bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 701: An inflammation paradox: Obesity vs. neutrophil-lymphocyte ratio in immunotherapy
Authors: Park Wungki , Florou Vaia , Torres Alfredo , Saravia Diana , Algaze Sandra , Lopes Gilberto ,   University of Miami
Published: August 2018

Abstract
Background: The dual roles of inflammation in malignancy has been well-described. Neutrophils play a key role in inflammation and carcinogenesis. We previously showed that high NLR may confer resistance to PD1/PDL1 inhibitors in lung cancer patients. In addition, obesity has been shown to produce chronic inflammation and neutrophil dysfunction have been described. The interplay between obesity and neutrophil in solid tumor patients treated with immunotherapy is unknown. Methods: We retrospectively evaluated 408 patients with solid tumors who treated with immunotherapies at the University of Miami. Cox regression was performed to evaluate correlation of obesity (BMI &gt;30) and NLR &lt;5 with Progression Free Survival (PFS) and Overall Survival (OS). Pearson Correlation was used for correlation between BMI and NLR. Results: Median follow-up was 8.6 months. There were head, neck and thoracic (n=257), gastrointestinal (n=32), genitourinary (n=58), skin and musculoskeletal (n=61). There were 230 males, mean age was 65.8. Treatments include nivolumab (n=204), pembrolizumab (n=128), atezolizumab (n=35), and combination with ipilimumab (n=41). There were underweight (BMI&lt;18.5, n=27), normal weight (18.5≤BMI&lt;25, n=186), overweight (25≤BMI&lt;30, n=117), and obese patients (BMI≥30, n=78). Obesity (BMI≥30) and NLR &lt;5 were strongly correlated with better OS with HR: 3.031 and HR: 2.424, respectively. (Table 1) There was trend of better PFS in obese patients, however it was not statistically significant. BMI and NLR showed inverse correlation. (r= -0.172, p=0.001) Conclusions: Surrogates of inflammation, such as obesity and NLR in patients with solid cancer may predict immunotherapy responses. High NLR was associated with adverse clinical outcomes and failure to checkpoint inhibitors, perhaps due to unfavorable tumor-associated neutrophil phenotypes. There was also a strong correlation between obesity and overall survival in these solid tumor patients.
Table 1. Multivariate analysisPFSOSFactorHR95% C.I.p-valueHR95% C.I.p-valueECOG&gt;12.188(1.561-3.068)0.00013.031(1.937-4.742)0.0001BMI&lt;301.136(0.806-1.601)0.4682.934(1.484-5.801)0.002NLR≥51.704(1.301-2.230)0.00012.424(1.661-3.538)0.0001
Citation Format: Wungki Park, Vaia Florou, Alfredo Torres, Diana Saravia, Sandra Algaze, Gilberto Lopes, University of Miami. An inflammation paradox: Obesity vs. neutrophil-lymphocyte ratio in immunotherapy [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 701.
Abstract 709: Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model
Authors: Kähkönen Tiina E. , Suominen Mari I. , Halleen Jussi M. , Bernoulli Jenni , Scholz Arne 
Published: August 2018

Abstract
Bladder cancer is a common and aggressive type of cancer occurring both in women and in men. At diagnosis, lymph node involvement is frequently observed and in some cases metastatic spread can already be seen at early stage. With advanced stages, the metastatic incidence increases and the most common metastatic sites are bones, lung, liver and peritoneum. Bone metastases count about 50% of all metastases and the 5-year survival rate in metastatic disease is only 15%. Bone metastases are incurable but can be treated to reduce tumor burden in bone, and new therapies such as immunotherapies hold the potential to treat patients with bone metastatic bladder cancer. The aim of the study was to establish a novel syngeneic model for bladder cancer bone metastasis that could be used to study efficacy of new immunotherapies, and to test efficacy of anti-PD-1 therapy in the model.
In the model establishment study, an intratibial injection of varying number of murine MBT-2 bladder cancer cells was given to 5-6 weeks old female C3H/HeN mice. Tumor-induced bone changes were followed by X-ray imaging once a week. At sacrifice, tumor-bearing tibias were collected and evaluated by histology. In the efficacy study, 5x105 MBT-2 cells were used. The mice were stratified to treatment groups based on similar bone lesion areas at 10 days after cancer cell inoculations and treated with anti-PD-1 therapy (RMP1-14) or isotype control (rat IgG2a, 200 µg per dose) at Q3D schedule. Bone lesion growth was followed by X-ray imaging one week after start of treatment and at sacrifice after three weeks on treatment.
In the model establishment study, tumor take rate of 50% was observed. MBT-2 cells induced an osteolytic bone reaction resulting in substantial bone loss in the mice. The osteolytic bone lesions started to be visible between 7-14 days and the maximum duration of the study was 4 weeks from the cancer cell inoculations. Histology confirmed a large tumor and decreased bone mass in the inoculated tibia. In the efficacy study, treatment with anti-PD-1 reduced bone lesion growth. A trend towards decreased bone lesion area was seen already at one week on treatment and a significant reduction of bone lesion area was seen at sacrifice.
A novel syngeneic bladder cancer bone metastasis model was established. According to the observed significant effects on bone lesion growth by anti-PD-1 treatment this model can be used in preclinical efficacy assessment of new immunotherapies as monotherapy or in combination with other therapies.
Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli, Arne Scholz. Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model [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 709.
Abstract 712: Immune checkpoint inhibitor induced tumor gene expression changes in murine syngeneic colon cancer models
Authors: Fadden Patrick , Weitzel Douglas , Davis Kelli , Bui Thi , Hurtado David , Haines Hannah , Roark Rhiannon , Derrick Ashleigh , Godfrey Beverly , Belle Ian , Krontz Katherine , Sokolowski Cristina , Synnott Aidan , Wood Edgar 
Published: August 2018

Abstract
The success of immune checkpoint therapy with anti-PD-1 and anti-CTLA-4 antibodies has generated broad interest in immuno-based interventions for oncology. Preclinical efficacy assessment of these novel immune-oncology therapies requires a functional immune system and therefore is frequently performed in murine syngeneic tumor models. In addition to tumor growth inhibition, syngeneic tumor models provide a platform to investigate the mechanism of action for a given novel therapeutic target. Characterization and mechanism of action for immune-based cancer therapies in murine syngeneic tumor models is often assessed by flow cytometry; measuring changes in tumor infiltrating leukocyte (TIL) populations following treatment induction. We assessed whether transcriptomic gene expression analysis could identify additional relevant biomarkers for immunotherapy response. Mice bearing subcutaneous syngeneic colon cancer tumors were dosed intraperitoneally with either vehicle alone, anti-CTLA-4, anti-PD-1, or a combination of the two immune checkpoint inhibitors on days 1, 4, and 8. Tumors were harvested on day 9 and half from each group were assessed for TIL population composition by flow cytometry and half by Clariom D mouse transcriptome array analysis. We identified a number of immune cell-related genes with differential expression that correlated to the therapeutic response and were consistent with changes identified in TIL populations by flow cytometry. These results provide an additional metric for assessing immunotherapy response in vivo. In addition, these data suggest that a smaller, defined panel of gene targets may be developed as biomarkers for specific immune system responses to immune checkpoint therapies in murine syngeneic models.
Citation Format: Patrick Fadden, Douglas Weitzel, Kelli Davis, Thi Bui, David Hurtado, Hannah Haines, Rhiannon Roark, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Katherine Krontz, Cristina Sokolowski, Aidan Synnott, Edgar Wood. Immune checkpoint inhibitor induced tumor gene expression changes in murine syngeneic colon cancer models [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 712.
Abstract 713: Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer patients
Authors: Kim Hye Ryun , Park Hyo Jin , Son Jimin , Shim Hyo Sup , Cho Byoung Chul , Rha Sun Young , Ha Sang-Jun 
Published: August 2018

Abstract
Purpose: Regulatory T (Treg) cells perform the immune suppressive function in cancer, but their suppressive mechanism in tumor microenvironment (TME) has not been clearly elucidated. We aim to identify the phenotype and functional mechanism of Treg cells in TME from cancer patients.
Experimental Design: We collected 72 malignant effusion (ME) and peripheral blood (PB) specimens from stage IV cancer patients and 10 tumor tissue (TM) and PB from lung cancer patients who underwent surgery. Lymphocytes from ME, TM, and PB were analyzed for subtype of Tconv and Treg cells, and their expressions of immune checkpoint (IC) molecules including programmed death (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and T cell immunoglobulin containing molecule-3 (TIM-3) using by flow cytometry. To examine the functional role of PD-1 expressed Treg cells, TC-1 lung cancer mouse model was used.
Result: Upregulation of PD-1 on Treg cells in TM and ME compared to PB was even more distinguishable than that on CD4+ and CD8+ Tconv cells. To clarify the characteristics of tumor infiltrating Treg cells, we comprehensively examined the characteristics of Treg cells from tumor, peri-tumor, and PB in lung cancer patients by analyzing the expression of IC molecules including PD-1, TIM-3, CTLA-4, and TIGIT, of which PD-1 is the highest expressed on tumor infiltrating Treg cells. To investigate the mechanism by which Treg cells mediate immune suppression, we compared the suppressive activity of Treg cells expressing high and low levels of PD-1 by co-culturing each population with naïve CD8+ T cells with or without αCD3/CD28 stimulation. This was more potently inhibited in co-cultures with PD-1high tumor infiltrating Treg cells than in those with PD-1low Treg cells. PD-1 blocked tumor infiltrating Treg cells demonstrated a significantly decreased suppressive function in the proliferation of CD8+ cells and their IFN-γ production. These results implicate that PD-1 expressed tumor infiltrating Treg confers the suppressive function of proliferation in CD8+ T cells through PD-1: PD-L1 interaction.
Conclusion: Our study evidently demonstrated that upregulated PD-1 on tumor infiltrating Treg cells and their PD-1: PD-L1 interaction could be potential cause of T cell suppression, which might be helpful to completely understand their suppressive mechanism in cancer patients.
Citation Format: Hye Ryun Kim, Hyo Jin Park, Jimin Son, Hyo Sup Shim, Byoung Chul Cho, Sun Young Rha, Sang-Jun Ha. Upregulation of immune checkpoint molecules on Treg cells in tumor microenvironment reinforces immune exhaustion in cancer 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 713.
Abstract 728: Optimization of peptide vaccines to induce robust antitumor CD4 T-cell responses
Authors: Kumai Takumi , Sultan Hussein , Kobayashi Hiroya , Harabuchi Yasuaki , Celis Esteban 
Published: August 2018

Abstract
Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor- associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL-2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies.
Citation Format: Takumi Kumai, Hussein Sultan, Hiroya Kobayashi, Yasuaki Harabuchi, Esteban Celis. Optimization of peptide vaccines to induce robust antitumor CD4 T-cell responses [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 728.
Abstract 751: A controlled affinity-guided ADC-linker (MAGNET) technology
Authors: Gupta Nimish , Biswas Goutam , Sengupta Aniruddha , Roy Monideepa , Roy Sudip , Sengupta Shiladitya 
Published: August 2018

Abstract
Antibody-drug conjugates (ADCs) have emerged as a powerful technology in cancer therapy. However, challenges with current linker technologies have limited the repertoire of ADCs. Currently-used linkers result in a heterogeneous mixture, unstable conjugates and/or involve complex processes such as genetic modification of the antibodies. Here, for the first time, we have explored high affinity non-covalent interactions between antibody and affinity ligands to design novel linkers that overcome the above challenges. The affinity ligands-based linkers coupled with payload, enable strong non-covalent association with the antibodies owing to their high specificity and affinity for antibodies without the need for any chemical reaction with the antibody. With a prototype affinity ligand, we demonstrated that the affinity ligand is able to guide the payload to six precise locations on the antibody conferring site-specificity to the resulting ADCs. Significantly, despite non-covalent interactions, the conjugates were found to be stable in presence of albumin and in human plasma. The ADC exhibited excellent antigen-specific internalization and nanomolar potency in vitro and were effective in suppressing tumor growth in a lung adenocarcinoma xenograft model with minimal systemic toxicity. This novel technology, which we term MAGNET (multivalent, affinity-guided antibody-empowerment technology) overcomes the existing limitations of ADC engineering by imparting trinity of (1) site-specificity, (2) stability and (3) homogeneity, while simplifying the ADC synthesis process. The self-assembled MAGNET ADCs pave the way for exploration of non-covalent conjugation of payloads to any biomolecule, and heralds a new paradigm for ADC generation.
Citation Format: Nimish Gupta, Goutam Biswas, Aniruddha Sengupta, Monideepa Roy, Sudip Roy, Shiladitya Sengupta. A controlled affinity-guided ADC-linker (MAGNET) technology [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 751.
Abstract 755: Synthesis and evaluation of sugar alcohol based molecules for drug conjugation and delivery
Authors: Huang Yumei , Chen Shuyan , Sun Binyuan , Griffin Amanda , Sweet Nathanial , Feng Mingqian , Ho Mitchell 
Published: August 2018

Abstract
Hydrophilic linkers, which are available in different motifs, have been used as agents of drug delivery, as aqueous solubility enhancers for hydrophobic molecules, and as tethers or spacers in conjugation. Polyethylene glycol (PEG) is one of the most commonly used hydrophilic linkers and commercially available. Lower molecular weight (MW) heterobifunctional PEG linkers are the most frequently used linkers for linking hydrophobic compounds, whereas high MW polymers have been used to conjugate proteins, peptides, oligonucleotides, siRNA, and other therapeutic biopolymers. Here, we describe a new type of biomaterial based on sugar alcohols: AqueaTether™ (AqT™) molecules. Various AqT™ linkers with different lengths and end groups were synthesized and their hydrophilic nature and ability to enhance the water solubility of hydrophobic compounds compared to different commercial and PEG linkers. Various antibody drug conjugates (ADCs) with water soluble AqT™-drugs were prepared. An ADC made with AqT™-monomethyl auristatin E (MMAE) with only two sugar alcohol units attached and an average drug-to-antibody ratio (DAR) of 4 demonstrated significant improvements in minimizing the aggregation of antibodies and long-term stability during storage. Due to increased water solubility, AqT™ linkers also allow higher loading of drugs per antibody, enabling the use of less toxic drugs, potentially increasing the overall efficacy and safety profile of an ADC. For example, ADCs with average DARs of 8 and 15 have been made using AqT™-doxorubicin with only two sugar alcohol units attached. In peptide-based drug discovery, discrete high MW AqT™ linker is used to label peptide, resulting in an increased half-life in human serum. In summary, AqT™ molecules are by far the most hydrophilic and versatile linkers currently in development. AqT™ molecules represent a great tool for drug conjugation and delivery.
Citation Format: Yumei Huang, Shuyan Chen, Binyuan Sun, Amanda Griffin, Nathanial Sweet, Mingqian Feng, Mitchell Ho. Synthesis and evaluation of sugar alcohol based molecules for drug conjugation and delivery [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 755.
Abstract 78: p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model
Authors: Capobianco Carla S. , Sidabra Johanna E. , Gottardo Maria F. , Aguirre-Ghiso Julio A. , Alonso Daniel F. , Farina Hernan G. 
Published: August 2018

Abstract
The mitogen activated protein kinase (MAPK) p38 is a kinase involved in the response to different external stimuli, extremely diverse such as oxidative stress or growth factors. Its activation triggers different responses which include from promoting cell apoptosis or cell cycle arrest, to cell differentiation and the activation of survival pathways. Although the role of p38 in cancer is a well studied field, there are still multiple unanswered questions, given the large amount of evidence supporting both a tumorigenic but also a tumor suppressor function for p38 in cancer development and progression. In this study, the effects produced by p38 negative modulation using the chemical inhibitor SB203580 in different aspects of tumor biology are analyzed in vitro and in vivo. As a study model, F3II cell line was used, which is an aggressive murine mammary carcinoma. We found that p38 inhibition provokes contradictory effects in our mammary carcinoma model. On one hand, p38 inhibition provoked the reduction of cell viability and colony formation. On the other hand, SB203580 treatment increased cell adhesion and proliferation in matrix coated surfaces. In vivo we found that SB203580 treatment increases tumor aggressiveness. The shortened latency times, higher number of lung metastasis and larger local recurrences are a reflection of the aforementioned effect. Taking together, the results presented in this work position p38 as a tumor suppressor kinase, in the context of cells adapting to a new environment and developing the first stages of growth. P38 inhibition represented an advantage for cells newly inoculated in vivo. We consider that this phenotypic adaptation is probably a consequence of ERK activation and integrin α5 increased expression. Data presented here is of importance to show how determinant is the microenvironment in the responses elicited by the modulation of p38 kinase. We propose a differential role according to the environment conditions, which reflects the complexity of the pathway and the importance of the extracellular stimuli when evaluating the implications of treatment with p38 MAP kinase inhibitors.
Citation Format: Carla S. Capobianco, Johanna E. Sidabra, Maria F. Gottardo, Julio A. Aguirre-Ghiso, Daniel F. Alonso, Hernan G. Farina. p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model [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 78.
Abstract 813: Development of anti-Globo H ADC against cancer
Authors: Sun Wei-Ting , Chuang Shih-Hsien , Lee Chao-Pin , Chen Yi-Jen , Wei Win-Yin , Lee Ying-Shuan , Hsu Chuan-Lung , Nieh Yu-Chin , Wu Chia-Cheng 
Published: August 2018

Abstract
Globo H antigen is a hexasaccharide originally isolated as a ceramide-linked glycolipid from the human breast cancer cell line MCF-7. Globo H is also highly expressed in many other cancers such as colon cancer, ovarian cancer, gastric cancer, pancreatic cancer, lung cancer, and prostate cancer. DCBD16001 is an ADC from humanized anti-Globo H antibody DCBPR1101. DCBPR1101 and DCBD16001 both show good binding affinities against Globo H antigen. DCBD16001 also shows high cytotoxicity in Globo H overexpressing cell line MCF-7 and HCC-1428 and shows no cytotoxicity in Globo H negative cell line BT-474. DCBD16001 can internalize to target cell more than 50% within 4.0 hours. In vivo evaluation data indicates that DCBD16001 shows acceptable PK profiles and good efficacy. It shows nearly 80% tumor growth inhibition in HCC-1428 xenograft model. DCBD16001 is a candidate under pre-clinical development and expected to apply IND submission within two years.
Citation Format: Wei-Ting Sun, Shih-Hsien Chuang, Chao-Pin Lee, Yi-Jen Chen, Win-Yin Wei, Ying-Shuan Lee, Chuan-Lung Hsu, Yu-Chin Nieh, Chia-Cheng Wu. Development of anti-Globo H ADC against 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 813.