bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1648: ImmunoGraft® platform for the evaluation of Immuno-Oncology agents in PDX tumors models
Authors: Cerna David , Ciznadija Daniel , Verma Bhavna , Sidransky David , Izumchenko Evgeny , Davies Angela , Mancini Maria 
Published: July 2017

Abstract
Recent breakthroughs in Immunotherapy have given new hope to treating previously untreatable tumor types and provide a better tolerated alternative to standard agents. There is an unmet need for a pre-clinical platform to test potential immune-oncology therapeutics that would also provide a tool to examine the mechanisms of response to better predict clinical outcomes. We have previously presented the Champions ImmunoGraft®, an innovative pre-clinical model enabling immunotherapeutic agents to be evaluated for efficacy in solid tumors. This platform is more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and may be one of the most translationally-relevant models to date for screening therapies targeting the immune system. However, optimization of humanization and PDX implantation protocols that allow a broader reconstitution of cell linage and higher engraftment rate are necessary to further improve the pre-clinical evaluation of immune-oncology therapeutics and enhance the value of this modality for patient’s benefit.
To this end, immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells using optimized procedure and blood was collected at different time points post engraftment to check for the major leukocyte linages. At ten weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the humanized animals. As a result of improved methodology of the reconstitution protocol we have achieved an 85% success rate of humanization with a shortened engraftment period utilizing fewer CD34+ cells that maintain humanization reconfirmed at 22 weeks post reconstitution.
Champions TumorGraft® database contains more than one-thousand clinically relevant well-annotated PDX models. We have complied data from extensive genetic and protein expression analyses to design applicable ImmunoGraft® studies for testing of Immuno-Oncology agents. We have identified tumors expressing key markers that may predict response to immunotherapy agents including PDL-1, CD40, IDO-1 and IDO-2 as well as tumors that harbor a high mutational load. Here we present the efficacy and clinically relevant endpoints of two well-studied checkpoint inhibitors Ipilimumab and Pembrolizumab in this highly translational PDX platform.
Citation Format: David Cerna, Daniel Ciznadija, Bhavna Verma, David Sidransky, Evgeny Izumchenko, Angela Davies, Maria Mancini. ImmunoGraft® platform for the evaluation of Immuno-Oncology agents in PDX tumors models [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 1648. doi:10.1158/1538-7445.AM2017-1648
Abstract 1649: In vivo CRISPR-Cas9 library screen for immune checkpoint regulators
Authors: Karassek Sascha , Long Min , Li Xi , Peng Zhengang , Ji Qunsheng , Cang Yong 
Published: July 2017

Abstract
Therapeutic antibodies blocking immune checkpoints such as programmed cell death protein 1 (PD1) have proven clinically beneficial in multiple cancer types. However, anti-PD1 drugs approved by FDA are neither effective in treating all cancer types nor in all patients in a responsive cancer type. Therefore, understanding the mechanism underlying the efficacy of immune checkpoint blockade is critical for our rational design of synergistic treatment combinations. Here we describe how we employ the latest CRISPR-Cas9 genome-wide knockout screening strategies to identify targets in cancer cells or in T lymphocytes that control the sensitivity or resistance to anti-PD1 treatment. We constructed a sgRNA library targeting the functional domains of 116 mouse methyltransferases and demethylases, which was infected into the mouse Cloudman S91 melanoma cell line. Syngeneic mouse xenograft models derived from these infected cells were treated with anti-mPD1 monoclonal antibody, and the xenograft tumors were harvest at different time points after antibody treatment. Deep sequencing of the integrated sgRNA sequences in the tumors has identified potential druggable targets to sensitize or antagonize the tumors resistance to anti-mPD1 immunotherapy. Alternatively, we introduced the same library to naïve T cells purified from the OT-1 transgenic mice. The T cell library was then injected to B16-OVA melanoma syngeneic mouse models, followed by anti-mPD1 treatment. Deep sequencing of the integrated sgRNA sequences in the tumor-infiltrating T cells would allow us to uncover novel signaling molecules in the immune system that can potentially be manipulated to enhance the anti-PD1 therapy. In summary, we provide in vivo knockout screen strategies that can be applied to identify and validate combination therapies with immune checkpoint antibodies.
Citation Format: Sascha Karassek, Min Long, Xi Li, Zhengang Peng, Qunsheng Ji, Yong Cang. In vivo CRISPR-Cas9 library screen for immune checkpoint regulators [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 1649. doi:10.1158/1538-7445.AM2017-1649
Abstract 1650: Targeting CD47- SIRPα interaction by novel peptide-based antagonists
Authors: Sasikumar Pottayil G. , Gundala Chennakrishnareddy , Gowda Nagaraj M. , Naremaddepalli Sudarshan S. , Bhumireddy Archana , Nair Rashmi , Balasubramanian Wesley Roy , Lakshminarasimhan Anirudha , Dodheri Samiulla S. , Aithal Kiran , Ramachandra Raghuveer K. , Daginakatte Girish , Ramachandra Murali 
Published: July 2017

Abstract
Background: Cluster of differentiation (CD47) is a trans-membrane glycosylated protein which is upregulated in several cancers. Increased expression of CD47 on tumor cells is associated with immune evasion and cancer progression. CD47 through its interaction with signal regulatory protein alpha (SIRPα), a cell-surface molecule on macrophages inhibits phagocytosis of tumor cells. Disrupting CD47-SIRPα interactions by monoclonal antibodies targeting CD47 and recombinant SIRPα proteins have been used as therapeutic strategies for treating cancer. Our objective was to discover and develop peptide/peptidomimetic based CD47 antagonists for disrupting CD47-SIRPα interactions.
Methods: Through rational design based on crystal structure of CD47/SIRPα interacting interface, we designed peptides having potential to disrupt CD47-SIRPα interactions. FACS based cellular binding assay was developed to assess the binding affinity of CD47 antagonists. SIRPα protein labelled with fluorescent dye was incubated with Jurkat T cells expressing high levels of CD47 in the presence/absence of peptides. Binding affinity was measured by decrease in fluorescence. Functional activity of the peptides was evaluated in a FACS-based phagocytosis assays, in which tumor cells were incubated with human/mouse macrophages in the presence/absence of CD47 antagonists.
Results: We identified CD47 antagonists demonstrating disruption of CD47-SIRPα interaction in a cellular binding assay. These peptides significantly inhibited phagocytosis of different tumor cells by macrophages. The lead CD47 antagonist displaying good ADME properties including moderate oral bioavailability was evaluated in a B16F10 syngeneic mouse tumor model. The lead CD47 antagonist inhibited primary tumor growth as well tumor metastasis to lungs. Biomarker characterization and efficacy studies in additional tumor models are ongoing.
Citation Format: Pottayil G. Sasikumar, Chennakrishnareddy Gundala, Nagaraj M. Gowda, Sudarshan S. Naremaddepalli, Archana Bhumireddy, Rashmi Nair, Wesley Roy Balasubramanian, Anirudha Lakshminarasimhan, Samiulla S. Dodheri, Kiran Aithal, Raghuveer K. Ramachandra, Girish Daginakatte, Murali Ramachandra. Targeting CD47- SIRPα interaction by novel peptide-based antagonists [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 1650. doi:10.1158/1538-7445.AM2017-1650
Abstract 1653: Modeling tumor immuno-dynamics to predict patient survival and immunotherapy efficacy
Authors: Akers Nicholas K. , Schadt Eric E. , Losic Bojan 
Published: July 2017

Abstract
State of the art models of cancer survival are increasingly utilizing molecular data that feature the number of non-synonymous mutations, or a network based stratification of mutations, as significant predictors. It is widely hypothesized that this association between mutations and survival is a result of neo-epitopes that induce a robust anti-tumor immune response. Naively this implies that patient neo-epitope burden should better predict survival than that of mutations alone, however this has generally been difficult to prove. Indeed, mutations and predicted neo-epitopes explain roughly the same survival variance, likely due to the intertwined difficulties of neo-epitope prioritization and the often immuno-suppressive tumor microenvironment.
Reasoning that integrating leading order immune response with novel neo-epitope prioritization will lead to superior performance, we built a statistical model to quantify the influence of tumor immune-dynamics on patient survival. Neoepitopes (MHC-I/II) were predicted from mutations and filtered on a self-ligandome. The clonal structure of these mutations and the distribution of resulting epitopes were assessed as predictive features. Additionally, the existing response to epitopes was assayed by incorporating TCR and BCR sequence counts and entropy as a proxy for clonal tumor infiltrating lymphocyte expansion.
Leveraging the cancer genome atlas (TCGA) for 9 major cancer types including bladder (BLCA), breast (BRCA), colorectal (COAD/READ), glioblastoma (GBM), liver (LIHC), lung (NSCLC), melanoma (SKCM), pancreatic (PAAD), and uterine (UCEC) cancer, we obtained omics data for a total of 2,866 patients. Random forest based recursive feature elimination was used to determine which features were most likely to be predictive while overfitting was controlled with k-fold cross validation. A cox proportional hazard model of survival as a function of mutation burden and functions of neoepitope and immune response predictors was constructed using the selected features. Our results confirm that neoepitope and immune response based predictors for survival often significantly outperform mutation burden alone and simultaneously suggest a quantitative classification of immunotherapy efficacy across cancer subtypes.
Citation Format: Nicholas K. Akers, Eric E. Schadt, Bojan Losic. Modeling tumor immuno-dynamics to predict patient survival and immunotherapy 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 1653. doi:10.1158/1538-7445.AM2017-1653
Abstract 1658: Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies
Authors: Ouyang Davy Xuesong , Chen Gang , Wang Zhensheng , Zheng Lei , An Annie Xiaoyu , Wery Jean-Pierre , Liu Jay , Dong Xin , Li Henry Q. X. 
Published: July 2017

Abstract
CD137 belongs to the TNF receptor super family, and its activation is essential to the function of T cells and NK cells. Multiple agonistic CD137 antibodies are currently being tested in humans with advanced cancer, which expected to become an important new immuno-oncology therapeutics in clinic. It is important to establish preclinical models for efficacy assessment of investigational CD137 antibodies before entering clinic. Currently available animal models cannot meet this need. Syngeneic mouse tumor models provide a useful platform for testing surrogate immuno-oncology therapies, but cannot be used for testing human therapeutic antibodies due to the species specificity; human immunity reconstituted models, by human PBMC or hematopoietic stem cell inoculation into immune deficient mice, suffering from highly variable responses, are not robust enough to provide a reliable system for efficacy studies. Establishing target humanized models by replacing mouse therapeutic target with human counterpart while maintaining normal mouse immunity is a practical approach to evaluate human therapeutic antibodies in vivo. Using CRISPR-Cas9 gene editing, we have engineered human CD137 knock-in model expressing chimeric human/mouse CD137 composed of human extracellular and transmembrane domains (Exon 4-7), with intact mouse signal peptide and intracellular domain. FACS analysis of splenocytes derived from homozygous knock-in mice showed that CD3/CD28 stimulated T cells only express chimeric CD137 reactive to human CD137 antibodies, but not mouse CD137; Yet the expression levels of the chimeric CD137 in the knock-in mice are generally lower than endogenous mouse protein in wild-type C57BL/6 mice. At present, we are testing the efficacy of reference human CD137 agonistic antibodies by treating these homozygous knock-in mice grafted with syngeneic MC38 tumor cells. Data will be presented at the conference.
Citation Format: Davy Xuesong Ouyang, Gang Chen, Zhensheng Wang, Lei Zheng, Annie Xiaoyu An, Jean-Pierre Wery, Jay Liu, Xin Dong, Henry Q. X. Li. Establishment of CD137 humanized mouse model for efficacy assessment of agonistic anti-CD137 therapeutic antibodies [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 1658. doi:10.1158/1538-7445.AM2017-1658
Abstract 1661: Humanized mouse models for immune-oncology biotherapeutics: Development, validation and applications
Authors: Chen Gang , Cai Bin , Zhou Feng , Zhou Jerry , Liu Jie , Dong Xin 
Published: July 2017

Abstract
With clinical success and FDA approval of Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, developing biotherapeutics against immune checkpoint targets, like CTLA-4, PD-1/PDL-1 and others, becomes hot pursuits for big pharma and biotech. However, traditional syngeneic models with surrogate murine reagents or human immune cell re-constitution in immune deficient mice are useful but not reliable and robust due to the species specificity and highly variable responses. It is crucial to establish additional preclinical models for efficacy assessment of investigational immune-oncology antibodies before entering clinic. Establishing human therapeutic target engineered mouse models by replacing mouse gene with human counterpart while maintaining intact mouse immunity is a practical approach for in vivo studies.
Applying CRISPR-Cas9 and other gene editing techniques, we have engineered genetically a series of single and double human immune-checkpoint genes, like PD-1/PDL-1, CTLA-4, TIM3, CD137 and others, knock-in model expressing chimeric human/mouse targets composed of human extracellular domains, with intact mouse signal peptide and intracellular domain. FACS analysis of immune cells derived from homozygous knock-in mice showed that activated cells only express chimeric targets reactive to anti human target antibodies, but not mouse gene specific antibodies. We have been testing the efficacy of reference antibodies by treating these homozygous knock-in mice inoculated with syngeneic murine tumor cells. Other applications, like target validation, combination therapy and biomarker discovery, are also explored.
Note: This abstract was not presented at the meeting.
Citation Format: Gang Chen, Bin Cai, Feng Zhou, Jerry Zhou, Jie Liu, Xin Dong. Humanized mouse models for immune-oncology biotherapeutics: Development, validation and applications [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 1661. doi:10.1158/1538-7445.AM2017-1661
Abstract 1664: Inhibition of 4T1 mammary tumor growth in BALB/c mice by subcutaneous and intraperitoneal injection of a 4T1 whole cell vaccine containing IL-2 and GM-CSF as adjuvants
Authors: Head Jonathan F. , Phillips Jeffrey T. , Jiang Xianpeng , Elliott Robert L. 
Published: July 2017

Abstract
Developing animal tumor models for human cancer vaccines creates a tool to investigate the mechanism of action, variations in formulation, dosing schedules, and combinations with other forms of cancer therapy. In this study we developed a mouse whole cell mammary cancer vaccine model with both subcutaneous and intraperitoneal injection of the vaccine. The vaccine, containing 4T1 mouse mammary cancer cells (1,000,000 cells), IL-2 (0.2 µg) and GM-CSF (0.1 µg) in a total volume of 150 µl, was injected either subcutaneously into the backs of BALB/c mice or intraperitoneally. There were six injections of the vaccine (weeks 1, 2, 3, 7, 11, 15) and one week after the last injection 100,000 4T1 cells from cell culture in a volume of 100 µl were injected into the scapular region of the mice. At 22 days post 4T1 tumor transplantation there was a 37% inhibition of the growth of the 4T1 tumor in the mice receiving the subcutaneous injection of the vaccine and a 42% inhibition of the growth of the 4T1 tumor in the mice receiving the intraperitoneal injection of the vaccine. The inhibition of 4T1 mammary tumor growth in this mouse model with subcutaneous injection of a whole cell vaccine gives further support for the previously reported efficacy in a Phase 1/2 clinical trial of our therapeutic breast cancer vaccine containing autologous and allogeneic breast cancer cells in the adjuvant setting. The inhibition of 4T1 tumor growth with intraperitoneal injection suggests a delivery method that may be applicable to ovarian cancer and cancer patients with malignant ascites.
Citation Format: Jonathan F. Head, Jeffrey T. Phillips, Xianpeng Jiang, Robert L. Elliott. Inhibition of 4T1 mammary tumor growth in BALB/c mice by subcutaneous and intraperitoneal injection of a 4T1 whole cell vaccine containing IL-2 and GM-CSF as adjuvants [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 1664. doi:10.1158/1538-7445.AM2017-1664
Abstract 1691: USP7 inhibitors impair Foxp3+ T regulatory cell function and promote antitumor immunity against solid tumors
Authors: Kumar Suresh , Wu Jian , Wang Liqing , Wang Feng , Sokirniy Ivan , Wang Hui , Sterner David , Grove Charles , Weinstock Joseph , Mattern Michael , Hancock Wayne 
Published: July 2017

Abstract
Tumor microenvironment (TME) plays critical role in suppressing the immune system’s ability to recognize and destroy cancer cells. Although T cell checkpoint blockers such as anti-PD1 antibodies unleash anti-tumor immune response against a variety of tumors, the complex immunosuppressive tumor milieu necessitates development of additional therapeutic agents to potentiate active drugs and expand the realm of the revolutionary cancer immunotherapy. The presence of highly immunosuppressive Foxp3+ T-regulatory cells (Tregs) in the TME has been correlated with poor prognosis. Thus, depletion of Tregs or impairment of Treg function is considered an attractive therapeutic approach. USP7, a deubiquitylase (DUB) implicated as a critical node in several cancer signaling pathways has emerged as an essential factor in maintaining Treg functions. Treg specific deletion of USP7 impairs Treg function leading to lethal autoimmunity. Using the UbiProTM discovery platform, Progenra has identified selective covalent USP7 inhibitors that were subjected to lead optimization and preclinical evaluation. Potent and selective candidate USP7 inhibitors have been shown to impair Treg functions ex vivo and in vivo as well as exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. Most importantly, Progenra’s USP7 inhibitors enhances the efficacy of anti-PD1 antibody and cancer vaccines. Along with the already established direct anti-tumor activities of USP7 inhibitors, these studies provide a strong rationale for combining USP7 inhibitors to suppress Treg functions and improve the efficacy of currently approved cancer immunotherapy agents.
Citation Format: Suresh Kumar, Jian Wu, Liqing Wang, Feng Wang, Ivan Sokirniy, Hui Wang, David Sterner, Charles Grove, Joseph Weinstock, Michael Mattern, Wayne Hancock. USP7 inhibitors impair Foxp3+ T regulatory cell function and promote antitumor immunity against solid tumors [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 1691. doi:10.1158/1538-7445.AM2017-1691
Abstract 17: Anti-metastatic platinum through glycan targeting in breast cancer
Authors: Katner Samantha J. , Peterson Erica Peterson J. , Katsuta Eriko , DeMasi Stephanie C. , Koblinski Jennifer , Takabe Kazuaki , Farrell Nicholas P. 
Published: July 2017

Abstract
The high affinity of polynuclear platinum compounds (PPCs) for heparan sulfate (HS) is mediated through a “sulfate clamp” and PPC interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding.1 Metalloshielding will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation.2 PPCs inhibit cleavage of a model pentasaccharide by heparanase and further modulate bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells.3 The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis.3 Following proof-of-principle of strong in vivo anti-metastatic activity of PPCs in clinically relevant breast cancer models,4 this contribution examines the underlying mechanism of platinums as anti-metastatic agents. We report on the cellular effects of PPC-HS metalloshielding on multiple growth factor signaling pathways (bFGF, HB-EGF) and specific syndecan (Sdc)-dependent signaling in breast cancer. Coupled with previously demonstrated DNA binding, PPCs represent intrinsically dual- function agents combining platinum cytotoxicity with anti-angiogenic effects derived from first principles through glycan targeting.
[1] Mangrum, J.B., Engelmann, B.J., Peterson, E.J., Ryan, J.J., Berners-Price, S.J., Farrell, N.P. Chemical Communications 2014, 50, 4056-4058.
[2] Chiodelli, P., Bugatti, A., Urbinati, C., Rusnati, M. Molecules 2015, 20, 6342-6388.
[3] Peterson, E.J., Daniel, A.G., Katner, S.J., Bohlmann, L., Chang,C., Bezos, A., Parish, C.R., von Itzstein, M., Berners-Price, S.J., Farrell, N.P. Chem. Sci. 2016, DOI: 10.1039/C6SC02515C.
[4] E. Katsuta, S. Demasi, S. Katner, H. Aoki, E. Peterson, E., N.P. Farrell and K. Takabe. (2016). Proc. AACR New Orleans, LA. Abstract #3064.
DC 1-5 April 2017
Citation Format: Samantha J. Katner, Erica Peterson J. Peterson, Eriko Katsuta, Stephanie C. DeMasi, Jennifer Koblinski, Kazuaki Takabe, Nicholas P. Farrell. Anti-metastatic platinum through glycan targeting in breast 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 17. doi:10.1158/1538-7445.AM2017-17