1 showed modulation of transcripts related to innate activation and antigen processing. In summary, this study identifies a narrow temporal window during which tissue resident DCs lose the ability to cross-present tumor associated antigens. Loss of DC1 function is accompanied by cell-intrinsic changes in gene expression, cell extrinsic changes in the tumor microenvironment and loss of activity in endogenous CD8+ T antitumor responses.

Citation Format: Nicoletta Caronni, Francesca Simoncello, Karla Cervantes-Luevano, Licio Collavin, Federica Benvenuti. Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses [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 B75.
Abstract B77: Low-density neutrophils (LDN) in circulating blood of postoperative patients may participate in the development of distant recurrence through the production of neutrophil extracellular traps (NETs)
Authors: Kumagai Yuko , Kanamaru Rihito , Ohzawa Hideyuki , Horie Hisanaga , Hosoya Yoshinori , Sata Naohiro , Kitayama Joji
Published: February 2019

Background: Low density neutrophils (LDN) which are co-purified with mononuclear cells by Ficoll-Hypaque density gradient preparations, have been reported to be increased in circulating blood in patients with autoimmune diseases, sepsis and cancer. Recent studies have suggested the LDN contributes to lupus pathogenesis as well as the development of organ damage in sepsis.

Method: In patients who underwent curative surgery for gastrointestinal malignancy, peripheral blood was obtained at the timing of laparotomy (preoperative) and just before wound closure (postoperative) and the ratios of LDN were evaluated with flowcytometry. The LDN and mononuclear cells (MNC) in postoperative samples were separated using CD66b microbeads and MACS column and the proliferation of T cells were evaluated by in vitro culture on anti-CD3 coated plate using CFSE dilution method. The LDN were cultured for 2 hours and neutrophil extracellular traps (NETs) were observed with the addition of SYTOX green, dye for extracellular double strand (ds)-DNA. In adhesion experiments, human colon cancer, DLD-1, were stained by PKH-26 and added on the cultured LDN for 5 min. After gentle washing, the remaining cells were counted under fluorescein microscope.

Results: 1. Ratios of CD66b(+) LDG in CD45(+) leukocytes were markedly increased in postoperative as compared with preoperative blood samples. 2. Division of CD3(+) T cells were significantly suppressed by the addition autologous CD66b(+) LDN. 3. Short term culture of the LDN produced massive thread-like structures stained with SYTOX green. Immunostaining with specific mAbs revealed that histone and myeloperoxidase (MPO) were colocalized on the fibrous structure, indicating NETs 3. DLD-1, selectively attached to the NETs, which was totally abrogated by the pretreatment with 100u/ml DNAse.

Conclusion: During abdominal surgery, immunosuppressive LDN are markedly increased in circulating blood. The LDN extensively produces NETs which support the metastasis formation by trapping the circulating tumor cells in target organ. Functional blockade of the LDN might effectively reduce the recurrence rate after curative surgery.

Citation Format: Yuko Kumagai, Rihito Kanamaru, Hideyuki Ohzawa, Hisanaga Horie, Yoshinori Hosoya, Naohiro Sata, Joji Kitayama. Low-density neutrophils (LDN) in circulating blood of postoperative patients may participate in the development of distant recurrence through the production of neutrophil extracellular traps (NETs) [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 B77.
Abstract IA05: Imaging- and single cell- based insights into the antitumor immune responses
Authors: Mujal Adriana , Barry Kevin , Roberts Edward , Binnewies Mikhail , Ruhland Megan , Chan Vincent , Krummel Matthew Frederick
Published: February 2019

The immune response to tumors is malleable as we have learned from the various success of immunotherapies across a diversity of tumor types. What are the foundations for a solid immune response, particularly one executed by T cells? Imaging and single-cell approaches provide key insights into immune cell types that can be unleashed on tumors, identifying both their identity and the immune interactions that are to be fostered. We discuss a few of these with particular emphasis on the diversity of the myeloid system and how its component parts can contribute toward antitumor immunity.

Citation Format: Adriana Mujal, Kevin Barry, Edward Roberts, Mikhail Binnewies, Megan Ruhland, Vincent Chan, Matthew Frederick Krummel. Imaging- and single cell- based insights into the antitumor immune responses [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 IA05.
Abstract IA08: Engineering T cells to resist and convert immunosuppressive tumor microenvironments
Authors: Chang ZeNan L. , Lorenzini Michael H. , Chen Yvonne Y.
Published: February 2019

A major challenge in adoptive T-cell therapy for solid tumors is the harsh immunosuppressive tumor microenvironment. Soluble factors such as transforming growth factor beta (TGF-β) play key roles in tumor immune evasion. Here, we report methods by which CARs can be engineered to respond to soluble antigens, and describe a novel TGF-β binding chimeric antigen receptor that rewires the T-cell response to TGF-β, converting this potent immunosuppressive molecule into a stimulant. We additionally elucidate mechanistic details of how CARs can be triggered by soluble ligands, as well as methods by which the signaling strength and ligand sensitivity of such CARs can be tuned. Given the modular nature of the engineered receptor, this work informs future efforts to redirect T-cell responses to extracellular soluble molecules.

Citation Format: ZeNan L. Chang, Michael H. Lorenzini, Yvonne Y. Chen. Engineering T cells to resist and convert immunosuppressive tumor microenvironments [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 IA08.
Abstract IA16: Macrophages orchestrate early dissemination and metastasis
Authors: Linde Nina , Casanova-Acebes Maria , Sosa Maria Soledad , Mortha Arthur , Rahman Adeeb , Farias Eduardo F. , Harper Kathryn , Tardio Ethan , Reyes-Torres Ivan , Jones Joan G. , Condeelis John S. , Merad Miriam , Aguirre-Ghiso Julio A.
Published: February 2019

Cancer cell dissemination can occur during very early stages of breast cancer, but the mechanisms controlling this process are unclear. Here we show that a previously reported early MMTV-HER2+/P-p38lo/TWISThi/E-cadherinlo cancer cell subpopulation depends on macrophages for early dissemination. Depletion of macrophages before overt tumor detection drastically reduced early dissemination and diminished the late metastatic burden. CD206+/Tie2+ macrophages were attracted into early lesions in part by CCL2 produced by early HER2+ cancer cells and myeloid cells. Upregulation of Wnt-1 by macrophages could be stimulated by CCL2 and correlated with loss of E-cadherin in HER2+ early cancer cells. Both MMTV-PyMT and MMTV-HER2 early lesions showed macrophage-containing tumor microenvironments of metastasis (TMEM) structures, and PyMT early cancer cells also showed a reduction in early lesion E-cadherin junctions. Intraepithelial macrophages and loss of E-cadherin junctions was also found more frequently in high-grade human DCIS than in low-grade and normal breast tissue, but no association was found with HER2 status. We reveal a previously unrecognized mechanism by which macrophages play a causal role in early dissemination, impacting long-term metastasis development.

Citation Format: Nina Linde, Maria Casanova-Acebes, Maria Soledad Sosa, Arthur Mortha, Adeeb Rahman, Eduardo F. Farias, Kathryn Harper, Ethan Tardio, Ivan Reyes-Torres, Joan G. Jones, John S. Condeelis, Miriam Merad, Julio A. Aguirre-Ghiso. Macrophages orchestrate early dissemination and metastasis [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 IA16.
Abstract IA32: Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination
Authors: Brody Joshua D.
Published: February 2019

Checkpoint blockade therapy of cancer has had tremendous impact; still, only a subset of patients experience remissions. One hypothesis is that resistant tumors lack sufficient somatic mutational burden and thus, targetable tumor-associated antigens (TAA). To the contrary, we described that Hodgkin’s lymphoma, despite a high anti-PD1 response rate (~65-87%), has significantly fewer mutations (Reichel et al., Blood 2015) than highly mutated tumors, such as lung cancer (anti-PD1 response rate ~20%). Recent, seminal work confirms that the presence of dendritic cells (DC) capable of cross-presenting TAA correlates with tumor immunogenicity (Spranger et al., Proc Natl Acad Sci USA 2016). Our hypothesis is that checkpoint blockade is limited by the tolerogenic microenvironment, specifically, suboptimal cross-presentation of TAA by suitably activated dendritic cells (DC). If so, then checkpoint blockade will be potentiated by optimal recruitment, loading, and activation of cross-presenting DC at the tumor site. We and others have recently found that tumors—including lymphomas—evade immune clearance by active exclusion of DC. Despite progress in mechanistic understanding of this immune evasion, we still lack means to modulate the phenomenon and facilitate T-cell entry and destruction of tumors.

We developed an early-phase trial (funded by Damon Runyon CRF) testing a unique, rationally designed in situ vaccine (ISV) comprising 1) Flt3L to recruit DC, 2) radiotherapy (XRT) to load Flt3L-mobilized DC with TAA, and 3) Toll-like receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. Strikingly, we observed partial and complete systemic tumor regressions, including distant and untreated tumors, improving months after therapy, and even elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic antitumor immune response. The trial is based on our preclinical dat,a which recapitulate the clinical findings and also show that the ISV cure rate (~40%) increases markedly by combination with PD1 blockade (80-90%). These data prompted a new trial combining ISV with PD1 blockade opening in 2018.

Though PD1/PDL1 blockade is potentiated by in situ vaccination, it is possible that there may be other, even more effective checkpoints for combination. We have developed two separate, complementary screening approaches using a novel EGFP-specific, murine CD8 T cell to enrich or probe for novel tumor-expressed (“PD-L1-like”) checkpoint molecules and have identified candidates for validation. Ultimately, the screening can be performed in vivo in the context of various immunotherapies, including in situ vaccination, stem cell transplantation, or PD-1 blockade.

Citation Format: Joshua D. Brody. Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination [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 IA32.
Functionality and Cell Senescence of CD4/ CD8-Selected CD20 CAR T Cells Manufactured Using the Automated CliniMACS Prodigy® Platform
Authors: Aleksandrova Krasimira , Leise Jana , Priesner Christoph , Melk Anette , Kubaink Fanni , Abken Hinrich , Hombach Andreas , Aktas Murat , Essl Mike , Bürger Iris , Kaiser Andrew , Rauser Georg , Jurk Marion , Goudeva Lilia , Glienke Wolfgang , Arseniev Lubomir , Esser Ruth , Köhl Ulrike
Published: February 2019

Clinical studies using autologous CAR T cells have achieved spectacular remissions in refractory CD19+ B cell leukaemia, however some of the patient treatments with CAR T cells failed. Beside the heterogeneity of leukaemia, the distribution and senescence of the autologous cells from heavily pretreated patients might be further reasons for this. We performed six consecutive large-scale manufacturing processes for CD20 CAR T cells from healthy donor leukapheresis using the automated CliniMACS Prodigy® platform. Starting with a CD4/CD8-positive selection, a high purity of a median of 97% T cells with a median 65-fold cell expansion was achieved. Interestingly, the transduction rate was significantly higher for CD4+ compared to CD8+ T cells and reached in a median of 23%. CD20 CAR T cells showed a good specific IFN-γ secretion after cocultivation with CD20+ target cells which correlated with good cytotoxic activity. Most importantly, 3 out of 5 CAR T cell products showed an increase in telomere length during the manufacturing process, while telomere length remained consistent in one and decreased in another process. In conclusion, this shows for the first time that beside heterogeneity among healthy donors, CAR T cell products also differ regarding cell senescence, even for cells manufactured in a standardised automated process.
Emulsion of Olive Oil and Calcium Hydroxide for the Prevention of Radiation Dermatitis in Hypofractionation Post-Mastectomy Radiotherapy: A Randomized Controlled Trial
Authors: Chitapanarux Imjai , Tovanabutra Napatra , Chiewchanvit Siri , Sripan Patumrat , Chumachote Ausareeya , Nobnop Wannapha , Tippanya Damrongsak , Khamchompoo Darat
Published: February 2019

Background: Most of the patients who have been treated by post-mastectomy radiotherapy (PMRT) experience skin toxicity. There have been few studies on acute radiation dermatitis in breast cancer patients who received hypofractionation PMRT. Methods: 62 patients were randomized to receive a general skin care regimen with or without the addition of an emulsion of olive oil and calcium hydroxide twice a day, from the initiation of PMRT to 2 weeks after radiotherapy. Adverse skin reactions and the Skindex-16 score were assessed. Results: At the 8th, 13th, and 16th fraction of PMRT, grade 1 dermatitis was found in 42, 90, and 90% of the control group and in 16, 30, and 71% of the intervention group. At the end of the study, the mean Skindex-16 score of the intervention group was significantly better than that of the control group (p = 0.019). Conclusions: Addition of an emulsion of olive oil and calcium hydroxide for patients undergoing hypofractionation PMRT yielded superior preventive results over a general skin care regimen alone, in terms of delaying skin toxicity, reducing the severity of acute radiation dermatitis, and a better quality of life in the intervention group. However, a larger number of patients will be required to confirm this result.
Profile of Syrian Asylum-Seekers from Neurological Clinic in a Tertiary Center
Authors: Senadim Songul , Uygun Ersin , Erdogan Mucahid , Koksal Ayhan , Soysal Aysun , Atakli Dilek
Published: February 2019

Background: The humanitarian response for Syria has been largely managed either from within Syria or from neighboring countries, particularly Turkey. This study was aimed at determining the sociodemographic and clinical profiles of Syrian asylum-seekers admitted to our clinic, changes in patient number across years, and the percentage of patients on follow-ups. Methods: Syrian patients who were admitted to the neurology outpatient clinics, neurology emergency department (ED), and hospitalized in the neurology clinics were included in the study. Age, gender, number of admissions, year of admissions, chief complaints, diagnoses, and follow-up percentages of patients were recorded. Results: The total number of Syrian patients who were first admitted to our hospital and consulted from other clinics, were found to be 763 (ED: 609 [79.8%], outpatient: 134 [17.6%] consultation: 20 [2.6%]). A total of 543 (96.1%) of the patients with a neurological disorder did not come to the follow-ups even though their conditions required regular follow-ups. The most common complaints were headache (24.2%), fainting (16.1%), weakness (11.9%), and dizziness (10%). Conclusion: Most of the patients admitted to our hospital did not come to the follow-ups and information regarding their treatments could not be obtained. Even though the Republic of Turkey provided the Syrian asylum-seekers with free medical care, utilization of these resources may be limited because of socioeconomic issues.
Insulin Resistance Index and Proatherogenic Lipid Indices in the Offspring of People with Diabetes
Authors: Sonuga Oyebola Oluwagbemiga , Abbiyesuku Fayeofori Mpakaboari , Adedapo Kayode Samson , Sonuga Ayobola Abimbola
Published: February 2019

Background: Diabetes mellitus and cardiovascular diseases significantly contribute to medical morbidity and mortality worldwide, especially in developing countries like Nigeria. Insulin resistance, a characteristic finding of type 2 diabetics and their offspring, is associated with an abnormal lipid metabolism and cardiovascular disease. Aims: This study therefore aims to determine the pattern of lipid biomarkers of atherogenesis and their relationship with insulin resistance index in young people with a family history of diabetes mellitus. Methods: This is a cross-sectional study carried out among 150 apparently healthy young adults between 18 and 25 years of age, including 76 with a family history of diabetes mellitus in first- and/or second-degree relatives (YWFH) and 74 with no family history of diabetes mellitus (YWoFH). Anthropometric characteristics, insulin resistance index, plasma glucose, fasting lipid profile (plasma total cholesterol, triglycerides [TG], high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), and serum levels of insulin, lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1), and ApoB/ApoA-1 ratios were compared in the 2 groups. Plasma glucose, total cholesterol, high-density cholesterol, and TG were measured using standard methods. The Friedewald equation was used to calculate low-density cholesterol. Serum insulin, Lp(a) levels, ApoB, and ApoA-1 were also measured using standard assays. The insulin resistance index was determined using homeostatic model assessment (HOMA). Statistical analysis was performed using SPSS version 20.0. Comparisons between variables were performed using the Mann-Whitney U test, and correlations between variables were performed using Spearman rank correlation coefficients. The level of significance was set at p < 0.05. Results: Offspring of diabetics (YWFH) had a significantly higher median BMI (p = 0.015), waist-to-hip ratio (WHR; p = 0.002), insulin resistance index (p = 0.038), total cholesterol (p = 0.017), TG (p = 0.004), Lp(a) (p = 0.045), ApoB (p = 0.002), and ApoB/ApoA-1 ratio (p = 0.001) than the age-matched control group with no family history of diabetes mellitus (YWoFH). There was no correlation between the insulin resistance index and each of the lipid biomarkers of atherogenesis except Lp(a), with which it was negatively correlated. Conclusion: This study demonstrates that a positive family history of type 2 diabetes mellitus is associated with a higher insulin resistance index and elevated atherogenic lipid indices; thus, a positive family history of diabetes mellitus in first or second-degree relatives when the index person is not diabetic confirms a significant cardiovascular risk.
Avaliação da incidência da SOP por clínica e ultrassonografia, em residentes na cidade de Paracatu - MG
Authors: Santos Lethícia Silva , Garcia Anna Luisa Oliveira , Souza Guilherme Alves , Benevides Jéssica Gonçalves , Faria Talitha Araújo
Published: February 2019

A síndrome do ovário policístico é um distúrbio endócrino, causado pela presença de microcistos produtores de hormônio nos ovários, que afeta de 4 a 13% das mulheres em idade reprodutiva. O hiperandrogenismo e a anovulação crônica estão presentes em praticamente todas as pacientes, sendo fatores essenciais para o fechamento do diagnóstico da SOP. A causa específica da síndrome é desconhecida, porém sabe-se que possui relação direta com a síndrome metabólica. O tratamento da SOP, envolve fármacos sensibilizadores de insulina, reguladores de hormônios femininos, e principalmente mudança de hábitos de vida. Assim, o presente trabalho objetivou avaliar a incidência de SOP por meio de clínica e ultrassonografia. Foi utilizado o método de coorte, onde os dados sobre a incidência da síndrome do ovário policístico foram levantados, em demanda examinada na cidade de Paracatu - MG, nos anos de 2009 ao primeiro semestre de 2016. Os casos de alterações em volumes uterinos e ovarianos foram maiores em adolescentes. A SOP, foi encontrada principalmente na faixa etária de 20 a 29 anos, o tipo de exame mais realizado nas pacientes foi o transvaginal. Identificou-se que as formações císticas mais comuns foram ovários com pequenos folículos esparsos na periferia e apenas 30 pacientes dentre as analisadas tiveram comorbidades associadas. Verificou-se que a SOP é mais presente na vida das adolescentes, porém o diagnóstico, na maioria, é tardio, o que favorece o não tratamento e pior qualidade de vidas às portadoras.
Yellow Fever
Authors: Ribeiro Junior Marcelo Augusto Fontanelle , Rodrigues Vinicius Cunha , Feng Celia Ya Dan , Nguyen Alexander Trong Minh , Bechara Giovana El Khouri , Moura Raíssa Reis de
Published: February 2019

Since January 2017, there have been at least 1563 suspected cases of Yellow Fever, 629 confirmed cases and 232 confirmed deaths. Yellow fever is a viral hemorrhagic disease endemic to the tropical parts of Africa and South America. At the present time, it has presented a significant increase in its incidence in Brazil, with important repercussions and impacts on the public health. This review paper outlines the causes of yellow fever, as well as the disease epidemiology, progression, diagnosis, treatment and prevention. We conclude by reporting on the current epidemic in Brazil and future directions for research. Method: Data from Pubmed, SciELO, Medline and government sources concerning Yellow Fever were used, dating from 2002 to 2018. In the collection of the data the following descriptors were used: Yellow-fever, Aedes, Arbovirus and Flavivirus.
Drenagem biliar pré operatória no câncer de cabeça de pâncreas
Authors: Santos Bruno Campos , Araujo Florence Costa Faria de , Sanches Marcelo Dias
Published: February 2019

Drenagem biliar pré-operatória (DBPO) é método utilizado com o objetivo de reduzir consequências da colestase em pacientes com neoplasias obstrutivas peri-ampulares (cabeça de pâncreas, colédoco distal, papila duodenal ou duodeno). Entretanto, sua indicação é controversa na literatura. Relata-se caso onde houve discordância entre definição terapêutica pelo médico assistente e a equipe cirúrgica, seguida de revisão da literatura disponível em busca de definição da melhor indicação de DBPO versus cirurgia precoce em tumores ressecáveis na cabeça do pâncreas. A pesquisa abrangeu artigos a partir de 1935, quando Whipple descreveu os benefícios teóricos da DBPO em relação à cirurgia definitiva direta. Diversos estudos não-randomizados, randomizados, multicêntricos, meta-análises e revisões foram avaliadas nas principais plataformas de pesquisa na presente revisão. Os resultados são variados e não permitem definição inequívoca. Os trabalhos com nível de evidência mais elevados são as revisões sistemáticas publicados pela Cochrane que sugerem a falta de evidências a favor ou contra o uso de DBPO na rotina. A maioria dos estudos sugere que a drenagem se relacione com maior taxa de complicações pós-operatórias. Drenagem biliar percutânea trans-hepática (DBPT) foi comparada à colangiopancreatografia endoscópica retrógrada (CPER) e não foram encontradas diferenças quanto aos custos, duração da hospitalização ou desfechos. Conclui-se que drenagem biliar pré-operatória deve ser evitada sempre que a ressecção definitiva estiver disponível dentro de até 7 dias, em centro de referência. A prática pode trazer benefícios em casos de colangite, instabilidade pré-operatória ou indisponibilidade de leito em centro especializado para realização de procedimento precocemente.
Risk of Stroke in Patients With Ocular Arterial Occlusive Disorders: A Retrospective Canadian Study
Authors: Avery Michael B. , Magal Itay , Kherani Amin , Mitha Alim P.
Published: February 2019

Background

Monocular vision loss, attributed to either central retinal artery occlusion (
CRAO
), branch retinal artery occlusion (
BRAO
), or ocular ischemic syndrome (
OIS
), is thought to be associated with an increased prevalence of cerebral infarcts. However, there is a paucity of data substantiating this. We aimed to investigate this relationship in a Canadian center and further understand the importance of associated internal carotid artery stenosis in potential clinical decision making.

Methods and Results

We performed a retrospective cohort study at a comprehensive stroke center of patients presenting initially with
CRAO
,
BRAO
, or
OIS
to a centralized ophthalmology center over a 5‐year period. Patients were followed for 3 years for the occurrence of a hemispheric stroke. We identified 83 affected eyes, with 31
CRAO
, 35
BRAO
, and 17
OIS
patients. Before ocular diagnosis, 32.3%, 11.4%, and 41.2% of
CRAO
,
BRAO
, and
OIS
patients, respectively, experienced a symptomatic stroke. Of the remaining patients, 4.8%, 12.9%, and 40%, respectively, suffered a hemispheric stroke within 3 years of ocular diagnosis. Logistic regressions suggested that for
CRAO
and
BRAO
patients together, the degree of ipsilateral internal carotid artery stenosis is unable to predict the occurrence of a stroke (
P
=0.18), whereas our model correctly predicted a stroke in 82.4% of
OIS
patients (
P
=0.005).

Conclusions

CRAO
,
BRAO
, and
OIS
are associated with significantly increased symptomatic stroke rates. Degree of ipsilateral internal carotid artery stenosis may not be useful in risk stratification for these patients, suggesting that they should be triaged appropriately for stroke risk‐factor management, independent of internal carotid artery stenosis.
Have You Ever Used Two Picture Planes to Draw a Single Perspective View?
Authors: Salgado Tomás García
Published: February 2019

Apparently, the use of two picture planes to draw a single view has not been attempted before. Most perspective methods, after Alberti, take for granted the use of a single picture plane, disregarding its likely use in dual positions. What if two picture planes are necessary to draw a single view—for example, given a lack of spatial references at ground level to estimate the distance between two objects? This article demonstrates that to draw the interior of a building from which another building can be seen about 190 m away, where the projection of such building on the first picture plane would be imprecise, it may be wise to use a second picture plane. This leads to consideration of how objects change shape as they move away from the viewer. For example, if a cube recedes from the observer up to 100 times its side length, it takes on an axonometric view. This raises a question: Could axonometric projection be a particular case of perspective?
Khulʿ Divorce in the Netherlands: Dutch Muslim Women Seeking Religious Divorce
Authors: Van Eijk Esther
Published: February 2019

In this article, the author examines the ways in which a number of Dutch Muslim women try to obtain an Islamic divorce. The road to a divorce, often long and winding, does not always lead to a satisfactory conclusion. I explore the question of why it can be difficult for Muslim women to obtain a religious divorce. Drawing on recent empirical research into the phenomenon of ‘marital captivity’ – a situation in which someone is unable to terminate a (religious) marriage, I examine the case of a Dutch Muslim woman who, at the instigation of a civil court, managed to negotiate a khulʿ agreement with her ‘ex’-husband, who released her from the marital bond. This exceptional example of a khulʿ practice in the Netherlands attests to the versatility of this under-researched form of Islamic divorce and how it is used in a Muslim minority context in Europe.
Khul‘ over the longue durée: the decline of traditional fiqh-based divorce mechanisms in Indonesian legal practice
Authors: van Huis Stijn Cornelis
Published: February 2019

In this essay, I describe the historical development of three traditional fiqh-based divorce mechanisms in Indonesia that commonly result in a khul‘ divorce: regular khul‘ (khuluk), conditional divorce (taklik talak), and marital discord (syiqaq). In the practice of present-day Islamic courts these traditional fiqh-based divorce mechanisms have lost almost all of their former prominence. Through a historical analysis of legal practices of female-initiated divorce, I will explain how this happened. Legal reforms under the 1974 Marriage Law, their adoption into the 1991 Compilation of Islamic Law, and case law of the Supreme Court broadened women’s divorce rights significantly. The same reforms made out-of-court divorce illegal. In contrast to fiqh-based divorce mechanisms, judicial divorce on the grounds of ‘continuous and irreconcilable marital discord’ does not require the consent of the husband or the payment of compensation and has therefore become an easier and cheaper option for Indonesian women.
Divorce Reform in Egypt and Morocco: Men and Women Navigating Rights and Duties
Authors: Sonneveld Nadia
Published: February 2019

This essay focuses on recent divorce reforms in Egypt (2000) and Morocco (2004), with equal attention to the positions of men and women who end their marriages. Whereas in Egypt, non-consensual, no-fault divorce reform (khul‘) is open only to women, in Morocco, another form of non-consensual, no-fault divorce, shiqāq, is open to both women and men, with men using it almost as frequently as women. Based on legal analysis and anthropological fieldwork, I consider first how men and women navigate rights and duties in divorce and then examine the differences between the two countries in the way men and women try to obtain divorce. I conclude that when both men and women are given opportunities for non-consensual, no fault divorce, highly gender-specific divorce regimes, such as the ṭalāq and taṭlīq, quickly lose their popularity.
The Power of Property: Land Tenure in Fāṭimid Egypt
Authors: Wickham Chris
Published: February 2019

Egyptian land tenure in the Fāṭimid period (969-1171) is often assumed to have been based on state ownership of agricultural land and tax-farming, as was in general the case in the Mamlūk period which followed it, and as many Islamic legal theorists rather schematically thought. This article aims to show that this was not the case; Arabic paper and parchment documents show that private landowning was normal in Egypt into the late eleventh century and later. Egypt emerges as more similar to other Mediterranean regions than is sometimes thought. The article discusses the evidence for this, and the evidence for what changed after 1100 or so, and, more tentatively, why it changed.
The Early Islamic Mining Boom
Authors: Morony Michael
Published: February 2019

The present article shows that, according to archaeological and literary evidence, an expansion in mining occurred in the early Islamic world as a result of changes in mining technology at the end of Late Antiquity. The production of gold, silver, copper, iron, and other minerals is shown to have peaked in the eighth and ninth centuries and then to have declined during the tenth and eleventh centuries due to insecurity and/or exhaustion of the mines. Mining development was financed privately, and mines were usually private property.