bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR06: Precision medicine for newly diagnosed and refractory/recurrent pediatric cancer patients: Lessons learned from “N=1” studies
Authors: McEachron Troy A. , Zabokrtsky Keri B. , Sassoon Aaron F. , Nasser Sara , Izatt Tyler , Garner Chad P. , Craig David W. , Carpten John D. , Sender Leonard S. 
Published: May 2016

Abstract
Whole genome sequencing has rapidly emerged as the preferred method for unbiased genomic interrogation. Leveraging this technology, we have developed a precision medicine clinical research protocol for pediatric, adolescent, and young adult cancer patients. The primary objective of this study is to arrive at genome informed treatment recommendations for individual patients suffering from aggressive and/or worsening disease in a clinically relevant time frame. The second objective is to survey the genomic landscape of newly diagnosed and recurrent/refractory patients. To accomplish this, we have employed an interdisciplinary workflow including a customized bioinformatic analysis pipeline, contextual biological interpretation of the data, and case reviews during weekly molecular tumor board meetings. Here we report the results of having sequenced over 50 patients diagnosed with both common and rare malignancies. Factors affecting the successful identification of therapeutically actionable targets and subsequent intervention are varied. The most consistent findings are the increased mutation burden in patients who have received chemotherapy and/or radiation prior to tissue collection. Lastly, we highlight the realistic opportunities, challenges, and insight gained from an ongoing single institution experience.
This abstract is also presented as Poster 27.
Citation Format: Troy A. McEachron, Keri B. Zabokrtsky, Aaron F. Sassoon, Sara Nasser, Tyler Izatt, Chad P. Garner, David W. Craig, John D. Carpten, Leonard S. Sender. Precision medicine for newly diagnosed and refractory/recurrent pediatric cancer patients: Lessons learned from “N=1” studies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr PR06.
Abstract A006: Analysis of immune checkpoint control protein co-expression in breast and ovarian cancer using novel rabbit monoclonal antibodies and multiplex IHC
Authors: Silver Matthew R. , Ziello Jennifer E. , Haack Herbert 
Published: May 2016

Abstract
With an increasing number of biomarkers, and often limited availability of biopsy material, there is a growing need for multiplexed assays for both research and clinical purposes. IHC based solutions are particularly attractive in the field of immuno-oncology, as maintaining special context within the tumor microenvironment provides meaningful, and potentially actionable, information. Immuno-assays with high specificity and sensitivity are a powerful tool; however, there are challenges associated with antibody based multiplexing when more than 2-3 markers are required. A multiplex IHC solution that bypasses antibody species/isotype concerns, while providing signal amplification, was used to examine the co-expression of immune checkpoint control proteins, such as PD-L1, B7-H3, B7-H4, VISTA, in breast and ovarian cancer.
Citation Format: Matthew R. Silver, Jennifer E. Ziello, Herbert Haack. Analysis of immune checkpoint control protein co-expression in breast and ovarian cancer using novel rabbit monoclonal antibodies and multiplex IHC. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A006.
Abstract A033: Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients
Authors: Kurose Koji , Ohue Yoshihiro , Wada Hisashi , Doi Toshihiko , Nishikawa Hiroyoshi , Oka Mikio , Ueda Ryuzo 
Published: May 2016

Abstract
Purpose: FoxP3+ Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has ADCC activity. Depletion of CCR4-expressing FoxP3+ CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients.
Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed.
Results: The results showed that KW-0761 infusion at dose range between 0.1 mg/kg to 1.0 mg/kg was safe and well tolerated. No DLT was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3+ Tregs in the PBMCs during treatment indicated efficient depletion of those cells even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T-cells and CD8 T-cells was limited, while a significant reduction was observed with Th 2 and Th 17 CD4 T-cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients.
Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3+ Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is promising to augment immune responses.
Citation Format: Koji Kurose, Yoshihiro Ohue, Hisashi Wada, Toshihiko Doi, Hiroyoshi Nishikawa, Mikio Oka, Ryuzo Ueda. Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A033.
Abstract A059: Efficacy of anti-ICOS agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer immunotherapeutics
Authors: Elpek Kutlu , Harvey Christopher , Duong Ellen , Simpson Tyler , Shu Jenny , Shallberg Lindsey , Wallace Matt , Sathy Sriram , Mabry Robert , Michaelson Jennifer , Briskin Michael 
Published: May 2016

Abstract
ICOS (inducible co-stimulator molecule) is a T cell encoded member of the extended B7/CD28 superfamily that is up-regulated upon early T cell activation. Previous studies have shown that higher ICOS expression on circulating T cells, post treatment with ipilimumab, is associated with better clinical outcome. In complementary pre-clinical studies, efficacy observed with a whole cell vaccine consisting of ICOS-L expressing B16 melanoma (IVAX) suggests that agonism of this pathway could provide therapeutic benefit in the cancer setting.
In accordance with these observations, we generated a panel of anti-ICOS monoclonal antibodies with in vitro agonist properties. A lead series of mAbs were shown to be efficacious as monotherapies in syngeneic tumors models with enhanced tumor inhibition observed in combination with anti-PD1. Mechanistic studies demonstrate that tumor regression is associated with enhanced ratios of cytotoxic CD8/regulatory T (Tregs) cells and that this change is related to preferential reduction in ICOS high Tregs in the tumor microenvironment.
These data provided the rationale for development of a high affinity humanized agonist monoclonal antibody to be tested in both mono therapy and in combination with other T cell checkpoints. Our lead anti-ICOS antibody is currently in IND-enabling studies and will be tested for activity in solid tumor indications.
Citation Format: Kutlu Elpek, Christopher Harvey, Ellen Duong, Tyler Simpson, Jenny Shu, Lindsey Shallberg, Matt Wallace, Sriram Sathy, Robert Mabry, Jennifer Michaelson, Michael Briskin. Efficacy of anti-ICOS agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer immunotherapeutics. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A059.
Abstract A064: Modeling checkpoint blockade inhibitor resistant immunoregulation induced by squamous epithelial cancers
Authors: Mattarollo Stephen , Leggatt Graham , Wells James , Lambert Paul , Frazer Ian H. 
Published: May 2016

Abstract
Aim: Squamous epithelial cancers are immunogenic, as demonstrated by an increased risk of development in immunosuppressed patients. Some however evade host immunity, and establishing the mechanism of immune evasion could assist with squamous cancer immunotherapy.
Method: We have used a model of squamous epithelial pre malignancy, in which HPV16 E7 transgenic and hyperproliferative mouse skin is transplanted to naïve mice, and have explored local regulation of effector T cell function by E7 transgenic epithelial cells through manipulation of the graft donor immune system.
Results: E7 transgenic skin is not rejected by naïve recipient mice, or by mice immunised with E7 protein and expressing E7 specific cytotoxic T cells. E7 expressing hyper proliferative epithelium demonstrates caspase-1 activation, production of IL-1β, IL-18, and CCL2, and attraction and activation of NKT cells and mast cells. Rejection of E7 transgenic skin grafts can be observed following depletion from the donor skin of bone marrow derived cells, of NKT cells or of mast cells, whereas adjacent E7 transgenic grafts, otherwise unmanipulated, are not rejected. E7 graft rejection can also be induced by suppression in the donor skin or recipient animal of NKT cell secreted IL-17 or IFN-γ, or by depletion of the soluble IL-1 receptor IL-1R1 or blockade of Arginase activity in the recipient. Inhibition of graft rejection is not overcome by antibody to PD-1, PD-L1, or PD-L2. Hyperproliferative cervix epithelium in patients with CIN3 expresses the factors identified as inhibitory to E7 transgenic skin graft rejection, whereas skin from E7 transgenic mice with a mutated Rb gene preventing E7 induced epithelial proliferation lacks the inhibitory factors.
Conclusion: Epithelial hyper proliferation induces immunosuppressive mechanisms that locally prevent cytotoxic T cell function through mechanisms independent of checkpoint blockade. We hypothesise from our data that the local balance of production of IL-1β and Il-18 locally determines cytotoxic T cell effector function targeted at epithelial antigens.
Citation Format: Stephen Mattarollo, Graham Leggatt, James Wells, Paul Lambert, Ian H. Frazer. Modeling checkpoint blockade inhibitor resistant immunoregulation induced by squamous epithelial cancers. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A064.
Abstract A098: Helicobacter-specific T cell responses in gut homeostasis and disease
Authors: Xu Mo , Littman Dan R. 
Published: May 2016

Abstract
The gastrointestinal tract is the major site for constant immunological challenge to the host immune system. The host must be able to mount protective immune responses against pathogenic micro-organisms while maintaining tolerance to most microbes under homeostatic conditions. A number of Helicobacter species, including Helicobacter hepaticus, have been isolated as the etiological agents of gastric ulcer disease or colitis in their respective hosts. H. hepaticus infection induces severe colitis in a number of immunocompromised mouse mutants, but interestingly does not usually cause disease in most WT mouse strains. Although Th17/Th1 responses are known to play an important role in H. hepaticus-mediated inflammation, how the immune response is contained such that it is harmless under homeostatic conditions and how perturbations lead to pathogenicity remain elusive questions. To answer these, it will be important to track H. hepaticus-specific T helper cells, which form a small proportion of total gut T helper cells, under homeostatic conditions. We have characterized TCRs specific for H. hepaticus antigens, which has allowed for development of TCR transgenic mice and MHCII tetramers to interrogate the specific T cell response that can contribute to inflammatory bowel disease in mouse models.
Citation Format: Mo Xu, Dan R. Littman. Helicobacter-specific T cell responses in gut homeostasis and disease. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A098.
Abstract A104: Eradication of large solid tumors in immunocompetent mice using dual specific CAR T cells and vaccination
Authors: Slaney Clare Y. , Westwood Jennifer A. , Beavis Paul A. , Darcy Phillip K. , Kershaw Michael H. 
Published: May 2016

Abstract
While adoptive cell transfer (ACT) using chimeric antigen receptor-expressing (CAR) T cells has led to remarkable complete responses in leukemia, complete responses of solid tumors in patients are few. Similarly, previous investigations in mice have demonstrated clearance of large burdens of disseminated cancer using CAR T cells, but large solid tumors (&gt;1 cm2) have not responded fully. Here we report the generation of transgenic mice containing dual specific CAR T cells with specificity for Her2 and the melanoma-associated antigen pMEL (gp100), designated CARaMEL mice. In response to Her2-positive cancer cells, T cells from CARaMEL mice could secrete cytokines and engage in cytolysis mediated by an anti-Her2 CAR. Through their endogenous TCR, CARaMEL T cells could proliferate extensively in response to gp100. We demonstrate the ability of CARaMEL T cells in ACT incorporating vaccination (ACTIV) therapy to induce eradication of large tumors of various histologies, including orthotopic breast tumors, subcutaneous sarcoma and colon carcinoma liver tumors. Tumor models were performed in immunocompetent mice expressing human Her2 in normal brain and breast tissue. Effective ACTIV therapy included a lymphodepleting preparative regimen, ACT, high-dose IL-2 and recombinant vaccinia virus expressing gp100. ACTIV therapy was associated with expansion of dual-specific T cells and extensive tumor infiltration by CARaMEL T cells. Infiltration of CARaMEL T cells was also observed in normal tissues including brain. Long term surviving mice were totally resistant to rechallenge with Her2-expressing tumor cells, and partially resistant to Her2-negative tumor cells. We anticipate studies currently underway to provide mechanistic insight into the antitumor activity of ACTIV therapy.
Citation Format: Clare Y. Slaney, Jennifer A. Westwood, Paul A. Beavis, Phillip K. Darcy, Michael H. Kershaw. Eradication of large solid tumors in immunocompetent mice using dual specific CAR T cells and vaccination. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A104.
Abstract A145: Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma
Authors: Tomkötter Lena , Werba Gregor , Nguy Susanna , Alothman Sara , Alqunaibit Dalia , Tiwari Shaun , Ly Nancy Ngoc Giao , Daley Donnele , Ochi Atsuo , Barilla Rocky , Torres-Hernandez Alejandro , Pellicciotta Ilenia , Du Kevin , Miller George 
Published: May 2016

Abstract
Radiation therapy (RT) has shown marginal efficacy in patients with pancreatic ductal adenocarcinoma (PDA). Two of the past three randomized controlled trials investigating the efficacy of RT for patients with locally advanced unresectable PDA have shown a statistically significant worse survival by 40% or more for patients receiving RT. We postulated that RT reprograms inflammatory cells within the tumor microenvironment to an immune suppressive phenotype limiting the efficacy of RT in invasive PDA and accelerating disease progression in surrounding pre-invasive foci. We found that RT markedly accelerates the progression of pre-invasive PDA in a dose-dependent manner and reduces animal survival by more than 6 months. In both invasive and pre-invasive PDA, RT reprograms immunogenic macrophages towards an immune-suppressive M2 phenotype resulting in CD8 T cell scarcity and Th2 and Treg differentiation of CD4 T cells. Moreover, adoptive transfer of T cells harvested from RT-treated tumors accelerates tumor growth in recipient hosts. We show that M-CSF blockade concurrent with RT prevents immune-suppressive macrophage and T cell reprogramming and markedly enhances the efficacy of RT in PDA. These data suggest that targeting macrophage reprogramming can unleash the utility of RT for PDA.
Citation Format: Lena Tomkötter, Gregor Werba, Susanna Nguy, Sara Alothman, Dalia Alqunaibit, Shaun Tiwari, Nancy Ngoc Giao Ly, Donnele Daley, Atsuo Ochi, Rocky Barilla, Alejandro Torres-Hernandez, Ilenia Pellicciotta, Kevin Du, George Miller. Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A145.
Abstract A161: Angiotensin II type 1 receptor antagonism suppresses tumor metastasis through inhibition of CCL2-CCR2 mediated monocyte recruitment
Authors: Regan Daniel P. , Guth Amanda M. , Hansen Ryan J. , Gustafson Daniel L. , Dow Steven W. 
Published: May 2016

Abstract
Purpose: Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, seeding, growth, and angiogenesis, as well as suppression of anti-tumor immunity. Migration of inflammatory monocytes to sites of inflammation or tumor metastasis is mediated primarily via the action of the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis through receptor or ligand blockade represents an attractive therapeutic target for the treatment of metastatic disease.
Methods: Losartan, an angiotensin II type 1 receptor (AT1R) antagonist, has been previously reported to suppress tumor growth through mechanisms associated with tumor angiogenesis and inhibition of TGF-β signaling. However, our studies also suggest an important contribution to the anti-tumor effects of losartan from monocyte migration inhibition. Therefore, we conducted studies in murine breast (4T1) and colon (CT26) carcinoma experimental pulmonary metastasis models, to determine the degree to which losartan's anti-metastatic effect was predominantly dependent on disruption of CCL2-CCR2 mediated monocyte recruitment to tumor metastases.
Results: We found that daily treatment with losartan prolonged survival, and significantly reduced metastatic burden, percentages of CD11b+/Ly6C+ lung monocytes, and tumor microvessel density in mice with 4T1 and CT26 pulmonary metastases. However, compared to pure CCR2 antagonists, our studies show that losartan does not act as a direct competitive antagonist to CCR2. Rather, in vitro assays and studies in CCR2 -\- mice indicated that losartan's anti-metastatic effect was primarily mediated via suppression of monocyte recruitment through indirect interruption of the CCL2-CCR2 axis. Importantly, losartan proved more effective at reducing monocyte recruitment and slowing CT26 pulmonary metastatic tumor growth compared to a specific CCR2 antagonist.
Conclusions: We conclude therefore that losartan exerts significant anti-metastatic activity in aggressive murine metastasis models, and that losartan's major anti-metastatic effect is mediated by blockade of CCL2-CCR2 dependent monocyte recruitment. Thus, by virtue of its myeloid cell activity, losartan, in combination with conventional cancer therapeutics, has potential for use as an anti-metastatic agent in animals and humans at high risk for tumor metastasis.
Citation Format: Daniel P. Regan, Amanda M. Guth, Ryan J. Hansen, Daniel L. Gustafson, Steven W. Dow. Angiotensin II type 1 receptor antagonism suppresses tumor metastasis through inhibition of CCL2-CCR2 mediated monocyte recruitment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A161.
Abstract A162: Cancer-specific T cell receptor isolation for cancer immunotherapy
Authors: Ryan Ruth , Hibbert Linda , Weigand Luise , Paston Samantha , Baker Debbie , Donnellan Zoe , Clark Vanessa , Hale Kathy , Conlon Louise , Dukes Joseph , Boudousquie Caroline , Bossi Giovanna , Hickman Emma , Powlesland Alex , Vuidepot Annelise , Hassan Namir , Jakobsen Bent 
Published: May 2016

Abstract
Malignant cells may be recognised by T cells binding cell surface Class I HLA (Human Leukocyte Antigen)-peptide complexes presenting disease-associated epitopes. Many cancer patients have been shown to generate CD8 cytotoxic T cell responses to tumour-associated antigens. However, this is often insufficient for the immune system to clear tumours, resulting in progression of cancer. This is in part due to the low avidity of these T cells, as well as the ability of cancer cells to develop escape mechanisms to avoid destruction by T cells. To overcome these issues, we have engineered novel, bi-functional protein therapeutics termed ImmTACs (Immune mobilising monoclonal TCR Against Cancer) which re-direct the immune system to target and destroy tumour cells with a high degree of potency and specificity. An ImmTAC comprises a high affinity ‘monoclonal’ T cell receptor (mTCR) targeting a cancer-associated HLA-peptide complex, fused to an anti-CD3 scFv domain which activates an anti-tumour T cell response.
In order to produce ImmTACs, we have developed an integrated in-house process leading to the isolation of TCRs specific for validated cancer epitopes. The critical steps in this process are: antigen selection, epitope identification, T cell cloning, TCR isolation and binding to soluble peptide:MHC on Biacore. High affinity ImmTACs are then generated through a process of affinity maturation. We describe the steps leading to cloning of wild type TCRs and present data to illustrate the successful isolation of TCRs as a result of this procedure.
Citation Format: Ruth Ryan, Linda Hibbert, Luise Weigand, Samantha Paston, Debbie Baker, Zoe Donnellan, Vanessa Clark, Kathy Hale, Louise Conlon, Joseph Dukes, Caroline Boudousquie, Giovanna Bossi, Emma Hickman, Alex Powlesland, Annelise Vuidepot, Namir Hassan, Bent Jakobsen. Cancer-specific T cell receptor isolation for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A162.