bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2214: GITR ligand fusion protein (GITRL-Fc) induces T cell mediated anti-tumor immune response and can combine with anti-PDL1 to enhance anti-tumor immunity and long-term immune memory
Authors: Srivastava Minu K. , Yun Rui , Mayes Erin , Jie Hyun_Bae , Axelrod Fumiko , Monteon Jorge , Xie Ming-Hong , Lewicki John , Hoey Tim , Gurney Austin , Park Angie Inkyung 
Published: July 2016

Abstract
GITRL (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Ligand, TNFSF18) is a member of the TNF superfamily and naturally exists as a membrane-anchored type II protein that self assembles as a trimer. GITRL activates the co-stimulatory receptor GITR. GITR is found primarily on activated T effector (Teff) cells and regulatory T (Treg) cells. Co-stimulation of GITR by agonist agents is hypothesized to promote anti-tumor immunity by enhancing Teff cell activity and inhibiting Treg suppression. We generated a novel single-gene GITRL trimer fused to an immunoglobulin Fc domain (GITRL-Fc). GITRL-Fc activated GITR signaling more effectively than prototype GITR agonist antibody DTA-1. GITRL-Fc promoted a robust anti-tumor immune response in multiple syngeneic mouse tumor models. GITRL-Fc enhanced tumor specific T-cell responses, particularly of the Th1 type, and also led to reduction in Treg-mediated immunesuppressive activity. GITRL-Fc displayed single agent activity in inhibiting tumor growth and promoting complete tumor rejection in the murine CT26 colon carcinoma model and combination activity with anti-PDL1 as compared to anti-PDL1 and control IgG2a alone. Mice “cured” with GITRL or GITRL/anti-PDL1 combination treatments were protected from re-challenge with tumor cells, suggesting the existence of immunologic memory. More mice were protected from tumor re-challenge with the combination of GITRL-Fc and anti-PDL1, as compared to GITRL-Fc alone. Our results demonstrate that agonist GITRL-Fc induces potent T cell responses, overcomes Treg inhibition, and promotes anti-tumor activity in preclinical models as a single agent or in combination with anti PDL1. The mechanism of tumor eradication and induction of long-term immune memory response by the combination is under investigation and will be discussed at the presentation.
Citation Format: Minu K. Srivastava, Rui Yun, Erin Mayes, Hyun_Bae Jie, Fumiko Axelrod, Jorge Monteon, Ming-Hong Xie, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park. GITR ligand fusion protein (GITRL-Fc) induces T cell mediated anti-tumor immune response and can combine with anti-PDL1 to enhance anti-tumor immunity and long-term immune memory. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2214.
Abstract 2221: HHLA2, a novel member of the B7 family of inhibitory ligands, is highly expressed in osteosarcoma
Authors: Koirala Pratistha , Roth Michael , Gill Jonathan , Chinai Jordan , Ewart Michelle , Piperdi Sajida , Geller David , Hoang Bang , Fatakhova Yekaterina , Ghorpade Maya , Zang Xingxing , Gorlick Richard 
Published: July 2016

Abstract
Purpose: Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma (OS). New targets and novel therapies are needed to improve outcomes for these patients. In this study, we sought to evaluate the prevalence and prognostic utility of the immune checkpoint inhibitor HHLA2 in OS.
Experimental Design: HHLA2 expression was evaluated in two cohorts of OS patients using a tumor microarray (TMA) (n = 62) and whole slides (n = 48). HHLA2 expression was assessed in primary tumor specimens and metastatic disease, and correlated with the presence of tumor infiltrating lymphocytes (TILs), and event free survival.
Results: HHLA2 was expressed in 68% of OS tumors in the TMA and in 54% in the second cohort. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p = 0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ≥25% or ≥50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p = 0.03 and 14% vs 59%, p = 0.02).
Conclusions: HHLA2 is expressed in the majority of OS tumors, is associated with metastatic disease, and is associated with poorer survival. Further studies are needed assessing the effect of HHLA2 expression on the function of the immune microenvironment, as well as assessing the feasibility and utility of targeting HHLA2 in OS.
Citation Format: Pratistha Koirala, Michael Roth, Jonathan Gill, Jordan Chinai, Michelle Ewart, Sajida Piperdi, David Geller, Bang Hoang, Yekaterina Fatakhova, Maya Ghorpade, Xingxing Zang, Richard Gorlick. HHLA2, a novel member of the B7 family of inhibitory ligands, is highly expressed in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2221.
Abstract 2228: Cbl-b inhibitors as novel intra-cellular checkpoint inhibitors for cancer immunotherapy
Authors: Agarwal Saket , Wu Jian , Riling Chris , Kodrasov Matthew , Weinstock Joseph , Sokirniy Ivan , Mattern Michael , Kambayashi Taku , Kumar Suresh 
Published: July 2016

Abstract
The approval by the FDA and clinical use of immune checkpoint inhibitors, such as anti-PD1 and anti-CTLA4 antibodies, that activate cytotoxic T lymphocyte (CTL) mediated anti-tumor immune responses against advanced solid tumors has resulted in a paradigm shift in cancer therapy. Antitumor activity of CTLs and NK cells is tightly regulated by intracellular signaling events orchestrated by the ubiquitin signaling system. In particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), a RING finger E3-ubiquitin ligase primarily expressed in immune cells, acts as an intracellular checkpoint and a master negative regulator of both CTLs and NK cells. Accordingly, Cbl-b-/- mice have been observed to reject a variety of implanted metastatic and non-metastatic tumors and to delay significantly the outgrowth of spontaneous tumors; these observed antitumor effects were seen to be mediated by activated CD8+ T cells and NK cells. Based on the overwhelming evidence supporting the role of Cbl-b in immune suppression, this ubiquitin conjugating enzyme is considered a novel target for developing small molecule cancer immunotherapy agents. Using proprietary high throughput screening technologies, Progenra identified novel, selective Cbl-b inhibitors that were shown to decrease ubiquitination of substrates such as TAM receptor kinases (Tyro3) and to activate T cells (as judged by increased IL-2 production) and NK cells (as judged by increased IFNγ production and degranulation) in ex vivo functional assays. ADME/DMPK evaluation and in vivo efficacy of selected Cbl-b inhibitors will be discussed in relation to the therapeutic utility of this class of small molecule agent, which is expected to potentiate the anticancer effects of approved immunotherapy agents.
Citation Format: Saket Agarwal, Jian Wu, Chris Riling, Matthew Kodrasov, Joseph Weinstock, Ivan Sokirniy, Michael Mattern, Taku Kambayashi, Suresh Kumar. Cbl-b inhibitors as novel intra-cellular checkpoint inhibitors for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2228.
Abstract 2233: PI3K/Akt/mTOR signaling and plasma membrane proteins are implicated in responsiveness to adjuvant dendritic cell vaccination for metastatic colorectal cancer
Authors: Qian David , Byun Jinyoung , Xiao Xiangjun , Her Stephanie , Suriawinata Arief , Amos Christopher , Barth Richard 
Published: July 2016

Abstract
Purpose: We have previously demonstrated that metastatic colorectal cancer patients who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared to patients in whom immune responses do not occur. We sought to characterize the patterns of T lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine.
Methods: Cytotoxic, memory, and regulatory T cells in resected metastases and in surrounding normal liver tissue from 22 patients (11 responders and 11 non-responders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the Combined Multivariate and Collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on genes that encode plasma membrane proteins.
Results: There was no relationship between vaccine response and intra-tumor, peri-tumor, or hepatic densities of T cell subpopulations. Associated genes were found to be statistically enriched in PI3K, Akt, and mTOR signaling pathways (P &lt; 0.001). With respect to prediction, applying a consistent score cutoff over the 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%).
Conclusions: Adjuvant dendritic cell vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as neoantigens on tumor cell surfaces.
Citation Format: David Qian, Jinyoung Byun, Xiangjun Xiao, Stephanie Her, Arief Suriawinata, Christopher Amos, Richard Barth. PI3K/Akt/mTOR signaling and plasma membrane proteins are implicated in responsiveness to adjuvant dendritic cell vaccination for metastatic colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2233.
Abstract 2239: Isolation and characterization of circulating tumor cells (CTCs) in non small cell lung carcinoma
Authors: Scrima Marianna , Malanga Donatella , De Marco Carmela , Viglietto Giuseppe 
Published: July 2016

Abstract
Purpose: Lung cancer is the most common cause of cancer-related deaths that frequently metastasizes prior to disease diagnosis. Circulating tumor cells (CTCs) are of great clinical interest in terms of prognosis and therapy intervention and may provide important prognostic and predictive information in non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate diagnostic performance of a non-invasive method based on filtration-based technology (ISET) using cytomorphologic criteria in patients undergoing surgery comparing with histologic features of corresponding primary lesions.
Materials and Methods: The CTCs analysis was performed through the following steps: isolation by ISET filtration method (ScreenCell®) from 5 ml of peripheral blood of 36 patients with NSCLC and 23 with benign lung lesions; classification of CTCs with haematoxylin and eosin (H&E) staining; identification of cell marker with co-immunostaining for epithelial and mesenchymal markers (Vimentin and Cytocheratin). CTCs were classified as tumor cells if: (i) they have a large (≥12 μm), hyperchromatic, irregular-shaped nuclei; (ii) high nuclear-cytoplasmic ratio (&gt;0.5).
Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from histological or cytological analysis.
Results: CTCs were detected in 27 of 36 (75%) NSCLC patients and in 2 of 23 (9%) negative control patients (p = 0.001). No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. A test sensitivity and specificity for diagnosing lung cancer was 75% and 91% respectively. After co-immunostaining (Cytocheratin, Vimentin, CD45) CTCs showed positivity (14/15, 93%) only to vimentin (mesenchymal marker) and completely absence of cytocheratin signal (epithelial marker).
Conclusions: The performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer showed by high test sensitivity and specificity. The vimentin high expression in CTCs showed both that is a possible marker to CTCs identification and isolation and the importance of EMT mechanism transition in CTCs.
Citation Format: Marianna Scrima, Donatella Malanga, Carmela De Marco, Giuseppe Viglietto. Isolation and characterization of circulating tumor cells (CTCs) in non small cell lung carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2239.
Abstract 2267: Efficacy of pemetrexed-based chemotherapy in patients with NSCLC harboring KRAS mutations
Authors: Okumura Shunsuke , Sasaki Takaaki , Chiba Shin-ichi , Sado Masatoshi , Miyokawa Naoyuki , Funakoshi Hiroshi , Ohsaki Yoshinobu 
Published: July 2016

Abstract
[Background]
Biomarkers like epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) rearrangement have been discovered in lung cancer, leading to targeted therapies developed in non-small cell lung cancer (NSCLC). Several oncogenes have been reported to be negative biomarkers for response to tyrosine kinase inhibitors (TKIs), for example, NSCLC with KRAS mutations are resistant to EGFR-TKIs. A preclinical study showed that KRAS mutant lung cancer cells were sensitive to pemetrexed, while a retrospective study reported that pemetrexed-based chemotherapy didn't show a favorable outcomes in patients with KRAS mutant NSCLC. We, therefore, studied efficacy of pemetrexed-based chemotherapy in patients with NSCLC, and compared the efficacy between KRAS and wild-type NSCLC.
[Methods]
We retrospectively studied the medical records of patients diagnosed with NSCLC between 2013 to 2015. Genomic DNA (gDNA) was extracted from FFPE tissue samples (QIAamp DNA FFPE Tissue Kit, QIAGEN). KRAS mutations were evaluated using Ion Torrent NGS systems (Ion PGM, Thermo Fischer Scientific) or PCR-rSSO. AmpliSeq Colon and Lung Cancer Research Panel v2 was used in the present study. We used Ion Reporter software for next-generation sequencing data analysis.
[Results]
We analyzed the data of 226 patients with NSCLC and successfully extracted gDNA from 94 tissue samples. Among them, mutation analysis by Ion PGM system was performed in 48 samples and PCR-rSSO in 46 samples. We will report response rate and progression free survival in the patients treated with pemetrexed-based chemotherapy.
Citation Format: Shunsuke Okumura, Takaaki Sasaki, Shin-ichi Chiba, Masatoshi Sado, Naoyuki Miyokawa, Hiroshi Funakoshi, Yoshinobu Ohsaki. Efficacy of pemetrexed-based chemotherapy in patients with NSCLC harboring KRAS mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2267.
Abstract 2281: DNA methyl transferase inhibitors (DNMTis) upregulate NY-ESO expression in several human primary cells: implications for co-therapy with engineered adoptive T-cell therapies
Authors: Laugel Bruno , Sevko Alexandra , Howe Karen , Ferjentsik Zoltan , Ferronha Tiago , Maroto Miguel , Brewer Joanna , Jakobsen Bent , Binder-Scholl Gwendolyn 
Published: July 2016

Abstract
The DNA methyl transferase inhibitors 5-aza-2’-deoxycytidine (decitabine or DECI) and 5-azacytidine (azacitidine or AZA) have recently been approved for the treatment of a variety of hematologic malignancies. These cytidine analogues remove repressive epigenetic DNA methyl marks and induce the transcription of numerous genes normally silenced during the processes of cellular differentiation or transformation. DNMTis have a net anti-neoplastic activity through the up-regulation of tumor-suppressor genes involved in the induction of apoptosis, cellular differentiation and cell cycle arrest. In addition, DNMTis promote the expression of several cancer testis antigens (CTAs) by tumor cells, including NY-ESO and MAGE-A1/A3. These observations suggest that the combination of DNMTis with immunotherapeutic modalities may provide some clinical benefit.
Adoptive immunotherapies using autologous CD4+ and CD8+ T cells expressing an affinity optimized NY-ESO TCR are in clinical trials and show robust clinical responses in patients across several indications including synovial sarcoma, multiple myeloma or melanoma. DNMTis were previously shown to induce the expression of NY-ESO in antigen-low or -negative tumor cells and consequently enable the activation of NY-ESO-specific T-cells. While there is compelling evidence for the combination of DNMTis with T cells containing engineered affinity-enhanced TCRs recognizing NY-ESO-1, safety data supporting this approach are lacking. Initial tests into the safety of combining these treatments investigated the effects of DECI and AZA on NY-ESO and LAGE-1 expression in a panel of primary adult human cells of different tissue origins. Our data demonstrate that treatment with either compound resulted in a significant up-regulation of NY-ESO transcription in a subset of primary cells tested. The magnitude of increase in transcript expression varied between cell types and, in some cases, was sufficient to activate T cells expressing an affinity-optimized NY-ESO-specific TCR. These findings raise important safety concerns with regards to the potential combination of DNMTi compounds with NY-ESO T-cell therapy and suggest that such co-therapies may result in on-target off-tumor toxicities.
Citation Format: Bruno Laugel, Alexandra Sevko, Karen Howe, Zoltan Ferjentsik, Tiago Ferronha, Miguel Maroto, Joanna Brewer, Bent Jakobsen, Gwendolyn Binder-Scholl. DNA methyl transferase inhibitors (DNMTis) upregulate NY-ESO expression in several human primary cells: implications for co-therapy with engineered adoptive T-cell therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2281.
Abstract 2285: Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression
Authors: Kim Sun-Hee , Hashimoto Yuuri , Cho Sung-Nam , Roszik Jason , Milton Denái R. , Dal Fulya , Kim Sangwon F. , Menter David G. , Yang Peiying , Ekmekcioglu Suhendan , Grimm Elizabeth A. 
Published: July 2016

Abstract
COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy.
Citation Format: Sun-Hee Kim, Yuuri Hashimoto, Sung-Nam Cho, Jason Roszik, Denái R. Milton, Fulya Dal, Sangwon F. Kim, David G. Menter, Peiying Yang, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2285.
Abstract 2286: Targeting the notch pathway: A potential therapeutic approach for desmoid tumors
Authors: Braggio Danielle , Shang Hui , Lee Ya-Jung , Al-Sannaa Ghadah A. , Creighton Chad J. , Bolshakov Svetlana , Lazar Alexander JF , Lev Dina , Pollock Raphael E. 
Published: July 2016

Abstract
Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.
Citation Format: Danielle Braggio, Hui Shang, Ya-Jung Lee, Ghadah A. Al-Sannaa, Chad J. Creighton, Svetlana Bolshakov, Alexander JF Lazar, Dina Lev, Raphael E. Pollock. Targeting the notch pathway: A potential therapeutic approach for desmoid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2286.