bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B50: Synergistic antitumor efficacy in mice with immunotherapy regimens combining recombinant live-attenuated Listeria with immune checkpoint inhibitors
Authors: Deng Weiwen , Liu Weiqun , Hudson Thomas , Rae Chris S. , Lemmens Ed , Desbien Anthony , Hanson Bill , Lauer Pete , Dubensky Thomas W. , Leong Meredith 
Published: March 2017

Abstract
Development of effective and durable antitumor immunity requires the activation, expansion and maintenance of function of tumor antigen-specific effector T cells. The mechanism of action of recently FDA approved monoclonal antibody (mAb) therapies which target immune checkpoints such as PD-1 and CTLA-4 and uncouple inhibitory pathways from the activation of antigen-specific T cells underlines the critical requirement for antigen-specific priming to elicit potent and long-lasting anti-tumor immunity. However, immune checkpoint blockade results in significant clinical benefit largely in malignancies with high mutational burden, where the tumor itself can initiate T cell priming, but is less effective when used as a single agent among cancers with lower mutational burden, associated typically with a low level of lymphocyte infiltration into the tumor microenvironment (TME). We are evaluating clinical immunotherapy regimens combining immune checkpoint blockade with recombinant live-attenuated double-deleted strains of the intracellular bacterium Listeria monocytogenes (LADD), based on a hypothesis that effective immunotherapy will result from agents that in combination re-polarize the TME to facilitate immune effector cell function, prime functional tumor-specific T cells in the appropriate context, and block inhibitory signaling pathways. Here we show that tumor antigen-expressing LADD therapy enhanced CD8+ T cell effector function, resulting in significant tumor eradication in several preclinical mouse models. LADD treatment in addition induced favorable changes in the TME, as shown by enhanced CD8+ T effector function, recruitment of antigen presenting cells and reduction of regulatory T cells. Treatment regimens combining LADD-based immunotherapy with PD-1 immune checkpoint blockade significantly enhanced antitumor efficacy in CT26, 4T1 and MC38 tumor models. Together these data support the rationale for integrating LADD-based immunotherapy into clinical regimens with immune checkpoint blockade on the basis that TME modification and priming of tumor Ag-specific T cells significantly enhances the activity of mAb therapies blocking T cell inhibitory pathways.
Citation Format: Weiwen Deng, Weiqun Liu, Thomas Hudson, Chris S. Rae, Ed Lemmens, Anthony Desbien, Bill Hanson, Pete Lauer, Thomas W. Dubensky, Jr., Meredith Leong. Synergistic antitumor efficacy in mice with immunotherapy regimens combining recombinant live-attenuated Listeria with immune checkpoint inhibitors. [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 B50.
Abstract B64: A high-throughput screen identifies fulvestrant as an enhancer of immune-mediated cytotoxicity of mesenchymal-like lung cancer cells
Authors: Hamilton Duane H. , Mathews-Griner Lesley , Keller Jonathan M. , Hu Xin , Southall Noel , Marugan Juan , David Justin M. , Ferrer Ferrer , Schlom Jeffrey , Palena Claudia 
Published: March 2017

Abstract
The phenomenon of epithelial-mesenchymal transition (EMT) is a phenotypic switch that allows epithelial tumor cells to acquire features of mesenchymal cells, including the ability to migrate and invade and, therefore, to disseminate from the primary site. In addition to promoting tumor dissemination, various reports have demonstrated that tumor EMT also associates with the acquisition of resistance to the cytotoxic effects of chemotherapy, radiation, and some targeted therapies. In the present report we have utilized a quantitative high-throughput screening of a pharmaceutical collection of more than 2000 compounds to identify FDA-approved drugs capable of augmenting the sensitivity of mensenchymal-like lung cancer cells to immune-mediated lysis. Using this approach we have identified the estrogen receptor antagonist fulvestrant as capable of rendering mesenchymal-like lung cancer cells more susceptible to the cytotoxic effects of natural killer or antigen-specific T cells and chemotherapy. Fulvestrant-treatment of human lung carcinoma cell lines, both in vivo and in vitro, was associated with a reduction of mesenchymal features. In silico analysis of publicly available gene expression datasets revealed a novel association between the expression of mesenchymal-associated features and the expression of estrogen receptor alpha in lung adenocarcinoma patients. Although the potential role of estrogen signaling in lung cancer remains controversial, this study supports a positive association between active estrogen signaling and the promotion of a mesenchymal phenotype in lung cancer. The findings from this study form the rationale for future combinations of fulvestrant and immune-mediated therapies in the treatment of advanced lung cancer.
Citation Format: Duane H. Hamilton, Lesley Mathews-Griner, Jonathan M. Keller, Xin Hu, Noel Southall, Juan Marugan, Justin M. David, Ferrer Ferrer, Jeffrey Schlom, Claudia Palena. A high-throughput screen identifies fulvestrant as an enhancer of immune-mediated cytotoxicity of mesenchymal-like lung cancer cells. [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 B64.
Abstract B81: Oncolytic adenovirus YSC-02 enhanced tumor cell killing and immune response with broad spectrums, which resulted in both TGF-β and HSP27 cooperatively becoming silenced
Authors: Han Zhezhu , Je Suyeon , Choi Hye J. , Kang Dongxu , Xu Rong , Kim Hyun S. , Song Jae J. 
Published: March 2017

Abstract
As combining therapeutic agents with different action mechanisms may enhance efficacy, YSC-02, an oncolytic adenovirus with multi targets was loaded with five different genes, which were designed with the expectation that different action mechanisms would cooperate. In spite of concerns regarding many APIs, YSC-02 was constructed to be an adenovirus-based anti-cancer drug. By using our own established mouse model system suitable for efficient adenoviral infection and replication, immune activity as well as survival potential could be precisely estimated for anti-cancer drug efficacy. YSC-02 was designed to decrease tumor cell survival, metastasis and to increase tumor cell death, and immune activation. It is composed of five different target genes, including one fused form and two shRNAs, but each of these genes functions is closely linked to produce the maximal antitumor effect. YSC-02 is like an organic complex designed to be applied primarily to heterogeneous liver cancer and melanoma. The greatest difficulty in developing anticancer drugs is deeply related to the existence of many genetic variations even in the same tumor tissue. However, in our study, the downregulation of HSP27 greatly increased the death potential of most tumor cell types, irrespective of differential cell death induced by TGF-β1 or TGF-β2 isotypes. The simultaneous silencing of both HSP27 and TGF-β could significantly repress the tumor survival potential of various cancer cells, which leads to most cell types of death in the complex network of cells. These combined shRNAs have also contributed to the increase of TRAIL sensitivity. Genetically modified mouse cancer cells within syngenic mice could make it possible to estimate the superiority of YSC-02 over its derivatives including GMCSF-expressing oncolytic adenovirus or GMCSF-FETZ-expressing oncolytic adenovirus. At the immunological level, NK cells or T cells were shown to be most activated in the treatment of YSC-02, which may be another contributor of anti-tumor activity. Additionally, even the highest dose of YSC-02 did not produce any toxicity in the liver.
Citation Format: Zhezhu Han, Suyeon Je, Hye J. Choi, Dongxu Kang, Rong Xu, Hyun S. Kim, Jae J. Song. Oncolytic adenovirus YSC-02 enhanced tumor cell killing and immune response with broad spectrums, which resulted in both TGF-β and HSP27 cooperatively becoming silenced. [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 B81.
Abstract B86: Radiation and TGFβ blockade bring back memories in metastatic breast cancer patients
Authors: Schaue Dörthe , Xie Michael W. , Ratikan Josephine A. , Micewicz Ewa D. , Hwang Lin , Faull Kym F. , Sayre James W. , Lee Percy P. , Glaspy John A. , Demaria Sandra , Formenti Silvia C. , McBride William H. 
Published: March 2017

Abstract
Purpose: This is a pilot study combining focal irradiation and systemic TGFβ blockade in metastatic breast cancer. The rationale for using TGFβ blockade was to limit tumor growth and further spread as well as to curb systemic immune suppression. Combining this systemic approach with hypofractionated radiation of selective tumor metastasis aimed at vaccinating each patient in vivo with her own, relevant tumor antigens by local radiation damage and allow T cells to reach their full potential while escaping TGFβ's grip.
Experimental Design: Serial blood samples from 22 patients undergoing treatment with 1mg or 10mg Fresolimumab and Radiation at the New York University School of Medicine (n=15) and at the David Geffen School of Medicine, University of California, Los Angeles (n=7) were immunophenotyped based on flow cytometric analysis of 21 surface antigens.
Results: There were significant differences between the 1mg and 10mg groups with respect to several immune parameters, especially the rise in circulating central memory CD8s at the higher dose level (relative increase at 2 weeks 10mg vs 1mg, p=0.027). Regulatory networks responded to the 10mg treatment regime with a consistent expansion in CD4 Tregs while mMDSCs declined (ratio Tregs/mMDSC rising in 10mg vs 1mg, p=0.026). An overall survival benefit was seen in the 10mg Fresolimumab arm (median OS 64.1 weeks versus 20 weeks, p=0.015 log rank test) albeit not striking. CART analysis allowed accurate survival classification based on 2-week changes in CD8/mMDSC ratios and plasma Tryptophan (ROC AUC 0.979).
Conclusion: Inhibiting TGFβ in the context of focal irradiation seems to create a favorable systemic immune landscape that drives T cell memory differentiation while limiting myeloid suppression.
Citation Format: Dörthe Schaue, Michael W. Xie, Josephine A. Ratikan, Ewa D. Micewicz, Lin Hwang, Kym F. Faull, James W. Sayre, Percy P. Lee, John A. Glaspy, Sandra Demaria, Silvia C. Formenti, William H. McBride. Radiation and TGFβ blockade bring back memories in metastatic breast cancer patients. [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 B86.
Abstract IA10: The interferon receptor pathway's role in response and resistance to PD-1 blockade
Authors: Ribas Antoni 
Published: March 2017

Abstract
As adaptive PD-L1 expression on cancer cells is induced by interferon gamma, if a cancer had genetic alterations that lead to inability to signal from the interferon gamma receptor then this cancer would not be protecting itself from immune attack by reactively expressing PD-L1. In this scenario, it would be useless to block PD-1:PD-L1 interactions with a therapeutic antibody and it would be a genetic mechanisms of primary resistance to PD-1 blockade therapy. We identified genetic mutations in the Janus kinases (JAK) 1 and 2 controlling signaling downstream of the interferon receptor that prevent PD-L1 upregulation on melanoma cells upon interferon exposure, which are associated with primary resistance to PD-1 blockade in patients. Whole exome sequencing of metastatic melanoma biopsies from 23 patients treated with pembrolizumab revealed a JAK1 missense mutation with chromosomal amplification in the tumour with the highest mutational load in a non-responding patient. In a second cohort of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade, a homozygous JAK1 loss-of-function mutation was similarly found in the tumour of a patient without an objective response to PD-1 blockade.
Similar alterations could explain the cases of relapse after a long period of response to PD-1 blockade therapy, termed acquired resistance. Out of the patients with metastatic melanoma who respond to pembrolizumab, approximately 75% have responses lasting years. However, delayed tumor reappearance and progression while on continuous therapy has been noted in 25% of patients. Until now, the mechanisms of immune escape in this setting were unknown. Comparing biopsies of melanoma before starting on anti-PD-1 therapy with the tumors that relapsed months to years later, we again found new JAK1/2 loss of function mutations. Among four pairs of biopsies, two had JAK1 or JAK2 new loss of function mutations with loss of heterozygosity, and the third case had a truncating mutation in the antigen presentation gene beta-2 microglobulin (B2M). JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its anti-proliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of the major histocompatibility complex (MHC) class I.
In conclusion, analysis of patient-derived biopsies is providing information about the cellular and molecular events required for response or resistance to PD-1 blockade therapy, highlighting the critical role of intact signaling through the interferon gamma receptor.
Citation Format: Antoni Ribas. The interferon receptor pathway's role in response and resistance to PD-1 blockade. [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 IA10.
Abstract IA15: Engineering combination immunotherapy agents for synergistic innate and adaptive immune attack on solid tumors
Authors: Irvine Darrell J. 
Published: March 2017

Abstract
Solid tumors evade destruction by the immune system through many parallel pathways of immunosuppression. Combination immunotherapies that act synergistically to recruit the breadth of the immune system's armamentarium against solid tumors provide the opportunity to counter this immunosuppressive network with a similarly complex immune attack. Many existing immunotherapeutic approaches may contain key elements to overcome the barriers presented by solid tumors, but are limited by issues of toxicity (e.g., agonist immunocytokines) or potency (e.g., therapeutic vaccines). Using both established and engineered immunotherapy reagents, we recently discovered a combination immunotherapy that recruits a diverse set of innate and adaptive immune effectors, enabling robust elimination of tumor burdens that to our knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended-pharmacokinetics IL-2 molecule, anti-PD-1, and a lymph node targeting peptide vaccine. This combination elicited durable cures of large established tumors in a majority of animals in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRrafV600E/Pten-/- melanoma model. Multiple innate immune cell subsets, CD8+ T-cells, and cross-presenting DCs were critical to successful therapy. Treatment induced high levels of intratumoral inflammatory cytokines and immune cell infiltration, enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading. These results demonstrate the capacity of the endogenous immune response to destroy large, established tumors and suggest essential characteristics of an integrated immune response capable of overcoming immunosuppressive tumors.
Citation Format: Darrell J. Irvine. Engineering combination immunotherapy agents for synergistic innate and adaptive immune attack on 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 IA15.
Abstract IA26: Genomic correlates of response and resistance to immune checkpoint blockade
Authors: Allen Eliezer M. Van 
Published: March 2017

Abstract
The rise of multiple immunotherapies, such as immune checkpoint blockade, has significantly improved outcomes for multiple patient populations, including melanoma, lung adenocarcinoma, and urothelial cancers, among others. In parallel, the expansion of precision cancer medicine through robust interrogation of cancer genomes at the point of care has enhanced patient stratification for multiple treatment selection strategies and cancer types. The intersection of clinical cancer genomics and immuno-oncology has created an opportunity to learn how the tumor and germline genomes, along with transcriptomic measurements of the immune microenvironment, impact clinical immune checkpoint blockade response. Here, we describe the current landscape of tumor and microenvironmental genomic correlates of immune checkpoint blockade across cancer subtypes, and examine how emerging genomic studies of immunotherapy responders and non-responders may inform patient selection strategies for clinical trial design in these diverse clinical settings. We explore how these approaches, paired with emerging computational biology methodology, may also enable discovery of new mechanisms of selective treatment response. Finally, we examine emerging genomic data on clinical resistance to immunotherapies, from both signaling pathway and neoantigen evolution perspectives, and discuss the implications for combination treatment strategies. Overall, the convergence of comprehensive clinical genomics and immuno-oncology treatment strategies may inform precision medicine for immunotherapies across cancer types.
Citation Format: Eliezer M. Van Allen. Genomic correlates of response and resistance to immune checkpoint blockade. [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 IA26.
Abstract PR10: Enhancing the efficacy of T cell-based immunotherapies using miR-155 engineered tumor-specific CD8+ T cells
Authors: Ji Yun , Hocker James , Hu Jinhui , Gautam Sanjivan , Lacey Neal , Gattinoni Luca 
Published: March 2017

Abstract
Lymphodepleting regimens are employed prior to adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic cytokine sinks. These conditioning modalities, however, are often associated with severe toxicities. We found that miR-155 enabled B16 melanoma-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T cell responsiveness to limited amounts of homeostatic γc cytokines by restraining the expression of the Akt inhibitor Ship1 and multiple negative regulators of Stat5, such as Socs1 and Ptpn2, resulting in delayed cellular contraction and sustained cytokine production. To translate these findings into new clinical trials, we tested whether the overexpression of miR-155 in human T cells would enhance the antitumor efficacy of CD19-specific chimeric antigen receptor (CD19-CAR) cells against systemic acute lymphoblastic leukemia xenografts. As a safety measure, the suicide gene, inducible caspase 9, was included in the miR-155 construct. We found that miR-155 also augmented the antitumor efficacy of T cells in this xenograft tumor model. Recapitulating our findings in mouse cells, human T lymphocytes overexpressing miR-155 showed increased Stat5 signaling and enhanced survival. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be employed to increase the effectiveness of adoptive immunotherapies in a cell intrinsic manner without the need of life-threatening, lymphodepleting maneuvers.
This abstract is also being presented as Poster A82.
Citation Format: Yun Ji, James Hocker, Jinhui Hu, Sanjivan Gautam, Neal Lacey, Luca Gattinoni. Enhancing the efficacy of T cell-based immunotherapies using miR-155 engineered tumor-specific CD8+ T cells. [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 PR10.
Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack
Authors: Young Lawrence H. , Viscoli Catherine M. , Curtis Jeptha P. , Inzucchi Silvio E. , Schwartz Gregory G. , Lovejoy Anne M. , Furie Karen L. , Gorman Mark J. , Conwit Robin , Abbott J. Dawn , Jacoby Daniel L. , Kolansky Daniel M. , Pfau Steven E. , Ling Frederick S. , Kernan Walter N. 
Published: March 2017

Background:
Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described.

Methods:
We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee.

Results:

The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54–0.94;
P
=0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40–0.96; log-rank
P
=0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58–1.91;
P
=0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22–0.87;
P
=0.02), but not smaller MIs.

Conclusions:
Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs.

Clinical Trial Registration:

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00091949.