bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5611: Inhibition of IL-6 trans-signaling in HNSCC
Authors: Simons Andrean L. , Dahl Rachel A. , Espinosa-Cotton Madelyn , Rodman Samuel N. , Rose-John Stefan 
Published: August 2018

Abstract
Various types of cancers including head and neck squamous cell carcinomas (HNSCCs) are highly inflammatory, and the cytokine interleukin-6 (IL-6) is believed to be associated with this inflammatory phenotype. Unfortunately, global inhibition of IL-6 signaling has demonstrated little to no clinical efficacy in various types of cancers. Previous studies in the field have reported major differences between IL-6 classical signaling through the membrane bound IL-6R (mIL-6R) and IL-6 trans-signaling through the soluble IL-6R (sIL-6R), and the idea that these 2 pathways may have vastly different functions. Recent studies in models of inflammation have proposed that IL-6 classical signaling serves an anti-inflammatory/homeostatic role while IL-6 trans-signaling stimulates proinflammatory events. Therefore, IL-6 trans-signaling (and not classical signaling) may be associated with the proinflammatory phenotype observed in HNSCCs and may also be responsible for the increased tumor progression and treatment resistance frequently encountered with this disease. The goal of this work is to investigate if selective inhibition of IL-6 trans-signaling will demonstrate superior antitumor efficacy compared to global inhibition of IL-6 signaling in HNSCC cells and if selective inhibition of IL-6 trans-signaling will enhance the antitumor efficacy of chemo/radiotherapy in HNSCC cells. We observed that the HNSCC cell lines SQ20B, SCC-25, FaDu and Cal-27 all express mIL-6R and secrete IL-6, sIL-6R, and the natural inhibitor of sIL-6R signaling–soluble glycoprotein 130 (sgp130)–at varying levels. Simultaneous inhibition of IL-6 classical and trans-signaling using the IL-6R antagonist tocilizumab, and selective inhibition of IL-6 trans-signaling using the extracellular portion of gp130 fused to the Fc portion of human IgG1 (sgp130-Fc), showed no significant effects on cell survival in vitro. However, sgp130-Fc significantly suppressed SQ20B tumor growth in athymic nude mice while tocilizumab had no effect. Significant antitumor effects of sgp130-Fc were also observed in a murine SCCVII/C3H syngeneic mouse model. Cell lines treated with cisplatin and/or X-ray radiation (0-4 Gy) increased IL-6, sIL-6R and sgp130 in a dose-dependent manner and sgp130-Fc significantly increased SQ20B tumor response to chemo/radiotherapy in vivo. Altogether, this work suggests that selective inhibition of IL-6 trans-signaling using sgp130-Fc may be more effective than global IL-6 inhibition with respect to suppressing HNSCC tumor growth and warrants further study as an adjuvant to standard HNSCC therapy.
Citation Format: Andrean L. Simons, Rachel A. Dahl, Madelyn Espinosa-Cotton, Samuel N. Rodman, Stefan Rose-John. Inhibition of IL-6 trans-signaling in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5611.
Abstract 5616: Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients
Authors: Milcent Benoit , Brice Pauline , Thieblemont Catherine , Teillaud Jean-Luc , Siberil Sophie 
Published: August 2018

Abstract
For many years, the clinical responses observed in cancer patients treated with antitumor antibodies have been viewed only as a consequence of the recruitment and activation of innate immune cells. Several preclinical studies have indicated that anti-tumor antibodies can also induce a potent anti-tumor adaptive T-cell response capable of protecting animals from tumor challenge. Our studies have shown that CD4+ Th1 cells play a central role in the response to anti-CD20 tumor therapy by opposing Treg expansion and that CD20-specific memory T cells are responsible for anti-tumor protection observed in surviving animals subjected to tumor rechallenge. Whether an adaptive T-cell response is elicited in patients with Follicular Lymphoma (FL) receiving anti-CD20-based treatment is not known. In the present work, we analyzed peripheral T cells before and during anti-CD20-chemotherapy treatment of FL patients (R-CHOP) with high tumor burden. We first examined in ELISPOT assays the IFN-γ production by PBMC from 20 patients against human CD20-derived peptides previously selected by combining in silico and in vivo screening using transgenic human HLA-DR mice. Both FL patients before treatment and patients undergoing R-CHOP treatment exhibited peripheral T-cell responses to the selected CD20-derived peptides. However, these responses were markedly lower than those observed in healthy donors. Similar results were also obtained when T cell responses against viruses commonly infecting large numbers of individuals (CMV, EBV, influenza) were assessed, suggesting that high tumor burden FL patients exhibit an immune exhaustion of T cells. Multiparametric flow cytometry analyses suggested that their poor ability to respond to viral and CD20-derived peptides is related to the presence of an immunocompromised and exhausted blood T-cell peripheral compartment with higher percentages of TIGIT- and PD-1-expressing T cells, of peripheral Treg, and terminally differentiated CD8+ TEMRA. R-CHOP therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype (TCM), an additional shift of CD8+ T cells to a naive phenotype, and a decrease in the number of PD-1+ and TIGIT+ T cells, making these cells evolving toward a lesser degree of exhaustion. However, it did not restore a level of specific responses similar to those observed in healthy donors. These results support the use of anti-PD-1 and anti-TIGIT antibodies in combination with anti-CD20 in FL patients with high-tumor burden.
Citation Format: Benoit Milcent, Pauline Brice, Catherine Thieblemont, Jean-Luc Teillaud, Sophie Siberil. Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5616.
Abstract 5643: TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial
Authors: Miller Michelle L. , Lohmueller Jason , McKolanis John R. , Schoen Robert , Finn Olivera J. 
Published: August 2018

Abstract
Mucin 1 (MUC1) is a large transmembrane glycoprotein that is overexpressed and hypoglycosylated in many adenocarcinomas, including colon cancer. In the hypoglycosylated state, the peptide core of the 20aa variable number of tandem repeats (VNTR) region is exposed, allowing it to function as an altered-self ligand for antibodies and T cells. VNTR peptides have been previously used as antigens in therapeutic cancer vaccines. A clinical trial was conducted to test immunogenicity and safety of a MUC1 100mer VNTR peptide+polyICLC adjuvant vaccine in a prophylactic setting in patients with premalignant colon adenomas who were at high risk for later developing colon cancer. In this premalignant setting, where patients were expected to have fewer immunosuppressive countermeasures usually present in patients with cancer, nearly half of the individuals generated IgG antibodies with no noted adverse effects. Because the antibody response was isotype-switched, it suggested simultaneous T cell activation. To determine whether changes in T cell clonal abundance following immunization could be detected, we sequenced and analyzed TCRβ repertoires from PBMCs of 21 antibody-responders collected before and after both primary and one-year booster vaccinations. Of the patients analyzed, we identified 8 TCRβ sequences from three patients that were significantly elevated after both priming and boosting immunizations, potentially identifying T cell clones that expanded in response to the vaccine. 16 TCRβ sequences from four individuals were significantly decreased at both time points, potentially identifying T cell clones that left circulation to participate in immune responses in secondary lymphoid organs or tissues. The timing of blood collection at two weeks post immunization may have been too late to allow us to detect all of the vaccine-expanded clones before they left circulation. In summary, we found 24 TCRβ CDR3 sequences from 7/21 vaccine responders that significantly changed in frequency after both primary and booster vaccinations. TCR sequencing studies from patients' T cells expanded in vitro with MUC1 peptide will be performed to determine if they overlap with those sequenced ex vivo.
Citation Format: Michelle L. Miller, Jason Lohmueller, John R. McKolanis, Robert Schoen, Olivera J. Finn. TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5643.
Abstract 567: The lysosomal transporter SLC46A3 is a potential predictive biomarker for antibody-drug conjugates bearing the non-cleavable warheads SG3376 and DM1
Authors: Kinneer Krista , Tai Yu-Tzu , Sridhar Sriram , Meekin John , Phipps Sandrina , Ruddle Ben , Fleming Ryan , Dimasi Nazzareno , Herbst Ronald , Tiberghien Arnaud , Masterson Luke , Howard Philip , Anderson Kenneth , Tice David 
Published: August 2018

Abstract
Antibody drug conjugates (ADCs) combine a monoclonal antibody with a potent cytotoxic drug to preferentially eliminate antigen-positive cells for the treatment of cancer. ADCs bearing non-cleavable drug-linkers such as the pyrrolobenzodiazepine (PBD) SG3376 or the maytansinoid DM1 rely upon lysosomal degradation of the antibody for release of the cytotoxic warheads, which must then escape the lysosome and bind to their intracellular targets. We sought to identify the mechanism of lysosomal transport of these membrane-insoluble warheads and have recently reported that the lysosomal transporter SLC46A3 is required for cytotoxic activity of ADCs bearing SG3376 and DM1, and that loss of SLC46A3 is a mechanism of acquired resistance to Trastuzumab-DM1 (T-DM1). Here we explore the potential translational relevance of SLC46A3. Analysis of SLC46A3 mRNA expression across several tumors showed that breast cancer cell lines and primary tumor samples have relatively high levels of SLC46A3 compared to samples derived from multiple myeloma (MM), esophageal, and upper aerodigestive tract malignancies, all of which are being targeted in clinical trials with non-cleavable DM1 ADCs. Deeper analysis indicates that levels of SLC46A3 are decreased in MM patients compared to healthy donors, and levels are further decreased in the relapsed/refractory setting compared to samples taken at diagnosis. We measured the expression of SLC46A3 in a panel of MM cell lines by RT-PCR and found that 5 of 9 (56%) had undetectable levels of SLC46A3. In vitro cytotoxicity assays demonstrate that SLC46A3-negative cells are resistant to B-cell maturation antigen (BCMA)-targeted ADCs prepared with non-cleavable DM1 and SG3376 warheads, but remain sensitive to the cleavable payload PBD SG3249 (Tesirine). Taken together, our results suggest that SLC46A3 may be a predictive response marker for ADCs bearing the non-cleavable warheads SG3376 and DM1, and this marker may be particularly useful in trials involving MM.
Citation Format: Krista Kinneer, Yu-Tzu Tai, Sriram Sridhar, John Meekin, Sandrina Phipps, Ben Ruddle, Ryan Fleming, Nazzareno Dimasi, Ronald Herbst, Arnaud Tiberghien, Luke Masterson, Philip Howard, Kenneth Anderson, David Tice. The lysosomal transporter SLC46A3 is a potential predictive biomarker for antibody-drug conjugates bearing the non-cleavable warheads SG3376 and DM1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 567.
Abstract 5713: Promising predictive biomarkers for immunotherapy in metastatic melanoma
Authors: Nyakas Marta , Aamdal Elin , Guren Tormod , Aamdal Steinar , Jacobsen Kari Dolven , Brunsvig Paal , Tasken Kristin Austlid , Mælandsmo Gunhild , Yndestad Arne , Halvorsen Bente , Aukrust Paal , Ueland Thor 
Published: August 2018

Abstract
Aim: to explore biomarkers in order to predict outcome in patients with metastatic melanoma who have had immunotherapy with ipilimumab in a real-world setting. Metastatic melanoma is a very aggressive, incurable cancer with historically few therapeutic options and poor survival. Immunotherapy represents a revolution for metastatic melanoma treatment but there is a lack of biomarkers to predict treatment response. Material and methods: In the Norwegian National Phase 4 Multicenter Study, IPI4, 150 patients were included to receive ipilimumab (anti-CTLA3). A subgroup of 73 patients (4 screening failure) was included at Oslo University Hospital -The Norwegian Radium Hospital. Serum was available from 56 patients of this subgroup and were examined before and during ipilimumab treatment concerning possible predictive biomarkers. Expression of a panel of 17 inflammatory markers reflecting different inflammatory pathways including extra cellular matrix remodeling and fibrosis, vascular inflammation, notch signaling, inflammation in general and monocyte/macrophage activation were measured at baseline and at the 2nd and/or 3rd treatment with ipilimumab. Results: During an average 33.7 months follow-up, 33 (59%) patients died. Six promising candidates (endostatin, osteoprotegerin, C-reactive protein, pulmonary and activation-regulated chemokine and galectin-3 binding-protein) were higher in non-survivors. In particular, high endostatin and galectin-3 binding protein levels were independently associated with poor long time survival also in adjusted analysis (age, gender, lactate dehydrogenase). A 1 standard deviation (SD) increase in Gal3BP gave a 1.8 x times higher risk of death (95% CI 1.10-2.95, p=0.019) while a 1 SD increase in endostatin was associated with a 2x higher risk of death (95% CI 1.12-3.64, p=0.020) in the final model. Conclusion: Endostatin and galectin-3 binding protein may represent biomarkers for prognosis during immunotherapy with ipilimumab and should be further evaluated.
Citation Format: Marta Nyakas, Elin Aamdal, Tormod Guren, Steinar Aamdal, Kari Dolven Jacobsen, Paal Brunsvig, Kristin Austlid Tasken, Gunhild Mælandsmo, Arne Yndestad, Bente Halvorsen, Paal Aukrust, Thor Ueland. Promising predictive biomarkers for immunotherapy in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5713.
Abstract 573: BRAF, KRAS, and NRAS mutations in archival tumor samples and samples of cell-free DNA from serum and bone marrow aspirates from patients with multiple myeloma
Authors: Janku Filip , Li Qian , Huang Helen J. , Wang Yafei , Cao Zeng , Karlin-Neumann George , Liu Zhiqiang 
Published: August 2018

Abstract
Background: Oncogenic mutations in BRAF, KRAS and NRAS genes have been reported in multiple myeloma and can be explored as biomarkers for selection of targeted therapies. Methods: Unamplified DNA from archival tumor tissue samples and cell-free DNA (cfDNA) from serum and bone marrow aspirates from patients with multiple myeloma was tested for BRAF V600, KRAS G12/G13, NRAS G12/G13 and NRAS Q61 mutations using multiplex assays for droplet digital PCR (Bio-Rad). Agreement among methods was evaluated and results were compared to clinical outcomes. Results: Of 88 patients with multiple myeloma (stage I, 13 [15%]; stage II, 26 [30%]; stage III, 34 [39%]; stage unknown, 15 [17%]), 4 (5%) patients were found to have BRAF V600 mutation (all confirmed V600E), 15 (17%) KRAS G12/G13 mutation, 3 (3%) NRAS G12/G13 mutation and 16 (18%) NRAS Q61 mutation in archival tumor tissue. Most mutations were subclonal with a median variant allelic frequency (VAF) 1.55% (range, 0.13%-34%). Survival data were available for 47 patients and patients with high mutation VAF had a trend to shorter survival than patients with low mutation VAF (25.3 months vs. not reached, P=0.087). Of 88 patients, 22 (25%) had simultaneous serum cfDNA collection, which demonstrated BRAF V600 mutation in 7 (32%; 3 confirmed as V600E), KRAS G12/G13 mutation in 2 (9%), NRAS G12/G13 mutation in 0 (0%) and NRAS Q61 mutation in 4/22 (18%) of samples and median VAF was 2.9% (range, 0.34%-18.8%). Agreement rates for serum compared to tissue were 73% for BRAF V600, 95% for KRAS G12/G13, 100% for NRAS G12/G13 and 95% for NRAS Q61. In addition, 13 (15%) patients had simultaneous bone marrow aspirate cfDNA collection, which demonstrated BRAF V600 mutation in 1 (8%; confirmed as V600E), KRAS G12/G13 mutation in 0 (0%), NRAS G12/G13 mutation in 0 (0%) and NRAS Q61 mutation in 1 (8%) of samples. Agreement rates for bone marrow aspirates compared to tissue were 100% for BRAF V600, 92% for KRAS G12/G13, 100% for NRAS G12/G13 and 100% for NRAS Q61. Conclusion: Common oncogenic mutations in BRAF, KRAS and NRAS genes are prevalent with relatively low VAF in multiple myeloma and can be detected with sensitive techniques such as ddPCR. Their prognostic significance and therapeutic utility needs to be further investigated.
Citation Format: Filip Janku, Qian Li, Helen J. Huang, Yafei Wang, Zeng Cao, George Karlin-Neumann, Zhiqiang Liu. BRAF, KRAS, and NRAS mutations in archival tumor samples and samples of cell-free DNA from serum and bone marrow aspirates from patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 573.
Abstract 5733: IL-11 as a therapeutic target to treat colorectal cancer
Authors: Huynh Jennifer , Chand Ashwini , Ernst Matthias 
Published: August 2018

Abstract
Introduction Colorectal cancer is a pressing health concern and there is a demand to develop novel therapeutics and improve current therapies to treat this disease. Immune checkpoint inhibitors (i.e. anti-PD-1 treatment) have been highly successful for the treatment of solid malignancies however, the majority of colorectal cancers do not typically respond to immunotherapy. Accumulating evidence alludes to a role for IL-11 signaling in tumor development although the mechanisms underlying IL-11 biology in colorectal cancer remain largely unknown. We postulate that IL-11 could be a mode of immunosuppression which can be targeted to overcome the poor responses of colorectal cancer to immunotherapy. Here we aim to investigate IL-11 signaling as a therapeutic strategy which can also be targeted in combination with anti-PD-1 treatment. Moreover, we present data that indicates an immunological function for IL-11 in modulating T cell anti-tumor activity.
Method To assess the therapeutic potential for targeting IL-11 signaling in colon cancer in vivo, wild type and Il11r-/- C57BL/6 mice were injected subcutaneously in the flank on Day 0 with 1 x 106 MC38 colon cancer cells. The mice were then treated with an anti-PD-1 antibody i.p. dose once every 3 days. Mice were euthanised at Day 18. Harvested tumors were analysed by FACs and immunohistochemistry. To ascertain a role for IL-11 signaling in T cell activity, CD8+ and CD4+ T cells were FACs-sorted from wild type and il11r-/- mice, and activated with PMA/ionomycin for 24h. T cell activation was assessed by measuring mRNA levels of granzyme B and perforin by qPCR, and IFNγ production by ELISA.
Results MC38 growth was attenuated in il11r-/- mice compared to wild type hosts. Lower tumor burden corresponded with a modest increase in tumor-infiltrating CD8+ T cells however we observed no differences in other immune cell subtypes (i.e. CD4+ T cells, MDSCs and macrophages). In addition, lower tumor burden corresponded with a marked reduction in Ki67 as assessed by immunohistochemistry. In addition, T cells harvested from il11r-/- hosts expressed lower levels of granzyme B, perforin and IFNγ under both basal conditions and following PMA/ionomycin stimulation.
Conclusion Here we report that IL-11 signaling supports tumorigenesis using the MC38 colon cancer mouse model. For the first time, we have characterized a functional role for IL-11 in modulating T cell function. Overall, the findings from this study indicate IL-11R as a potential therapeutic target to improve the efficacy of immune checkpoint inhibitors for the treatment of colorectal cancer.
Citation Format: Jennifer Huynh, Ashwini Chand, Matthias Ernst. IL-11 as a therapeutic target to treat colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5733.
Abstract 5734: Interleukin-1 signaling is required for HNSCC tumor response to cetuximab
Authors: Espinosa-Cotton Madelyn M. , Dahl Rachel A. , Fertig Elana , Jensen Isaac , McLaren Ayana J. , Miller Kenley , Rodman Samuel N. , Schmitz Sandra , Simons Andrean L. 
Published: August 2018

Abstract
Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of head and neck squamous cell carcinoma (HNSCC), limited to no long-term changes in overall survival are observed in HNSCC patients even though EGFR is expressed at high levels in these tumors. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that cetuximab activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the implications of activating this pathway are unclear. The IL-1 pathway plays a central role in immune response and displays both pro-tumor and anti-tumor activities. IL-1 may promote tumor growth by upregulating the secretion of pro-inflammatory mediators involved in angiogenesis and metastasis. On the other hand, IL-1 signaling may promote antitumor immunity specifically via natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC), which is also an important mechanism of action of cetuximab. The goal of our work is to determine how modulation of the IL-1 pathway affects HNSCC tumor response to cetuximab. We found that blockade of IL-1 signaling using an IL-1-receptor antagonist (IL-1RA, anakinra), neutralizing IL-1α/IL-1β antibodies, and genetic knockdown of the IL-1R all suppressed the anti-tumor efficacy of cetuximab, while IL-1α overexpression and treatment with recombinant IL-1α enhanced HNSCC tumor response to cetuximab in immunodeficient and immunocompetent HNSCC mouse models. Mechanistically, these results appear to be due to modulation of ADCC, as we found that IL-1 blockade significantly reduced cetuximab-mediated ADCC in vitro. Additionally, we found that HNSCC patients with high baseline circulating levels of IL-1 ligands (IL-1α, IL-1β) were significantly more likely to respond favorably to cetuximab monotherapy compared to patients with low or no baseline circulating IL-1 ligands. Altogether, these results suggest that IL-1 signaling is necessary for HNSCC tumor response to cetuximab. Therefore, IL-1α warrants further study as a novel therapeutic to enhance response to cetuximab and as an immunologic biomarker for cetuximab response.
Citation Format: Madelyn M. Espinosa-Cotton, Rachel A. Dahl, Elana Fertig, Isaac Jensen, Ayana J. McLaren, Kenley Miller, Samuel N. Rodman, Sandra Schmitz, Andrean L. Simons. Interleukin-1 signaling is required for HNSCC tumor response to cetuximab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5734.