bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3640: Novel humanized anti-Sialyl-Tn, anti-CD3 bispecific antibodies demonstrate tumor and T-cell specificity for immune activation at the tumor site
Authors: Eavarone David A. , Prendergast Jillian , Rao Patricia E. , Stein Jenna , Behrens Jeff , Dransfield Daniel T. 
Published: July 2017

Abstract
Tumor-associated carbohydrate antigens (TACAs) historically have been challenging targets for antibody therapeutics. Sialyl-Tn (STn) is a cancer specific antigen that is expressed on the surface of carcinomas including ovarian, colon, prostate, and pancreatic tumors but is rarely present in normal tissue. STn expression has been linked to innate immune suppression, a chemoresistant phenotype, metastasis, and poor prognosis. Previous attempts to target this antigen in the clinic with synthetic glycan vaccines proved safe but lacked efficacy. We have developed humanized bispecific antibodies targeting STn and CD3 for T-cell recruitment and activation at the tumor site. These bispecific antibodies were selected for optimal tumor targeting using our glycan microarray that enriches for candidates whose binding is protein-independent and glycan specific. STn-selective binding was demonstrated. Current lead candidates exhibited low nanomolar EC50 binding in flow cytometric assays against both STn expressing tumor cells and T cells. Quantification of T-cell activation and T-cell induced tumor killing in vitro provides a basis for the further clinical development of these bispecific antibody candidates.
Citation Format: David A. Eavarone, Jillian Prendergast, Patricia E. Rao, Jenna Stein, Jeff Behrens, Daniel T. Dransfield. Novel humanized anti-Sialyl-Tn, anti-CD3 bispecific antibodies demonstrate tumor and T-cell specificity for immune activation at the tumor site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3640. doi:10.1158/1538-7445.AM2017-3640
Abstract 3665: Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy
Authors: Voloshin Tali , Tal-Yitzhaki Orna , Kaynan Noa , Giladi Moshe , Shteingauz Anna , Munster Mijal , Blat Roni , Porat Yaara , Schneiderman Rosa S. , Cahal Shay , Itzhaki Aviran , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: July 2017

Abstract
Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt cancer cell mitosis by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation and ER stress, which trigger different forms of cell death.
We evaluated the in vitro and in vivo effects of TTFields combined with an immune checkpoint inhibitor (anti-PD1) on immunogenic cell death.
Murine Lewis lung carcinoma (LLC) and ovarian surface epithelial (MOSE) cells were treated with TTFields using the inovitroTM system. Levels of calreticulin (CRT) on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice were implanted with LLC cells were treated with TTFields, anti-PD-1, or a combination of the two modalities. Tumor volume was monitored; flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.
TTFields induced elevated cell surface expression of CRT, decreased intracellular ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of lung tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CS11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression as compared to infiltrating immune cell in the control group.
Our results demonstrate that TTFields treatment potentiates immunogenic cell death in cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control.
Citation Format: Tali Voloshin, Orna Tal-Yitzhaki, Noa Kaynan, Moshe Giladi, Anna Shteingauz, Mijal Munster, Roni Blat, Yaara Porat, Rosa S. Schneiderman, Shay Cahal, Aviran Itzhaki, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2017-3665
Abstract 3682: Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer
Authors: Adeegbe Dennis O. , Liu Yan , Lizotte Patrick , Kamihara Yusuke , Awad Mark , Barbie David , Ritz Jerome , Jones Simon , Quayle Steven , Hammerman Peter , Wong Kwok-Kin 
Published: July 2017

Abstract
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. This study evaluated the immunoregulatory properties of two classes of drugs that modulate the epigenome, histone deacetylase (HDAC) and bromodomain inhibitors with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes associated with enhanced T-cell priming and function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight immunomodulatory effects of two epigenetic modifiers that together promote T-cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for NSCLC treatment.
Citation Format: Dennis O. Adeegbe, Yan Liu, Patrick Lizotte, Yusuke Kamihara, Mark Awad, David Barbie, Jerome Ritz, Simon Jones, Steven Quayle, Peter Hammerman, Kwok-Kin Wong. Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3682. doi:10.1158/1538-7445.AM2017-3682
Abstract 3686: Generation of an off-the-shelf cell-based platform (PDC-vac) for active antitumor immunotherapy
Authors: Plumas Joel , Lenogue Kevin , Walencik Alexandre , Molens Jean-Paul , Chaperot Laurence , Pule Martin 
Published: July 2017

Abstract
The development of efficient vaccines for the treatment of cancers in combination or not with other agents such as checkpoint inhibitors represents a major public health issue but remains a challenge. A dozen of vaccine drug products is expected to be marketed in the next few years. In this context, off-the-shelf and potent platforms are more attractive than individualized vaccines that are tailored to each patient in many aspects. We have recently developed a new cell-based vaccine approach named PDC*vac (formerly GeniusVac). This cell-based vaccine was developed thanks to the establishment, from leukemic PDC, of unique human PDC line (PDC*line). We have previously shown the potential of peptide-loaded PDC*line to induce strong and fully functional HLA-A*02:01-restricted anti-tumor immunity in vitro and in vivo (Aspord et al, 2010, 2012). PDC*mel (GenusVac-Mel4), our first product is currently developed for the treatment of melanoma patients (NCT01863108). The high efficiency of PDC*vac renders the strategy very attractive for further clinical developments in active immunotherapy field. Our aim is to optimize PDC*vac technology by passing use peptides and render the vaccine easier to manufacture. We engineered our PDC*line using retrovirus to force the endogenous expression of one or more tumor or viral antigenic peptides or whole tumor/viral proteins (gp100, tyrosinase, Melan-A, Mage-A3, CMVpp65, flu, EBV) that broaden the panel of antigens presented. Data obtaining with different polypeptide and protein gene coding constructions and the expansion of multi-specific antigen-specific T-cells at the same time will be presented. Moreover, we will present how we succeed to obtain 100% of efficacy in antigen presentation by the PDC*line engineered to express tumor proteins or polyepitopes. We have validated the use of retrovirus constructs to create a new generation of an “off-the-shelf” cancer vaccines highly potent to stimulate antitumor-specific T-cells.
Citation Format: Joel Plumas, Kevin Lenogue, Alexandre Walencik, Jean-Paul Molens, Laurence Chaperot, Martin Pule. Generation of an off-the-shelf cell-based platform (PDC-vac) for active antitumor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3686. doi:10.1158/1538-7445.AM2017-3686
Abstract 369: Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications
Authors: Kagey Michael H. , Wu Yinyuan , Zhang Xinjun , Sirad Cynthia A. , Mulligan Shane E. , He Xi , Mirabelli Christopher K. 
Published: July 2017

Abstract
Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt antagonist DKK1 is expressed in a variety of tumor types which frequently correlates with a poor prognosis, including overall survival. DKK1 has known oncogenic activity by stimulating proliferation, metastasis, and angiogenesis, and recently been implicated in contributing to an immunosuppressive tumor microenvironment. The neutralization of DKK1 is hypothesized to have efficacy from both a direct antitumor effect and through an immune stimulated response. Here we describe the characterization of DKN-01, a humanized monoclonal therapeutic antibody to DKK1. DKN-01 binds DKK1 with high affinity and selectivity, disrupts the interaction of DKK1 with the LRP6 co-receptor, and neutralizes DKK1 activity in a cell based assay. In vivo, DKN-01 has efficacy both as a monotherapy and in combination with chemotherapies in a non-small cell lung (NSCLC) cancer A549 xenograft model. Results suggest that DKN-01 has an antiangiogenic effect and may stimulate a NK cell mediated antitumor response. Clinically, DKN-01 is being evaluated in relapsed/refractory esophageal cancer patients in combination with paclitaxel, and preliminary results demonstrate promising activity. Archival patient tumor samples are currently being analyzed genetically and by IHC for DKK1 and β-catenin staining for biomarker identification. Taken together, our results suggest that DKN-01, a novel therapeutic, has clinical efficacy by disrupting Wnt signaling, which results in a direct anti-tumor effect and stimulates a pro-inflammatory tumor response.
Citation Format: Michael H. Kagey, Yinyuan Wu, Xinjun Zhang, Cynthia A. Sirad, Shane E. Mulligan, Xi He, Christopher K. Mirabelli. Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2017-369
Abstract 3721: DLL3 analysis of circulating tumor cells predict treatment outcome in phase 1 rova-T study in small cell lung cancer
Authors: Roy Somdutta , Martinez Kevin , Dilip Archana , Karsunky Holger , Dylla Scott 
Published: July 2017

Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with early dissemination and poor prognosis that accounts for 15-20% of all lung cancer cases worldwide. Most cases are inoperable and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible liquid biopsy. Here we present CTC data from aggressive, late stage SCLC patients who were enrolled on a Phase 1 trial studying Rova-T (anti-DLL3 antibody drug conjugate). CTCs were captured using a microfluidic platform (IsoFlux) that uses flow control and immunomagnetic capturing of epithelial cell surface marker (EpCAM)-positive cells. CTCs were isolated before dosing (baseline) of Rova-T and at successive time points post treatment. CTCs from each time point were distinguished and enumerated using DAPI, EpCAM and the cytoplasmic marker (pan-CK), in addition to the absence of CD45. Enriched CTCs were also collected for RT-PCR for expression analysis of genes confirmed to be absent in blood cells. The number of CTCs varied among the 58 baseline samples collected, ranging from 5-1000 CTCs per 7.5ml of blood. When the CTCs were assessed for DLL3 target expression, 37/58 baseline samples expressed DLL3 by RT-PCR. Interestingly, the expression of DLL3 on the baseline CTCs correlated with treatment outcome. When additional time points after treatment were enumerated for CTCs, patients that presented with DLL3 expression on CTC at baseline showed a significant decrease in CTCs after treatment. This suggests that Rova-T might kill DLL3-expressing CTCs. These data support continued investigation of DLL3 expression on CTC in SCLC patients with the goal of facilitating a liquid biopsy able to assess DLL3 status as a prospective companion diagnostic for Rova-T.
Citation Format: Somdutta Roy, Kevin Martinez, Archana Dilip, Holger Karsunky, Scott Dylla. DLL3 analysis of circulating tumor cells predict treatment outcome in phase 1 rova-T study in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3721. doi:10.1158/1538-7445.AM2017-3721
Abstract 3729: Tumor-specific antibody labeling of pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model using a fluorescent humanized anti-CEA antibody
Authors: Lwin Thinzar , Murakami Takashi , Hoffman Robert M. , Yazaki Paul J. , Bouvet Michael 
Published: July 2017

Abstract
Introduction: Delineation of tumor margins is critical in oncologic surgery, particularly in resection of pancreatic cancer. Surgeons are limited in visualization with bright light surgery. Fluorescence guided surgery (FGS) can help surgeons better visualize all potential cancer cells during the operation. In the present study, we show that the use of an anti-CEA antibody conjugated to an 800nm NIR fluorescent dye can selectively label pancreatic cancer in both pancreatic cancer cell lines and patient derived xenograft mouse models (PDOX).
Materials/Methods: BxPC3-GFP cells or pancreatic cancer tissue specimens were grafted into flanks of nude mice. Both types of tumors were allowed to grow until 1 cm. Fragments tumors (2 mm3) were grafted onto the pancreatic tail of recipient mice to create PDOX models. After tumors reached 7-10mm in size, 75 ug of Anti-CEA-800 dye was injected into the tail-vein (LI-COR 800 CW IRDye®, Lincoln, NE). Mice were imaged via the Maestro CRI imaging system (Perkin Elmer, Waltham, MA) 24 hours after injection.
Results: Images obtained after fluorescent antibody injection showed that anti-CEA-800 specifically labeled both the cell-line-derived tumors and patient-derived tumors with an adequate tumor to background contrast at 24 hours. The dye co-localized with GFP in tagged tumor cells lines. GFP fluorescence had poor penetration if covered by overlying tissue, which was not an issue with the anti-CEA-800 dye. The dye allowed clear identification of the tumor and tumor margin. In the BxPC-3 based tumor, the dye allowed identification of a small 1mm satellite lesion in the spleen that would otherwise have been missed.
Conclusions: Fluorescent humanized anti-CEA-800 antibody specifically labeled orthotopically implanted pancreatic cancer xenografts from cell lines and patient derived tissue. Tumor-specific fluorescence imaging clearly identified the primary tumor and satellite lesion. The 800nm wavelength allowed deeper tissue penetration, particularly in areas of tumor covered by normal pancreatic parenchyma. Humanized anti-CEA antibodies conjugated to a radio-labeling agent and LI-COR 800 dye is already in Phase I/II trials. Humanized anti-CEA conjugated with the IR-800 dye is a promising agent for future clinical FGS applications.
Citation Format: Thinzar Lwin, Takashi Murakami, Robert M. Hoffman, Paul J. Yazaki, Michael Bouvet. Tumor-specific antibody labeling of pancreatic cancer in a patient-derived orthotopic xenograft (PDOX) mouse model using a fluorescent humanized anti-CEA antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3729. doi:10.1158/1538-7445.AM2017-3729
Abstract 3730: Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma
Authors: Mittal Sandeep , Barger Geoffrey R. , Bosnyák Edit , Shah Varun B. , Juhász Csaba 
Published: July 2017

Abstract
PURPOSE. Tumor-Treating Fields (TTFields) is an FDA-approved treatment approach for patients with both newly-diagnosed and recurrent glioblastoma. The main purpose of the present study was to explore if amino acid positron emission tomography (PET) is able to detect an early, objective metabolic tumor response during the first months of TTFields therapy.
METHODS. Patients with MRI signs of recurrent glioblastoma eligible for TTFields along with maintenance temozolomide were recruited for PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) at baseline (before start of TTFields application) and up to 3 months later. Serial MRIs were also performed in 1-2 months intervals. AMT accumulation in the MRI-detected tumor mass was measured by standardized uptake values (SUVs), and PET-based tumor volumes were also calculated. Interval changes of these PET variables were compared to changes in areas of MRI enhancement.
RESULTS. Out of 7 recruited patients, 5 showed appropriate compliance (&gt;75%) with the device and underwent follow-up PET. Four of the 5 patients showed a clear metabolic response during TTF treatment on PET imaging. Two patients, who received TTFields treatment only (in addition to maintenance temozolomide), showed 25% and 100% decrease of PET-based tumor volumes, respectively. MRI was stable (patient #1) or showed increasing contrast enhancement (#2) during the same period. In this latter patient, TTFields was continued with bevacizumab treatment, leading to decreased contrast enhancement and further decrease of AMT uptake on a second follow-up PET. In two other patients (#3 and #4), TTFields were combined with bevacizumab rescue treatment. Patient #3 showed a markedly decreased tumoral AMT uptake and metabolic volume along with stable MRI enhancement. Patient #4 showed interval decrease of tryptophan PET uptake 2 months after initiation of TTFields therapy. Finally, patient #5 showed an interval expansion of the PET-based tumor volume along with MRI progression during a 2-month follow-up despite TTFields combined with bevacizumab and carboplatin.
CONCLUSIONS. This is the first study to demonstrate an objective metabolic response of recurrent glioblastoma within 1.5-3 months after initiation of TTFields. The data suggest that amino acid PET can identify early responders to TTFields therapy.
Citation Format: Sandeep Mittal, Geoffrey R. Barger, Edit Bosnyák, Varun B. Shah, Csaba Juhász. Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3730. doi:10.1158/1538-7445.AM2017-3730
Abstract 3731: A novel multidimensional cfDNA assay for real time analysis of chemotherapy response
Authors: Shah Pavan P. , Patsch Katherin , Matasci Naim , Soudararajan Anjana , Diaz Patricia , Agus David B. , Ruderman Daniel , Gross Mitchell E. 
Published: July 2017

Abstract
Due to its non-invasive nature and transient lifespan (~30 mins), circulating cell free DNA (cfDNA) may provide novel insights into cancer evolution and response to therapy. Here, we have developed a multidimensional cfDNA assay to measure patients’ responses to chemotherapy on a time scale that would be impossible using traditional biopsy methodologies.
We extracted cfDNA from plasma collected immediately before and after infusion of cytotoxic chemotherapy, and 24 hours after treatment. We developed assays to (1) quantify cfDNA via qPCR of a 288 base pair amplicon of Long Interspersed Nuclear Elements (LINE1), (2) determine the DNA Integrity Index based on additional analysis of 115bp and 516bp LINE1 amplicons, and (3) analyze androgen receptor exon 8 via targeted deep sequencing.
We analyzed cfDNA extracted from 17 patients with metastatic castration-resistant prostate cancer through sequential application of these 3 assays. Median PSA levels were 69 (0-2223) ng/dl, Hgb 12 (8.2-15) g/L, Alk Phos 117 (35-879) IU/mL. Deep sequencing of AR exon 8 revealed 6 of the 17 patients presented with 1-2 SNVs (H874Y, T877A, D890H or D879Y) at ≥1% frequency. Considering LINE1 quantification alone, the average change pre/post chemotherapy was 38.78 pg/mL (0.5-292.0 pg/mL). A variety of responses was noted including: 8 of the patients expressed elevated LINE1 levels post-treatment when compared to baseline, and 5 expressed depressed levels. Importantly, therapy did not affect tumor subclones equally, as demonstrated by sequencing and quantitation of mutant AR exon 8 species. Additional data on changes in DNA Integrity Index will be presented.
We conclude that cytotoxic chemotherapy produces immediately observable effects on cfDNA. The effect of docetaxel chemotherapy on distinct clones within the tumor can be measured within hours. Now that a short-time dynamics response has been demonstrated, follow up studies will be performed involving more patients to determine the prognostic value.
Citation Format: Pavan P. Shah, Katherin Patsch, Naim Matasci, Anjana Soudararajan, Patricia Diaz, David B. Agus, Daniel Ruderman, Mitchell E. Gross. A novel multidimensional cfDNA assay for real time analysis of chemotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3731. doi:10.1158/1538-7445.AM2017-3731