bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2311: Adenovirus-transduced allogeneic dendritic cells for cancer immunotherapy
Authors: Essand Magnus , Fotaki Grammatiki , Jin Chuan , Ramachandran Mohanraj , Ma Jing , Karlsson-Parra Alex , Yu Di 
Published: July 2016

Abstract
Immunotherapy is currently being established as standard treatment for cancer. Immune checkpoint blockade antibodies can cure a large proportion of patients with refractory melanoma and lung cancer, and adoptive transfer of patient-derived CD19 chimeric antigen receptor (CAR) T cells results in complete remission in a majority of patient with refractory leukemia. Cancer vaccines based on patient-derived dendritic cells (DC) modified ex vivo to present tumor antigens are promising for cancer treatment especially when combined with immune checkpoint blockade antibodies. Ex vivo-modified DCs are however poor in migrating to secondary lymphoid organs after re-administration. In reality, it is more likely endogenous DC that endocytos the injected DC, mature and then migrate to lymph nodes where they present peptide fragments of tumor antigen to T cells together with required co-stimulation.
Herein, we present a new strategy utilizing adenovirus (Ad)-transduced allogeneic DCs (alloDCs) as immunostimulatory adjuvant to induce both innate and adaptive immune response. Ad/alloDC can be prepared, tested and made ready for release in advance and quickly be prepared for injection in cancer patients upon request, thereby minimizing GMP-processing and handling of cells. Besides encoding tumor antigens, adenovirus also provides stimulatory danger signals for DC activation. We show that Ad/alloDCs secret a panel of proinflammatory cytokines and chemokines including IL-12 and CXCL10 at high levels in a sustainable fashion. We also show that Ad/alloDC recruit and activate neutrophils and NKs to the site of injection. Ad/alloDC can also recruit and interact with allo-reactive T cells to create a proinflammatory milieu, which further recruit and activate endogenous DCs. We verified that endogenous DCs activated in situ by an Ad/alloDC injection migrate to draining lymph node, where they present the engulfed tumor antigen to T cells. We show that these migratory endogenous DCs facilitate T cell activation and proliferation. Moreover, when injected intratumorally, Ad/alloDCs modulate the immunosuppressive environment by reducing the ratio of monocytic to granulocytic myeloid-derived suppressor cells (MDSC). To evaluate the therapeutic efficacy, we use B16 melanoma tumor-bearing C57Bl/6 mice injected with adenovirus-transduced DCs from Balb/c origin to obtain an allogeneic reaction. We show that Ad/alloDC treatment could significantly delay tumor growth and prolong survival of tumor-bearing mice.
Citation Format: Magnus Essand, Grammatiki Fotaki, Chuan Jin, Mohanraj Ramachandran, Jing Ma, Alex Karlsson-Parra, Di Yu. Adenovirus-transduced allogeneic dendritic cells 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 2311.
Abstract 2340: PD-1 blockade suppresses gastric cancer development by promoting antitumor immunity in mice
Authors: Kim Woosook , Hayakawa Yoku , Fox James G. , Wang Timothy C. 
Published: July 2016

Abstract
Since advanced gastric cancer is difficult to cure with chemo and/or radiation therapy, new therapeutic approaches are clearly needed. Targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1 has shown promising antitumor immunity in many malignancies by modulating T cell activity. PD-L1 and to a lesser extent of PD-L2 are expressed in human gastric cancer and expression of PD-L1 is associated with poor prognosis. Therefore, developing immunotherapies is an attractive strategy for the treatment of gastric cancer. We evaluated the efficacy of anti-PD-1 therapy in a mouse model of gastric cancer. Gastrin-deficient (GAS-KO) mice have been shown to develop large antral tumors with the combination of N-methyl-N-nitrosourea (MNU) and Helicobacter felis (H. felis) infection. Tumors developed in GAS-KO mice exhibited increased expression of PD-L1 and higher mutation rates than those in wild-type mice. To study the effect of anti-PD-1 antibody in tumor initiation or an early stage of progression, GAS-KO mice were induced with H.felis/MNU to develop tumors, one week later (10 weeks post-MNU) treated with anti-PD-1 antibody or isotype control (10 mg/kg IP qw) and sacrificed at 30 weeks post-MNU. We confirmed that GAS-KO mice treated with isotype control had moderate tumor burdens. Of interest, however, less and much smaller tumors were observed in mice treated with anti-PD-1. To compare immune cell populations in spleen tissue and peripheral blood from each group of mice, flow cytometric analysis was performed. Anti-PD-1-treated mice showed an increase in T cells including cytotoxic CD8+ T cells and a decrease in regulatory T cells and myeloid-derived suppressor cell (MDSC) populations compared with controls. In accordance with this, CD3-positive T lymphocytes were more frequently found in gastric tumors of anti-PD-1-treated mice than controls. Furthermore, qRT-PCR analysis revealed differential cytokine gene expression profiles including Il6, Il1b, and Il23 following anti-PD-1 treatment. Together, these data implicate that PD-1 blockade promotes immune infiltrates and therefore potentiates antitumor immune responses, suggesting targeting PD-1 as a potential new anticancer strategy in gastric cancer. Understanding anti-PD-1 therapy at the cellular and molecular level could provide new strategies for developing highly efficacious combination therapies.
Citation Format: Woosook Kim, Yoku Hayakawa, James G. Fox, Timothy C. Wang. PD-1 blockade suppresses gastric cancer development by promoting antitumor immunity in mice. [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 2340.
Abstract 2357: Therapeutic potential of the natural human IgG1k antibody pritumumab
Authors: Babic Ivan , Mukthavaram Rajesh , Nomura Natsuko , Pingle Sandeep , Glassy Mark C. , Kesari Santosh 
Published: July 2016

Abstract
Pritumumab is a natural human IgG1 kappa antibody derived from a regional draining lymph node of a patient with cervical carcinoma. The recognized antigen is an altered form of vimentin, called ecto-domain vimentin (EDV), that is expressed on the cell surface of epithelial tumor cells. A recombinant version of the mAb was made using the GPEx® system in CHO cells. In a series of comparable studies the CHO mAb was compared with the original hybridoma. Binding specificity with both flow cytometry and immunohistochemical analysis, Western blot analysis, and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) activity confirms the comparability of the two versions. A concentration-dependent study of pritumumab-mediated ADCC suggests an EC50 of 39.6ng/ml. Further studies include establishing a xenograft model with both SCID and athymic nude mice in which pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Analysis of a blood brain barrier model suggests pritumumab shows minimal distribution in normal brain tissues and significant binding in tumor areas of brain tissues indicating the mAb crosses the tumor brain barrier. Overall, these data together suggest pritumumab is suitable for development as an anti-tumor therapeutic.
Citation Format: Ivan Babic, Rajesh Mukthavaram, Natsuko Nomura, Sandeep Pingle, Mark C. Glassy, Santosh Kesari. Therapeutic potential of the natural human IgG1k antibody pritumumab. [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 2357.
Abstract 2363: Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit
Authors: Gabitzsch Elizabeth , Rice Adrian , Latchman Yvette , Balint Joseph P. , Jones Frank 
Published: July 2016

Abstract
Effective immunotherapeutic treatment of various cancers may require combinational approaches to induce specific immunity to the tumor as well as inhibition of immune check-points. We have developed a viral gene delivery platform to immunize against numerous tumor associated antigens (TAA) such as carcinoembryonic antigen (CEA), HER2/neu and HPV 16. We investigated the therapeutic benefit of the immunotherapeutics alone and in combination with check-point inhibitors such as programmed death-ligand 1 (PD-1) blockade and LAG3 blockade in murine tumor models. As single agents, immunization with the viral delivery platform encoding the TAA induced target-specific cell-mediated immunity and anti-tumor responses in the respective model. When the immunotherapies were combined with immune checkpoint blockade, an increased level of anti-tumor activity against was observed in addition to an improvement in survival. Tumor microenvironment analysis immunized mice revealed an increase in CD8+ tumor-infiltrating lymphocytes (TILs). In addition, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. When immunotherapy was combined with anti-PD-1 antibody, we observed CD8+ TILs at the same increased level but found that a smaller fraction of these were PD-1+. Furthermore, we observed a reduction in PD-L1 expression on tumor cells, providing a mechanism by which combination therapy favors tumor clearance and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials.
Citation Format: Elizabeth Gabitzsch, Adrian Rice, Yvette Latchman, Joseph P. Balint, Frank Jones. Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit. [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 2363.
Abstract 2365: Checkpoint inhibitors and a multivalent melanoma vaccine as a novel combinatorial therapy
Authors: Maniyar Rachana R. , Tuli Neha , Suriano Robert , Geliebter Jan , Wallack Marc , Tiwari Raj K. 
Published: July 2016

Abstract
Over 1 million cases of skin cancer are diagnosed in the US every year, of which 75% deaths result due to melanoma, one of the deadliest forms of skin cancer, arising from melanocytes. We have isolated five patient derived melanoma cell lines (MEL-V, 3MM, GLM2, Mel2, KFM) and characterized the expression of various melanoma associated antigens (MAAs). The presence of a multitude repertoire of common MAAs (Gp100, MART-1, MAGE-A1, NY-ESO-1, Tyrosinase, TRP-1 (Gp75), TRP-2, Melanotransferrin, CD71, CD146) enabled us to use composite cell membrane preparations of these cells as a multivalent vaccine. To this end, we designed a vaccinia virus vaccine that was composed of membrane lysate preparations of the five primary cells and recombinant IL-2. When tested in a pilot study, delayed type hypersensitivity and a multivalent immune response were noted. In an effort to correlate genetic lesions with MAA expression we observed that in BRAF mutant melanoma cells, treatment with a BRAFv600E inhibitor, PLX4032, enhanced the expression of MAAs making the melanoma cells more visible to the vaccination driven immune response. We also observed that melanoma cells constitutively expressed CTLA-4 as determined by Immunofluorescence and Western Blots. This expression was found on the membranes as well as in the cytoplasm in comparatively high levels on wild type as well as the BRAFV600E mutant melanoma cell lines. Further our results suggest that CTLA-4 expression on melanoma cells promotes the immunosuppressive tumor microenvironment enabling tumor evasion. Given that CTLA-4 monoclonal antibodies such as Ipilimumab are approved for clinical treatment, this study opens up a new avenue into a plausible combinatorial therapy for our vaccinia virus based vaccine with Ipilimumab for BRAF mutant as well as wild type melanoma cells.
Citation Format: Rachana R. Maniyar, Neha Tuli, Robert Suriano, Jan Geliebter, Marc Wallack, Raj K. Tiwari. Checkpoint inhibitors and a multivalent melanoma vaccine as a novel combinatorial therapy. [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 2365.
Abstract 2369: Molecular profile of a GM-CSF overexpressing breast cancer whole-cell vaccine with systemic anti-tumor activity
Authors: Lacher Markus Daniel , Wiseman Charles L. , Wagner Joseph 
Published: July 2016

Abstract
BACKGROUND AND PURPOSE OF STUDY: The allogeneic whole-cell cancer vaccine BriaVax(TM) (formerly SV-BR-1-GM) is an ER/PR negative, HER2/neu positive breast cancer cell line (SV-BR-1) we engineered to stably overexpress GM-CSF. BriaVax, rendered proliferation incompetent by irradiation, has thus far been applied to 4 advanced stage cancer patients (3 subjects with breast cancer, 1 subject with ovarian cancer). One breast cancer subject responded to BriaVax with complete remission of a measurable lung lesion and near complete remission of multiple breast lesions after only 3 inoculations. Nevertheless, she relapsed 3 months after completing the protocol, with brain metastases as well as multiple breast lesions. We obtained FDA permission to resume vaccinations, and, upon doing so, all metastatic sites responded with a prompt tumor regression after only 3 inoculations. To prospectively identify patients with a high likelihood of benefiting from BriaVax therapy we began a program to identify molecular factors of diagnostic potential. Here, we describe a gene expression signature that might both be informative about BriaVax’ mechanism of action and helpful for developing diagnostic or monitoring biomarkers.
METHODS: To prospectively identify patients with tumors responsive to BriaVax we began a molecular analysis of both the BriaVax cell line and cells obtained from the special clinical responder's blood. BriaVax gene expression profiles were obtained through Illumina BeadArray and NanoString nCounter technologies and compared to gene expression data sets publically available through the Gene Expression Omnibus (GEO; National Center for Biotechnology Information) portal.
RESULTS: BriaVax expresses a gene signature consistent with a mechanism of action involving not only the activation of cytotoxic T cells but also the induction of a humoral response. In addition, BriaVax expresses known cancer antigens. Notably, blood-derived cells of the special clinical responder expressed genes complementing BriaVax’ gene expression signature, thus possibly explaining the unusually prompt and robust clinical response to BriaVax.
CONCLUSIONS: Our findings suggest that BriaVax exerts its therapeutic effects via multiple modes. We identified both candidate immunogens overexpressed in BriaVax compared to normal breast cells and unraveled a potential mechanism of action explaining the encouraging clinical response observed.
Citation Format: Markus Daniel Lacher, Charles L. Wiseman, Joseph Wagner. Molecular profile of a GM-CSF overexpressing breast cancer whole-cell vaccine with systemic anti-tumor activity. [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 2369.
Abstract 2373: Assessing intra-tumor heterogeneity and tracking longitudinal and spatial clonal evolution by next-generation sequencing
Authors: Jiang Yuchao , Qiu Yu , Minn Andy J. , Zhang Nancy R. 
Published: July 2016

Abstract
Cancer is a disease driven by genetic and epigenetic alterations that follows Darwinian evolution. Recently, there have been increasing efforts to sequence the tumor from the same patient at multiple time points and/or from multiple spatially separated resections. Different snapshots of the same tumor have proved invaluable for identifying subclonal populations and inferring the tumor's history.
We propose a method, Canopy, for estimating the clonal history and for longitudinal and spatial comparison of mutation profiles from one or more samples derived from a single patient. Canopy accounts for normal cell contamination and reconstructs subclonal phylogeny utilizing both somatic copy number alterations (CNAs) and somatic single nucleotide alterations (SNAs). Canopy provides a general mathematical framework that enumerates all possible CNA-SNA phases and temporal orderings. Taking as input the mutant and reference allele frequencies for SNAs, and depth of coverage for CNAs, Canopy gives confidence assessments of all possible configurations of the cancer's clonal evolution.
Canopy is applied to three cancer sequencing datasets of varying study design, as well as to an extensive simulation study. On a whole-exome study of a transplantable metastasis model derived from human breast cancer cell line MDA-MB-231, Canopy successfully deconvolutes the mixed cell sublines, using the single cell sublines as ground truth, and identifies DNA signatures that can be prognostic of distant metastasis. On a whole-genome sequencing dataset of the primary tumor and relapse genome of a leukemia patient, Canopy predicts phylogenetic histories in concordance with existing knowledge. On a whole-genome sequencing dataset of the breast cancer tumor and its subsequent metastatic xenograft, Canopy's inferred clonal phylogeny is concordant with genomic markers of major clonal genotype and is confirmed by single-cell sequencing. Finally, through simulations, we explore the effects of various parameters on deconvolution accuracy, and evaluate performance with comparison against existing methods. Collectively, Canopy provides a rigorous foundation for statistical inference on repeated sequencing experiments from evolving populations delineated temporally and spatially.
Citation Format: Yuchao Jiang, Yu Qiu, Andy J. Minn, Nancy R. Zhang. Assessing intra-tumor heterogeneity and tracking longitudinal and spatial clonal evolution by next-generation sequencing. [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 2373.
Abstract 2381: A multiancestral model of colorectal cancer: in vivo evidence that early heterogeneity contributes to cancer progression
Authors: Leystra Alyssa A. , Luers Brook , Son Junbo , Sievers Chelsie K. , Wisinger Amanda M. , Schwartz Alexander R. , Zahm Christopher D. , Matkowskyj Kristina A. , Albrecht Dawn M. , Clipson Linda , Deming Dustin A. , Newton Michael A. , Halberg Richard B. 
Published: July 2016

Abstract
Background: Intratumoral heterogeneity has been linked to tumor progression and chemotherapy resistance in the clinic. Recent models of colorectal tumor evolution indicate that heterogeneity likely arises early during the first few cell divisions and is maintained in a non-Darwinian fashion with discrete clones coevolving. However, how this heterogeneity arises is not fully understood. We propose that some cancers are derived from multiple unique ancestors, and that discrete clones enhance establishment, growth, progression, and resistance to therapy.
Methods: Mice carrying the Min allele of Apc and expressing a constitutively active form of PI3K in a subset of colonic epithelial cells develop multiple adenomas and adenocarcinomas in the colon. Cell lineage tracing and fluorescent endoscopy were used to follow the progeny of individual founding cells through establishment, growth, progression, and response to targeted therapy. Cell sorting and 3D tumor spheroid co-culture were used to further examine the growth behavior and treatment response in vitro.
Results: Nearly half (44%; 30/68) of the tumors were derived from at least two ancestral clones. The presence of multiple clones was associated with an increased likelihood of a tumor becoming invasive (p = 0.006). Moreover, each clone was more invasive within multi-ancestral tumors than within their homotypic counterparts, indicating that the increased invasion is shared among clones rather than owing to a single dominant clone (p = 0.05). Additionally, the presence of both clones appeared to protect susceptible clones from targeted therapy. In vitro experiments demonstrated that co-evolved clones adopted similar growth patterns, whereas independently evolved clones did not.
Conclusions: Taken together, these data strongly indicate that distinct tumor founding cells and their coevolving progeny can contribute to tumor establishment and moreover can enhance growth and survival during tumor progression and response to therapy.
Citation Format: Alyssa A. Leystra, Brook Luers, Junbo Son, Chelsie K. Sievers, Amanda M. Wisinger, Alexander R. Schwartz, Christopher D. Zahm, Kristina A. Matkowskyj, Dawn M. Albrecht, Linda Clipson, Dustin A. Deming, Michael A. Newton, Richard B. Halberg. A multiancestral model of colorectal cancer: in vivo evidence that early heterogeneity contributes to cancer 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 2381.