bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 13: Individualized approach for ovarian cancer: Identification of potential therapeutic targets based on genomic analyses, testing efficiency of treatments, and monitoring
Authors: Harris Faye R. , Halling Geoffrey C. , Becker Marc A. , Haluska Paul , Vasmatzis George , Kovtun Irina V. 
Published: May 2016

Abstract
Ovarian cancer (OCa) is fifth leading cause of death among women. Most of OCa patients diagnosed with high stage invasive disease. Although, majority experience remission after surgical debulking and adjuvant chemotherapy, about 80% of patients relapse and/or develop chemoresistant disease. More efficient diagnostics and therapies are needed to improve outcome in ovarian cancer.
We used an integrated approach to characterize genomic rearrangements in serous OCa inordet to identify potentially targetable alterations and test treatments with corresponding drugs using matching mouse avatar models. Mate-pair next generation sequencing protocol and BIMA2 algorithm were used to identify chromosomal rearrangements, including gene fusions and copy number changes, in primary tumors. Further analysis was then performed to determine alterations that may also be therapeutically targeted. Total of 25 primary tumors were analyzed, out of which four were selected for genomically guided treatments in corresponding mouse avatars. The tumors propagated in the selected mouse lines were also sequenced and showed identical to original patient tumor landscape of rearrangements. In addition, the selected targetable alterations were validated in both patient and avatar tumor DNA. For several of the analyzed cases pre-surgical and postsurgical blood was available for detection of selected alterations in cell free circulating tumor DNA. The analysis revealed presence of selected rearrangements in pre-surgical blood of all tested cases and in a number of those that showed presence of the disease after surgery. In summary, we showed that the whole genome sequencing of DNA rearrangements in conjunction with analyses of therapeutic targets and treatment testing in mouse avatars, developed using primary tumors, is a promising approach to aid treatment decisions for individual ovarian cancer patients.
Note: This abstract was not presented at the conference.
Citation Format: Faye R. Harris, Geoffrey C. Halling, Marc A. Becker, Paul Haluska, Jr., George Vasmatzis, Irina V. Kovtun. Individualized approach for ovarian cancer: Identification of potential therapeutic targets based on genomic analyses, testing efficiency of treatments, and monitoring. [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 13.
Abstract IA09: Single cell RNA-sequencing of circulating tumor cells
Authors: Miyamoto David T. , Zheng Yu , Wittner Ben S. , Lee Richard J. , Zhu Huili , Broderick Katherine T. , Desai Rushil , Brannigan Brian W. , Arora Kshitij S. , Dahl Douglas M. , Sequist Lecia V. , Smith Matthew R. , Kapur Ravi , Wu Chin-Lee , Shioda Toshi , Ramaswamy Sridhar , Ting David T. , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A. 
Published: May 2016

Abstract
Isolation of circulating tumor cells (CTCs) in the blood allows noninvasive tumor sampling from patients with cancer. Molecular analysis of single CTCs may uncover heterogeneous cellular pathways that underlie disease progression and resistance to therapy. Using a microfluidic device, we isolated individual CTCs from patients with metastatic prostate cancer. Single candidate CTCs were micromanipulated after cell surface staining for epithelial (EpCAM) and mesenchymal (CDH11) markers, and then subjected to single cell RNA-sequencing. Digital gene expression profiles of lineage-confirmed CTCs were compared with each other, with primary prostate tumors, and with annotated markers of cellular signaling pathways. Single prostate CTCs displayed considerable heterogeneity in transcriptional profiles, but clustered according to patient of origin, indicating higher diversity in CTCs across different individuals (mean correlation 0.10 for CTCs within patients vs. 0.0014 for CTCs across patients, P=2.0x10E-11). Compared to primary tumors, CTCs were significantly enriched in 37 molecular pathways (FDR &lt;0.1), with the majority implicated in growth factor, cell adhesion, and hormone signaling. Gene mutations and alternative splice variants of the Androgen Receptor (AR) gene were rare in primary prostate tumors and CTCs from untreated patients, but were prevalent in patients with castration-resistant prostate cancer. Distinct AR variants, including AR-V7, were present within different cells of individual patients, as well as within individual CTCs. Together, single cell molecular analysis of human CTCs points to multiple mechanisms of drug resistance in advanced prostate cancer, and suggests the role of heterogeneous signaling pathways that cooperate with co-existing abnormalities in AR in mediating disease progression.
Citation Format: David T. Miyamoto, Yu Zheng, Ben S. Wittner, Richard J. Lee, Huili Zhu, Katherine T. Broderick, Rushil Desai, Brian W. Brannigan, Kshitij S. Arora, Douglas M. Dahl, Lecia V. Sequist, Matthew R. Smith, Ravi Kapur, Chin-Lee Wu, Toshi Shioda, Sridhar Ramaswamy, David T. Ting, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber. Single cell RNA-sequencing of circulating tumor cells. [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 IA09.
Abstract IA19: Human melanoma neoantigens: Identification and vaccination
Authors: Linette Gerald P. 
Published: May 2016

Abstract
Cancer medicine is in the midst of a dramatic shift towards new therapeutics directed by alterations in the cancer genome. Melanoma genomes harbor somatic mutations that are caused by exposure to mutagens such as ultraviolet light. Tumor missense mutations (MM), translated into amino acid substitutions (AAS), may provide a form of non-self that elicits tumor specific T cell immunity. Indeed, T cell immunity directed against tumor encoded AAS has been reported in humans with cutaneous melanoma, thus implicating MM as a source of patient specific (private) neoantigens. However, a systematic evaluation of these putative neoantigens as validated targets is lacking and it is unknown whether the immune response directed against tumor encoded AAS can be augmented by vaccination. We show that vaccination against melanoma AAS-encoding peptides augments naturally occurring T cell immunity and reveals new HLA class I restricted private neoantigens in patients with advanced melanoma. Neoantigen specific T cells recognized naturally processed and presented antigen but failed to recognize wild type (non-mutated) antigen. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. As determined by TCR beta CDR3 DNA sequencing, vaccination promotes a repertoire of neoantigen-specific T cells that is highly diverse in terms of both TCR beta usage and clonal composition. No evidence of autoimmunity was apparent after vaccination. Our results demonstrate that tumor MM can be targeted as neoantigens and vaccination directed at tumor AAS somatic mutations broadens the antigenic breadth and clonal diversity of anti-tumor immunity. Personalized cancer immunotherapies targeting private somatic tumor alterations may become feasible in the near future.
Citation Format: Gerald P. Linette. Human melanoma neoantigens: Identification and vaccination. [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 IA19.
Abstract IA22: Reflections on precision medicine
Authors: Sawyers Charles L. 
Published: May 2016

Abstract
The clinical success of molecularly targeted therapies such as imatinib for chronic myeloid leukemia sparked a revolution in cancer drug development as well as global efforts to define the landscape of genomic alterations across all cancers. Today we live in a world with a near complete understanding of all cancer gene mutations, giving us an unprecedented opportunity to leverage this knowledge to improve treatment outcomes, through precision medicine. Despite the many remarkable successes over the past 15 years, the goal of improved therapy for all cancers remains daunting due to the complexity of the genomic landscape and the challenges of overcoming drug resistance. With the rapid spread of next generation sequencing into the clinical arena at various cancer centers and health care institutions throughout the world, we have an opportunity to accelerate our understanding of treatment response and resistance through data sharing across these growing silos of genomic and clinical datasets. In this lecture I will illustrate the power of this approach through specific examples in prostate cancer and discuss interactional efforts to catalyzed data sharing through the Global Alliance for Genomics and Health (GA4GH).
Citation Format: Charles L. Sawyers. Reflections on precision medicine. [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 IA22.
Abstract A018: Onset of dysthyroidism during treatment with immune checkpoint inhibitors is increased in responder patients
Authors: Signorelli Diego , Vecchio Michele Del , Garassino Marina , Intini Alice , Cona Maria Silvia , Magni Michele , Seregni Ettore , Nicola Massimo Di , Braud Filippo De 
Published: May 2016

Abstract
Background: Immune checkpoints inhibitors (ICI) are characterized by a high therapeutic index; among toxicities, immune-related thyroiditis has been reported. The aim of this study is to evaluate either the grade and severity of thyroiditis or its frequency in responder patients.
Material and Methods: We retrospectively evaluated 104 metastatic solid tumor patients treated at our Institute with ICI from 2010. We defined thyroid toxicity according to CTCAE version 4.0 and the disease control rate (DCR: CR, PR, SD) as efficacy endpoint. Correlation between dysthyroidism and DCR was assessed by Fisher's exact test.
Results: Of 104 patients, 32 (30.8%) were treated by anti PD-1, 32 (30.8%) by anti PDL-1, 34 (32.7%) by anti CTLA-4 and 6 (5.7%) by combo (anti PD-1+anti CTLA-4). Population was heterogeneous, ranging from the first to the 8th line of therapy, and affected by the following cancers: 42 (40.4%) lung (38 NSCLC, 4 SCLC), 40 (38.5%) melanoma, 9 (8.6%) RCC, 7 (6.7%) gastric, 2 (1.9%) bladder and one each for colon, salivary glands, thyroid and uterine leiomiosarcoma. Best responses were: 3 CR, 14 PR, 33 SD and 54 PD; 50 (48%) of patients achieved DCR, 18 (37.5%) treated by anti PD-1, 16 (33.3%) by anti PDL-1, 12 (25%) by anti CTLA-2 (4.2%) by combo. Overall, 29 patients developed dysthyroidism (subclinic, G1, G2 hypo/hyperthyroidism): 2/34 (6%) in anti CTLA-4, 10/32 (31%) in anti PD-1, 13/32 (41%) in anti PDL-1, 4/6 (67%) in combo group, respectively; 19/29 (65.5%) of these patients achieved DCR. Of 75 patients who did not develop dysthyroidism, only 29 (38.6%) achieved DCR. The onset of dysthyroidism statistically significant correlated with DCR (65.5% vs 40.0%, p= 0.016); no correlation was detected between toxicity grade (subclinic and G1 from oneside, G2 from the other side) and DCR (p= 1.0).
Conclusions: In responding patients, we found a statistically significant increase of thyroiditis during treatment with ICI. Thyroid function evaluation should be recommended routinely during ICI therapy, in particular with anti PD-1 and anti PDL-1 agents. Finally, the role of thyroiditis in predicting response to ICI must be confirmed in a large and homogeneous series of patients.
Note:This abstract was not presented at the conference.
Citation Format: Diego Signorelli, Michele Del Vecchio, Marina Garassino, Alice Intini, Maria Silvia Cona, Michele Magni, Ettore Seregni, Massimo Di Nicola, Filippo De Braud. Onset of dysthyroidism during treatment with immune checkpoint inhibitors is increased in responder 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 A018.
Abstract A043: Safety and efficacy of a genetic vaccine targeting telomerase against various canine cancers
Authors: Impellizeri Joseph A. , Gavazza Alessandra , Lubas George , Greissworth Eliana , Jemiolo David , Ciliberto Gennaro , Aurisicchio Luigi 
Published: May 2016

Abstract
Purpose of the study: we have recently shown that a genetic vaccine targeting dog telomerase (dTERT) and based on Ad (Adenovirus)/DNA-EP (DNA electroporation) technology can induce strong immune response and increase overall survival (OS) of dogs affected by B-cell malignant lymphoma (ML) when combined to COP therapy in a limited number of subjects. In this study, we have conducted a double arm clinical trial with an extended number of ML patients and evaluated the immunotherapy in dogs affected by other tumor types, such as mesothelioma, hemangiosarcoma, melanoma and renal cancer.
Methods: Dogs are vaccinated by a protocol consisting of 2Ad vector injections (Priming phase) and followed by DNA-EP (Boosting phase) by means of a Cliniporator device, currently utilized and approved in Europe for Electrochemotherapy applications and adapted to Electro-Gene-Transfer. The vaccine was combined with Standard of care (SOC) therapies. The immune response was measured by ELISPOT, Intracellular staining for cytokines and ELISA assays.
Results: No adverse effects were observed in any dog patient that could be attributed to treatment. dTERT-specific immune response was induced in almost all treated animals. The OS of vaccine/COP treated ML-dogs was significantly increased over contemporaneous COP-treated animals (&gt;76.1 vs 29.3 weeks, respectively, p&lt;0.0001). The evaluation of the OS for the other tumor types is in progress. The association of the therapeutic effects and vaccine potency with biomarkers such as T regulatory cells (Tregs) and Myeloid derived suppressor cells (MDSC) is also in progress.
Conclusions: Ad/DNA-EP-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of ML canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and hold promise for the treatment of dogs affected by other cancer types. Most importantly, our study outlines the relevance of canine patients as relevant preclinical models for human cancer vaccines.
Citation Format: Joseph A. Impellizeri, Alessandra Gavazza, George Lubas, Eliana Greissworth, David Jemiolo, Gennaro Ciliberto, Luigi Aurisicchio. Safety and efficacy of a genetic vaccine targeting telomerase against various canine 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 A043.
Abstract A116: A predictive model to identify immunogenic neoepitopes in patients with melanoma treated with CTLA-4 blockade
Authors: Chowell Diego , Krishna Sri , Snyder Alexandra , Vladimir Makarov , Chan Timothy A. , Anderson Karen S. 
Published: May 2016

Abstract
Recent studies have shown that CD8+ T cells that recognize neoantigens presented by tumor cells, but the target specificity of these tumor infiltrating T cells are largely unknown. Developing a predictive model that identifies immunogenic neoepitopes presented by major histocompatibility complex (MHC) class I molecules is critical to identify potential vaccine targets and to improve prediction of response to immune checkpoint inhibitors. We hypothesize that the immunogenic heterogeneity of tumors may explain, in part, differences in clinical response that individual patients derive to checkpoint blockade therapy. We have recently shown that the relative hydrophobicity of T cell receptor (TCR) contact residues is a hallmark of immunogenic MHC class I epitopes, and that this may represent a biochemical basis by which T cells discriminate immunogenic epitopes within the background of self-peptides. Here, we extend this analysis using candidate MHC class I tumor neopeptides from patients with melanoma. Somatic missense mutations were identified from recently published data on whole-exome sequencing of tumors from 11 patients who derived a long-term benefit and 14 patients who derived a minimal or no benefit from ipilimumab or tremelimumab. Mutational burden ranged from 1 to 1,304 mutations per tumor. More than 3,200 potential MHC class I neopeptides were identified based on a predicted binding algorithm (binding affinity, ≤500 nM). Our preliminary results indicate significant differences in hydrophobicity at the anchor residues P2 and P9 (P &lt; 0.001 for both), reflecting MHC binding differences. In addition, there is an increase in hydrophobicity at the TCR contact residues P4 and P7 (P &lt; 0.01 for both) in long-term responders. The overall frequency of mutations in neoepitopes is significantly different at the TCR contact residues P4 and P7 between long-term responders and minimal or no responders (P &lt; 0.01), suggesting genetic immunoediting of these tumors. Based on these results, we have developed a probabilistic Bayesian-based model to predict immunogenic neoepitopes. The model is being applied on the overall pool of neopeptides from each individual patient with melanoma. The sets of predicted immunogenic neoepitopes may serve as potential therapeutic vaccine candidates for patients with melanoma.
Citation Format: Diego Chowell, Sri Krishna, Alexandra Snyder, Makarov Vladimir, Timothy A. Chan, Karen S. Anderson. A predictive model to identify immunogenic neoepitopes in patients with melanoma treated with CTLA-4 blockade. [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 A116.
Abstract A141: The vigorous immune microenvironment of microsatellite instable colon cancer isbalanced by multiple counter-inhibitory checkpoints
Authors: Llosa Nicolas J. , Housseau Franck , Wick Elizabeth , Lizzy Hechenbleikner , Cruise Michael , Anders Robert , Sears Cynthia , Pardoll Drew M. , Fan Hongni , Siegel Nicholas , Blosser Lee , Tam Ada , Wang Hao 
Published: May 2016

Abstract
We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-gamma production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five - PD-1, PD-L1, CTLA-4, LAG-3 and IDO - currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC. Our findings are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair defective subset of CRC selectively up-regulates at least 5 checkpoint molecules that are targets of inhibitors currently being clinically tested. Furthermore, our results were clinically validated in a phase 2 study at Hopkins which showed mismatch-repair status as a predictor of clinical benefit to immune checkpoint blockade with pembrolizumab.
Citation Format: Nicolas J. Llosa, Franck Housseau, Elizabeth Wick, Hechenbleikner Lizzy, Michael Cruise, Robert Anders, Cynthia Sears, Drew M. Pardoll, Hongni Fan, Nicholas Siegel, Lee Blosser, Ada Tam, Hao Wang. The vigorous immune microenvironment of microsatellite instable colon cancer isbalanced by multiple counter-inhibitory checkpoints. [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 A141.
Abstract A155: Unmasking cancer to innate sensing by anti-CD47 antibody triggers adaptive immune-mediated destruction of immunogenic tumors
Authors: Xu Meng 
Published: May 2016

Abstract
Blocking macrophage phagocytosis of tumor cells by anti-CD47 antibody (Ab) has demonstrated therapeutic efficacy in xenograft models. We have observed that in an immunocompetent host, a CTL adaptive response is essential for immungenic tumor regression after anti-CD47 Ab treatment. Furthermore, anti-CD47 Ab treatment promotes DC but not macrophage-mediated cross priming of CTLs in a type I IFN dependent fashion. In addition, we found that anti-CD47 Ab-mediated immunity requires the functional adaptor protein STING, but not MyD88, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 Ab treatment futher bridging the innate and adaptive responses. Importantly, we observed that the timing of standard chemotherapeutics impacts anti-CD47 Ab-initiated anti-tumor immunity. Together, our study reveals that anti-CD47 antibody can trigger DNA sensing pathway for adaptive immune-mediated destruction of immungenic tumors.
Citation Format: Meng Xu. Unmasking cancer to innate sensing by anti-CD47 antibody triggers adaptive immune-mediated destruction of immunogenic tumors. [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 A155.