bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B30: Signal peptide –mediated immunization against mouse mammary tumor virus (MMTV)-associated tumors
Authors: Braitbard Ori , Gross Tamar , Roniger Maayan , Bar-Sinai Allan , Hochman Nira , Hochman Jacob 
Published: October 2015

Abstract
Signal peptides (SPs) are N-terminal extensions on nascent secretory and membrane proteins that mediate insertion into, or translocation across the membrane of the endoplasmic reticulum (ER). A growing number of SPs have been shown to carry out post-ER targeting functions. A case in point is the SP of the envelope precursor protein of Mouse Mammary Tumor Virus (MMTV), a beta retrovirus known to cause lymphoma and mammry carcinoma in laboratory mice. This signal peptide (named MMTV-p14 , or p14 for short) is uniquely localized to nucleoli of cells that harbor the virus where it binds to specific protein targets and functions as a nuclear export factor for viral transcripts. P14 is also a phosphoprotein tumor modulator, the phosphorylation status of which determines whether it will function, in vivo, in a tumor promoting or tumor suppressing capacity.
Here we report that p14 is expressed also on the surface of a variety of cells that contain MMTV (murine lymphoma and mammary carcinoma, and human breast cancer cells ectopically expressing p14). Furthermore p14 is immunogenic and vaccination with purified recombinant p14 (using different adjuvants) is sufficient to immunize mice against malignant cells that harbor MMTV. This can be adoptively transferred into naïve mice.
Furthermore, newly derived monoclonal anti-p14 antibodies with different epitope specificity are now available to study their effect on MMTV associated tumors in vivo as well as for targeted drug delivery to these tumors
In view of reports suggesting involvement of MMTV in about 30% of human breast cancers we propose p14 and anti-p14 antibodies as candidates for immunization against MMTV associated malignancies, and as a functional example for other viral signal peptides.
Citation Format: Ori Braitbard, Tamar Gross, Maayan Roniger, Allan Bar-Sinai, Nira Hochman, Jacob Hochman. Signal peptide –mediated immunization against mouse mammary tumor virus (MMTV)-associated tumors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B30.
Abstract B59: The combined effects of piperlongumine, vitamin C, and vitamin D on Caenorhabditis elegans and Volvox carteri
Authors: Winters Ashley M. 
Published: October 2015

Abstract
Apoptosis, part of the everyday cell growth, essential for killing tumor cells, vital in organism's survival, kills pernicious cells, thus ridding the organism of mutations. The p53 gene is a tumor suppressor that is mutated in over half of all human tumor cells. When activated, it can stimulate DNA repair and apoptosis, making it crucial in the killing of tumor cells. Piperlongumine, vitamin C, and vitamin D have shown to increase p53 activity, thus increasing survival. Caenorhabdits elegans (C.elegans) underwent ultraviolet-C radiation, subjected to these reagents, and were counted daily in an eight day observation period for survival. Western blot analysis was used to compare the p53 gene activity. Similarly, Volvox carteri were observed for population after heat shock and the administration of the reagents. The results showed the combination of all three reagents led to the largest increase in p53 protein activity, lifespan in the nematodes, and population in the green algae. In C. elegans, the combination of vitamin C and D, statistically, led to the same increase in lifespan as piperlongumine alone. It was found that increasing reagent dosage induced a heighten population in Volvox carteri, while the control drastically decreased. These findings provide further evidence that there indeed exists a p53 gene in Volvox carteri.
Citation Format: Ashley M. Winters. The combined effects of piperlongumine, vitamin C, and vitamin D on Caenorhabditis elegans and Volvox carteri [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B59.
Abstract B78: Histamine dihydrochloride in the treatment of mesothelioma
Authors: Newick Kheng , O'Brien Shaun , Kapoor Veena , Wang Liang-chuan , Moon Edmund , Haas Andrew , Alley Evan , Sterman Daniel , Albelda Steven 
Published: October 2015

Abstract
Our recent adoptive T cell transfer trial for mesothelioma revealed a striking anti-tumor response in a patient which was accompanied by anaphylaxis, suggesting endogenous histamine release. In animal models, histamine has direct and immune-based anti-tumor effects. In fact, histamine dihydrochloride is approved in Europe in combination with interleukin-2 (IL2) for leukemia treatment. We thus explored the anti-tumor role of histamine in mesothelioma. An in vitro MTT assay was used to measure cell proliferation. Daily doses of histamine (1 mg/kg) – alone, or in combination with other immunotherapies – was used to treat four subcutaneous flank tumor models in three different mouse strains. Flow cytometric analyses were subsequently performed on tumors. Histamine had in vitro anti-tumor activity against all five cell lines tested with an IC50 of 1.8 mM. Histamine also significantly reduced tumor volume in all four in vivo models without toxic side effects. Immunodepletion studies revealed that the effect was partially due to T cells. When combined with two immunotherapy approaches (adenovirally-delivered interferon-α or a tumor antigen), anti-tumor efficacy was augmented. Histamine resulted in more interferon-γ and IL2 production by tumor-infiltrating lymphocytes (TIL), downregulation of CD206 expression on tumor-infiltrating macrophages, and reduced numbers of T regulatory cells (Tregs). Histamine has direct anti-tumor effects and immune-stimulatory effects within the tumor microenvironment (as seen with macrophage polarization, increase in cytokine production, and reduction in Tregs). This pre-clinical data suggests that histamine alone, or in combination with immunotherapy, should be explored in the treatment of mesothelioma.
Citation Format: Kheng Newick, Shaun O'Brien, Veena Kapoor, Liang-chuan Wang, Edmund Moon, Andrew Haas, Evan Alley, Daniel Sterman, Steven Albelda. Histamine dihydrochloride in the treatment of mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B78.
Abstract B79: CXCR4 inhibition facilitates anti-PD-1 immunotherapy by reprogramming the tumor microenvironment during sorafenib treatment in hepatocellular carcinoma
Authors: Chen Yunching , Reiberger Thomas , Ramjiawan Rakesh , Ng Mei Rosa , Hato Tai , Unan Elizabeth C. , Reddy Tejaswini P. , Ochiai Hiroki , Huang Peigen , Zhu Andrew X. , Jain Rakesh K. , Duda Dan G. 
Published: October 2015

Abstract
Although the tyrosine kinase inhibitor sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC), treatment response is often transient. Using orthotopic HCC models, we showed that resistance to sorafenib is linked to hypoxia and an associated increase in SDF1alpha and CXCR4 expression levels in tumors, which resulted in tumor desmoplasia and an increase in the infiltration of Gr1+ myeloid-derived suppressive cells, regulatory T cells and M2-type macrophages. Treatment with the CXCR4 inhibitor AMD3100 in combination with sorafenib prevented these effects. Addition of the immune checkpoint blocking antibody anti-PD1 further synergized with sorafenib and AMD3100 in delaying tumor growth and reducing metastasis. Anti-PD1 treatment significantly increased intratumoral infiltration of cytotoxic CD8+ T cells and their activity. Modulation and activation of immune responses by combining AMD3100 and anti-PD1 may be a novel approach to prevent tumor evasion from sorafenib treatment in HCC.
Citation Format: Yunching Chen, Thomas Reiberger, Rakesh Ramjiawan, Mei Rosa Ng, Tai Hato, Elizabeth C. Unan, Tejaswini P. Reddy, Hiroki Ochiai, Peigen Huang, Andrew X. Zhu, Rakesh K. Jain, Dan G. Duda. CXCR4 inhibition facilitates anti-PD-1 immunotherapy by reprogramming the tumor microenvironment during sorafenib treatment in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B79.
Abstract B80: Patients treated with oncolytic adenovirus Ad5/3-hTERT-E2F-Δ24-GMCSF induce immunological antitumor responses
Authors: Hemminki Otto , Parviainen Suvi , Hemminki Akseli 
Published: October 2015

Abstract
Background: Gene therapy with oncolytic viruses is a promising novel treatment modality for cancer due to their selective replication and lytic effect on cancer cells. Although the clinical safety profiles of individual agents are encouraging, the efficacy of oncolytic viruses as monotherapy has been limited. Arming the virus with an immune stimulatory molecule is an appealing strategy and may increase overall antitumor potency. Granulocyte-macrophage colony-stimulating factor (GMCSF) is one of the most potent inducers of antitumor immunity. GMCSF is associated with recruitment and maturation of antigen presenting cells (APCs), mainly dendritic cells, as well as activating the innate immunity by recruiting natural killer cells and neutrophils. Local GMCSF expression could ensure sufficient local concentration for induction of an anti-tumor immune response circumventing the problems with toxic systemic exposure and side effects.
Results: 5/3 chimeric oncolytic adenovirus selective for the p16-Rb pathway engineered to contain a tumor specific E2F promoter and carrying GMCSF (Ad5/3-hTERT-E2F-Δ24-GMCSF aka. CGTG-602) was constructed. Preclinical studies in vivo showed promising efficacy in immune competent Syrian hamster model. Encouraged by these results, 13 patients were treated with Ad5/3-hTERT-E2F-Δ24-GMCSF in Advance Therapy Access Program. Treatments were well-tolerated and overall signs of antitumor efficacy were seen in 9/12 patients (75%) when evaluated by PET-CT or tumor markers. Patient samples were analyzed for virus circulation in blood, neutralizing antibody titers, tumor- and adenovirus-specific PBMCs and antibodies against selected tumor associated antigens. Microarray analysis and immunohistochemistry were performed on available tumor biopsies and indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
Conclusions: These findings demonstrate that Ad5/3-hTERT-E2F-Δ24-GMCSF was safe and able to show promising signs of efficacy in preclinical studies and in patients. Clinical trials are needed to confirm these preliminary findings in larger patient cohorts.
Citation Format: Otto Hemminki, Suvi Parviainen, Akseli Hemminki. Patients treated with oncolytic adenovirus Ad5/3-hTERT-E2F-Δ24-GMCSF induce immunological antitumor responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B80.
Abstract B83: Quantitative recovery of aspartyl (asparaginyl) beta hydroxylase (HAAH) from an exosomal fraction of human sera from cancer patients
Authors: Semenuk Mark A. , Ghanbari Eleanor B. , Lebowitz Michael S. , Ghanbari Hossein A. 
Published: October 2015

Abstract
Human Aspartyl (Asparaginyl) Beta Hydroxylase (HAAH) is an overexpressed cell surface enzyme in tumor cells that is closely associated with cancer etiologyincluding cell proliferation, motility, and invasiveness. In keeping with this correlation, we have pursued HAAH as a target for both diagnostic and therapeutic applications. Our monoclonal sandwich ELISA detecting HAAH in serum performs with a clinical specificity and sensitivity greater than 90% to distinguish the presence of cancer. However, we have encountered occasional assay interference by some samples that result in under-detection of HAAH. Trouble shooting and follow-up resulted in the discovery that detectable HAAH resides in the exosomal fraction of serum. Isolation of cancer patient serum exosomes and reconstitution into normal serum or serum-free buffer, results in quantitative recovery of HAAH compared to the original intact serum for most cancer patients. When this exosomal reconstitution is done on false negative cancer patient samples, HAAH detection is restored. The HAAH signal is lost when the exosomal fraction is reconstituted in serum that contains the interfering substance(s). The nature of the interfering substance(s) is yet to be determined but the extraction of HAAH signal producing exosomes from serum improves assay performance. Since exosomes are produced by cells and released into the tumor microenvironment, studying this association with HAAH will help in the understanding of exosomal role in elimination, distribution and other functions in the body. This, in turn, is expected to greatly enhance and expand our development of diagnostic and therapeutic programs targeting HAAH.
Citation Format: Mark A. Semenuk, Eleanor B. Ghanbari, Michael S. Lebowitz, Hossein A. Ghanbari. Quantitative recovery of aspartyl (asparaginyl) beta hydroxylase (HAAH) from an exosomal fraction of human sera from cancer patients. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B83.
Abstract IA06: Designing immunostimulatory antibodies for cancer treatment
Authors: Glennie Martin J. , Al-Shamkhani Aymen , Beers Stephen A. , White Ann L. , Johnson Peter W. , French Ruth R. , Cragg Mark S. 
Published: October 2015

Abstract
Immunomodulatory mAb, led by the checkpoint blockers against CTLA-4 and PD-1/PD-L1, are changing the outlook for a number of difficult to manage cancers, such as melanoma and non-small cell lung cancer, and look set to become blockbuster drugs in the near future. While there is still some uncertainty concerning how these reagents work, it is generally agreed that they target exhausted effector T cells and Tregs within the tumour tissue. An alternative way to regulate anti-cancer T cells is using immunostimulatory mAb which trigger activatory T-cell co-receptors, often of the TNF receptor superfamily. Interestingly, most preclinical models show that immunostimulatory mAb are as good if not better than checkpoint blockers in terms of therapeutic potency. However, other than some limited success with anti-CD40 mAb in pancreatic cancer, immunostimulatory mAb have yet to display the level of clinical success seen with the checkpoint blockers. In this lecture we will discuss the mechanisms of action of these two groups of reagents and explore how differences in the rodent and human antibody effector functions might explain why immunostimulatory mAb have not performed as well in patients. We will show how the mouse inhibitory Fc gamma Receptor (FcγR), FcγRIIB, plays a critical role in hyper-crosslinking agonistic anti-TNFR mAb, yet in humans the equivalent receptor is less available to perform this function. We will also discuss how this knowledge is being used to engineer new immunostimulatory mAb which can exploit human FcγR effectively, or even mAb which can operate independently of FcγR with the opportunity of potent agonistic function regardless of bio-availability of FcγR.
Citation Format: Martin J. Glennie, Aymen Al-Shamkhani, Stephen A. Beers, Ann L. White, Peter W. Johnson, Ruth R. French, Mark S. Cragg. Designing immunostimulatory antibodies for cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA06.
Abstract IA18: Fighting fire with fire: Developing a personalized neoantigen cancer vaccine
Authors: Wu Catherine J. 
Published: October 2015

Abstract
One of the critical steps to developing curative and tumor-specific immunotherapy is the identification and selection of antigens with tumor-restricted expression in order to avoid undesirable immune responses against normal tissues. Tumor neoantigens are analogous to non-self foreign proteins, therefore bypassing central tolerance and are also exquisitely tumor-specific. Seminal studies have provided compelling evidence suggesting their immunogenicity. However, the comprehensive identification of such neoantigens has only become feasible recently using next-generation massively-parallel sequencing technologies, providing unprecedented genetic information about cancer cells. In addition, refinements in class I HLA prediction algorithms, particularly NetMHCpan, have enabled the reliable prediction of peptide binding for a broad range of class I HLA alleles. Recent studies by us and others in humans and mice have leveraged these tools to demonstrate evidence of protective immunity when targeting tumor neoantigens. We have developed pipelines that leverage WES to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in a multi-epitope personalized therapeutic vaccine. We are pioneering this approach in a first-in-man clinical trial in melanoma.
Citation Format: Catherine J. Wu. Fighting fire with fire: Developing a personalized neoantigen cancer vaccine. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA18.
Abstract PR08: Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma
Authors: Stromnes Ingunn M. , Brockenbrough Scott J. , Schmitt Thomas M. , Hingorani Sunil R. , Greenberg Philip D. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that employs numerous mechanisms of immune suppression. Here we demonstrate the therapeutic activity and safety of an affinity-enhanced T cell receptor (TCR)-based therapy targeting a naturally overexpressed self/tumor antigen in an autochthonous, genetically engineered mouse model of PDA (KPC). T cells engineered to recognize Mesothelin infiltrated the desmoplastic tumor, induced tumor cell lysis and remodeled the extracellular matrix without apparent toxicities to normal tissues. However, this anti-tumor activity was transient despite T cell persistence in PDA. Donor T cells progressively upregulated inhibitory receptors and became dysfunctional specifically in the tumor microenvironment, indicating selective immunosuppression at the tumor site. However, the T cell dysfunction in PDA also was, in part, independent of antigen specificity and the observed upregulation of inhibitory receptors. Nevertheless, a second infusion of engineered T cells still preferentially accumulated in PDA and increased tumor epithelial cell death indicating that PDA remains susceptible to the effects of serial T cell infusions. Finally, we demonstrate that serial T cell infusions significantly increased survival in KPC mice enrolled with invasive PDA indicating that the observed anti-tumor activity can be associated with therapeutic benefits to the host. These results support the clinical advancement of TCR-based therapies for treatment of PDA.
This abstract is also presented as Poster B20.
Citation Format: Ingunn M. Stromnes, Scott J. Brockenbrough, Thomas M. Schmitt, Sunil R. Hingorani, Philip D. Greenberg. Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr PR08.
Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis
Authors: Gupta Nilaksh , Li Wei , McIntyre Thomas M. 
Published: October 2015

Objective—
Platelets express a functional ubiquitin–proteasome system. Mass spectrometry shows that platelets contain several deubiquitinases, but whether these are functional, modulate the proteome, or affect platelet reactivity are unknown.

Approach and Results—

Platelet lysates contained ubiquitin–protein deubiquitinase activity hydrolyzing both Lys
48
and Lys
63
polyubiquitin conjugates that was suppressed by the chemically unrelated deubiquitinase inhibitors PYR41 and PR619. These inhibitors acutely and markedly increased monoubiquitination and polyubiquitination of the proteome of resting platelets. PYR41 (intravenous, 15 minutes) significantly impaired occlusive thrombosis in FeCl
3
-damaged carotid arteries, and deubiquitinase inhibition reduced platelet adhesion and retention during high shear flow of whole blood through microfluidic chambers coated with collagen. Total internal reflection microscopy showed that adhesion and spreading in the absence of flow were strongly curtailed by these inhibitors with failure of stable process extension and reduced the retraction of formed clots. Deubiquitinase inhibition also sharply reduced homotypic platelet aggregation in response to not only the incomplete agonists ADP and collagen acting through glycoprotein VI but also to the complete agonist thrombin. Suppressed aggregation was accompanied by curtailed procaspase activating compound-1 binding to activated IIb/IIIa and inhibition of P-selectin translocation to the platelet surface. Deubiquitinase inhibition abolished the agonist-induced spike in intracellular calcium, suppressed Akt phosphorylation, and reduced agonist-stimulated phosphatase and tensin homolog phosphatase phosphorylation. Platelets express the proteasome-associated deubiquitinases USP14 and UCHL5, and selective inhibition of these enzymes by b-AP15 reproduced the inhibitory effect of the general deubiquitinase inhibitors on ex vivo platelet function.

Conclusions—
Remodeling of the ubiquitinated platelet proteome by deubiquitinases promotes agonist-stimulated intracellular signal transduction and platelet responsiveness.