bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA15: Promise and challenges of pediatric cancer PDX models
Authors: Houghton Peter J. , Kurmasheva Raushan T. 
Published: March 2017

Abstract
The Pediatric Preclinical Testing Program (PPTP) has evaluated almost 97 single agents and several combinations over the last 10 years. A total of 89 xenograft models that encompass solid tumors, brain tumors, and acute leukemias have been used as a screen to identify novel agents that could be accelerated for clinical trial. With few exceptions, all models were directly established in mice from patient biopsies, and approximately half of the models were established from patients who were refractory or had relapsed.
Expression analysis showed that tumor models clustered with their appropriate clinical histotype, and exome sequencing showed mutation frequency and identity to be similar to published genomic data for patient cancers. The models accurately identified known active agents that are used as standard of care therapy for solid tumors and leukemias, thus validating the models.
Criteria for assessing response similar to clinical criteria were developed. Of the 97 agents tested, twenty-four signaling inhibitors (ligand or receptor binding antibodies, kinase inhibitors etc.) were evaluated. With the exception of inhibitors of Aurora kinase A, and Polo-like kinase 1, the overall objective response rate (ORR) was &lt;2%. The low response rate is probably an accurate reflection of likely ORR in clinical trials, as the models identified selumetinib in an astrocytoma with BRAF (V600E) mutation, dasatinib in a Ph+ ALL, sorafenib in a Flt3 mutant ALL, and crizotinib in an ALK mutant neuroblastoma.
The models identified several cytotoxic agents as having broad-spectrum antitumor activity (eribulin, alisertib, PR-104), with small molecule and antibody conjugated antimitotic agents showing high-level activity in many models (eribulin in sarcoma and ALL, glembatumab in osteosarcoma). The major issue is that the models overpredict drug activity due to tolerance of the host (mouse) compared to patients. Thus, it is imperative to adjust dose/schedule to accurately reproduce clinical exposures.
Another issue to be addressed is whether the models adequately encompass genomic and epigenomic heterogeneity. With increasing evidence of molecular subtypes within histotypes previously considered as relatively homogeneous, it is clear that additional models need to be established. We have analyzed 2134 tumor/drug studies undertaken as part of the PPTP to determine whether alternative experimental designs can be used that would allow an increased genomic diversity to be interrogated using current resources.
Citation Format: Peter J. Houghton, Raushan T. Kurmasheva. Promise and challenges of pediatric cancer PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA15.
Abstract IA16: Patient-derived xenograft models in glioblastoma
Authors: Seoane Joan 
Published: March 2017

Abstract
One the most important challenges in the treatment of cancer is its evolving genomic intratumor heterogeneity. Tumors are composed of assortments of cells with subclonal genomic alterations that evolve following Darwinian selection. Glioblastoma (GBM) is a prototypical heterogeneous tumor and still little is known about how intratumor heterogeneity influences the progression of GBM and, most importantly, determines the response to treatments and tumor relapse. The study of the spatial and temporal genomic architecture of GBM is essential to understand the biology and improve the treatment of this dismal disease. Through the study of primary and relapsed tumors and patient-derived xenograft models (PDX) of GBM, we are studying the genomic subclones emerging after treatment since these subclones might be enriched in genomic alterations that confer a selective advantage and resistance to treatment. Putative genomic alterations involved in tumor resistance to treatment are further studied and validated through PDX models.
Citation Format: Joan Seoane. Patient-derived xenograft models in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA16.
Abstract IA22: Studying drug resistance through PDX models
Authors: Scaltriti Maurizio 
Published: March 2017

Abstract
Emergence of drug resistance is the main limitation for a durable response to therapy. The mechanisms of such resistance need to be uncovered in order to identify those patients that are more likely to respond and/or develop novel strategies to overcome tumor adaptation to therapy.
Patient-derived xenografts can be established from patients at any stage of their treatment. However, samples collected before the exposure to the pharmacological pressure (therapy-naïve) and tumors from patients that progressed to therapy after an initial response (acquired resistance) are preferable.
Of particular interest are the models derived from outliers; that are either patients unexpectedly refractory to a given therapy (e.g. BRCA-mut tumors not responding to PARP inhibitors or HER2-positive tumors not responding to anti-HER2 agents) or patients that exhibited an exceptional response (magnitude/durability) to specific targeted agents.
There are at least two advantages in using patient-derived material for this kind of studies. The availability of virtually limitless tissue allows deep genomic and proteomic analysis of tumor cells that supposedly resemble the clinical scenario. Moreover, the possibility to perpetuate these tumors is crucial to confirm the resistance phenotype and test novel and more efficacious therapeutic options.
In my presentation I will include several examples of how patient-derived models have helped demonstrating the genuineness of previously hypothesized mechanisms of resistance to targeted therapy and have been instrumental to test combinatorial strategies that resulted in remarkable antitumor activity. Furthermore, I will show that patient-derived models can also serve as tools to test novel “smart” drug delivery systems.
Citation Format: Maurizio Scaltriti. Studying drug resistance through PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA22.
Abstract IA28: Innovative PDX models for studying immunotherapy of cancer
Authors: Sanmamed Miguel F. 
Published: March 2017

Abstract
PDX models are limited by the absence of a complete and functional immune system. Overwhelming evidence now exists to suggest that immune cells play an integral role in the development and maintenance of tumors. Without a functional immune system, PDX models cannot reflect the dynamic processes of tumor-immune surveillance and immune-mediated editing, limiting the translation of antitumor results obtained in these models. Another important consequence of lacking an immune system is the impossibility to test in these models anticancer drugs that directly target immune cells. To overcome these important limitations, PDX models with human immune systems are needed. There are different approaches to enrich PDX models with human immune cells: engrafting human peripheral blood mononuclear cells, engrafting hematopoietic stem cells, or engrafting primary patient-derived tumor xenografts with human tumor infiltrating lymphocytes. All these alternatives have different strengths and weaknesses that are important to know for obtaining preclinical results that are meaningful for clinical translation.
Citation Format: Miguel F. Sanmamed. Innovative PDX models for studying immunotherapy of cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA28.
Abstract PR01: Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids
Authors: Muthuswamy Senthil K. 
Published: March 2017

Abstract
There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.
This abstract is also being presented as Poster B10.
Citation Format: Senthil K. Muthuswamy. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR01.
Abstract PR04: Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer
Authors: Hong Andrew L. , Tseng Yuen-Yi , Cowley Glenn , Jonas Oliver , Cheah Jaime , Doshi Mihir , Kynnap Bryan , Oy Coyin , Keskula Paula , Kryukov Gregory , Cima Michael , Langer Robert , Schreiber Stuart , Root David , Boehm Jesse , Hahn William 
Published: March 2017

Abstract
Loss-of-function screening using RNAi technologies over the past decade and more recently with CRISPR-Cas9 technologies have been applied to well-established cancer models. We asked if minimally passaged cancer models would tolerate such screening modalities, particularly perturbations focused on actionable drug targets. We have established a patient derived model, CLF-PED-015-T, as a proof of concept to test this question. After validating that the cell line retains the major genomic, transcriptomic and tumorigenic properties of the tissue it was derived from, we then performed systematic genetic screens using both CRISPR-Cas9 and RNAi to identify potentially actionable vulnerabilities. We then overlapped this with pharmacologic screens. We identified dependencies to CDK4 and XPO1 that spanned all three screens. These dependencies have subsequently validated in an in vivo model. These results suggest use of such technologies at early stages of patient derived model development is feasible.
This abstract is also being presented as Poster B14.
Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Glenn Cowley, Oliver Jonas, Jaime Cheah, Mihir Doshi, Bryan Kynnap, Coyin Oy, Paula Keskula, Gregory Kryukov, Michael Cima, Robert Langer, Stuart Schreiber, David Root, Jesse Boehm, William Hahn. Integration of CRISPR-Cas9, RNAi and pharmacologic screens identify actionable targets in a rare cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR04.
Abstract A02: A pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors
Authors: Xin Gang , Schauder David , Jiang Aimin , Joshi Nikhil , Cui Weiguo 
Published: March 2017

Abstract
Despite the remarkable success in treating hematological malignancies, adoptive cell transfer (ACT) still faces several challenges in treating solid tumor. The main stumbling blocks include insufficient quantity of tumor-specific T cells for transfer, impaired migration of transferred T cells into the tumor and the immunosuppressive microenvironment within the tumor. To overcome these problems, we designed an innovative approach that not only overcomes immunosuppression, but also induces robust anti-tumor T cell responses in the tumor. We first genetically engineered dual-specific CD8 T cells that can recognize both a tumor associated antigen and a bacterial antigen in vitro. Then, we treated tumor-bearing mice with ACT using a small number of the dual-specific CD8 T cells. This was accompanied by intratumoral injection of a low dose of the bacteria, which was sufficient to break local immunosuppression. The dual-specific CD8 T cells expanded robustly and migrated to the tumor bed in response to the infection. At the same time, the second TCR of these effector CD8 T cells recognized tumor antigen and executed effector function, causing tumor regression. As a result of this enhanced anti-tumor effects, 60% of the treated mice successfully eradicated their solid tumor at the primary site. Our approach not only overcomes immunosuppression, but also recruits robust anti-tumor T cell responses to the tumor. Overall, our study harnesses the power of multiple arms of the immune system with promising translational value, which can be used to target many types of solid tumors.
Citation Format: Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui. A pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A02.
Abstract A20: A tumor-penetrating recombinant protein anti-EGFR-iRGD enhance efficacy of antigen-specific CTL in gastric cancer in vivo
Authors: Sha Huizi , Liu Baorui 
Published: March 2017

Abstract
Background: Strategies that enhance the function of T cells are critical for immunotherapy. Targeted delivery of T cells through BiTE (bispecific T-cell engager) platform to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for cells penetration in solid tumor tissues due to the complicated tumor microenvironment. Activated T cells expression integrin, which is the target of peptide RGD. Peptide iRGD (CRGDK/RGPD/EC) increased vascular and tissue permeability in a tumor-specific and neuropilin-1-dependent manner, allowing co-administered drugs to penetrate into extravascular tumor tissue. Recombinant protein anti-EGFR-iRGD was purified and examinated.
Methods: Recombinant protein anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability were expressed in E. coli BL21 (DE3) and purified by nickel-nitrilotriacetic acid affinity chromatography. We use tumor cell lines and mice to analyze the targeting, penetrating and antitumor activity of antigen-secific T cells together with recombinant protein.
Results: We have successfully constructed a recombinant protein named anti-EGFR-iRGD, a dual targets of EGFR and integrin and high permeable protein. It could spread extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD could help more T cells infiltrating into tumor mass and also exhibited antitumor activity in tumor cell lines and mice.
Note: This abstract was not presented at the conference.
Conclusions: Our results provide impetus for further studies for potentially using iRGD based fusion protein anti-EGFR-iRGD with immune therapy regimens for enhancing therapy of gastric cancer patients.
Citation Format: Huizi Sha, Baorui Liu. A tumor-penetrating recombinant protein anti-EGFR-iRGD enhance efficacy of antigen-specific CTL in gastric cancer in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A20.
Abstract A35: Biomarker Strategy To Guide Clinical Development Of ImmTAC™ molecules , A Novel Class Of Bispecific T Cell Engaging Biologic Drugs
Authors: McAlpine Cheryl , Gonzalez Sandra Herrero , Bawden Lindsay , Krige David , Shingler William , Johnson Andy , Patel Sanjay , Parker Debbie , Coughlin Christina M. , Hassan Namir J. , Jakobsen Bent K. 
Published: March 2017

Abstract
IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data supported a favourable safety profile and durable responses in cutaneous and uveal melanoma (CM and UM) were observed. To complement the clinical studies we have developed a comprehensive biomarker strategy, which includes analysis of markers in both the tumour and periphery, to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance. The data obtained provide evidence of the pharmacodynamic effects of chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors over 2 days post dose. Changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. In addition, biological differences in marker responses were also seen between CM and UM patients.
The biomarker strategy developed forms the basis for the on-going Ph II development of IMCgp100 in CM and UM and for other ImmTAC molecules, both as single agents and in combination, for the treatment of solid tumours.
Citation Format: Cheryl McAlpine, Sandra Herrero Gonzalez, Lindsay Bawden, David Krige, William Shingler, Andy Johnson, Sanjay Patel, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker Strategy To Guide Clinical Development Of ImmTAC™ molecules , A Novel Class Of Bispecific T Cell Engaging Biologic Drugs. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A35.
Abstract A38: Checkpoint blockade elicits unique T cell expansion to promote tumor regression
Authors: Crosby Erika J. , Wei Junping , Yang Xiao Yi , Lei Gangjun , Wang Tao , Liu Cong-Xiao , Agarwal Pankaj , Lyerly H. Kim , Hartman Zachary C. 
Published: March 2017

Abstract
While PD-1 and CTLA-4 immune checkpoint antibodies have led to durable clinical activity in certain cancers, only a fraction of patients exhibit responses. In these responsive tumors, PD-1 and CTLA-4 antibodies are thought to interfere with tumor immunosuppression of T-cells; however, the exact mechanisms of action and potential synergism between these therapies remains unclear. As triple-negative breast cancers (TNBCs) are characterized by elevated expression of inflammatory and immunosuppressive molecules, as well as high levels of immune infiltrating T cells (TILs), we hypothesized that they would be susceptible to treatment with PD-1 and CTLA-4 antibodies. To test this hypothesis and further define the mechanisms of action of checkpoint blockade, we generated a model of murine TNBC (E0771) utilizing ovalbumin (OVA) as a defined antigen that is tumor-specific and recognizable by transgenic T cells (OT-I cells). Consistent with human TNBCs, E0771 tumors exhibit robust T cell infiltration, with &gt;60% of CD4+ T cells being T-regulatory cells (Tregs), and tumor cells express high levels of PDL1. We found that despite the generation of systemic anti-tumor responses and the addition of OT-I cells, TNBC immunosuppression shielded tumors from immune mediated regression. We then tested the efficacy of anti-PD1 and anti-CTLA4 targeting antibodies to inhibit this tumor immunosuppression and demonstrate that they had an anti-tumor effect by blocking PD-1 signaling in the tumor microenvironment and reducing intratumoral Tregs, respectively. When combined, these distinct mechanisms of action led to regression of ~80% of tumors and were significantly associated with anti-tumor adaptive responses. T cell receptor (TCR) sequencing of TILS in treated mice demonstrated a hyperexpansion of several clones, while also a broadening of the total number of unique clones present. Surprisingly, we found that despite using a homogenous tumor model and adoptively transferring OT-1 cells, TCR sequencing revealed clonal populations that were almost entirely unique for each tumor, with the OTI TCR not representing an expanded clone. As such, our study demonstrates that dual CTLA-4 and PD-1 checkpoint blockade inhibits immunosuppression of T cells in the tumor microenvironment through different and complementary mechanisms to expand and broaden unique intrinsic T cell repertoires in the tumor.
Citation Format: Erika J. Crosby, Junping Wei, Xiao Yi Yang, Gangjun Lei, Tao Wang, Cong-Xiao Liu, Pankaj Agarwal, H. Kim Lyerly, Zachary C. Hartman. Checkpoint blockade elicits unique T cell expansion to promote tumor regression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A38.