bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B054: Evaluation of NY-BR-1 as a suitable antigen for CAR based immunotherapy
Authors: Schmidt Patrick , Minden Claudia Luckner , Ziegelmeier Claudia , Gosch Isabella , Halama Niels , Momburg Frank , Eurich Rosa , Schott Sarah , Marmé Frederik , Schneeweiß Andreas , Heußel Claus Peter , Jäger Dirk , Zörnig Inka 
Published: November 2016

Abstract
Despite the tremendous clinical success of CAR-T-cell therapy in leukemia, translation of this treatment option to solid tumors still remains challenging. Off-target toxicity of CAR-T-cells against low-level antigen expressing healthy tissue is considered to be the most dangerous scenario when treating cancer patients yielding eventually to at least one reported fatal SAE. To avoid such fatalities a straight assessment of target antigen expression including all known isoforms of the respective protein in tumors as well as healthy tissues must be performed before drug application. The breast differentiation antigen NY-BR-1 (ANKRD30A) is known to serve as a perfect antigen for active immunotherapy of female breast cancer due to absence of expression in any female healthy tissue except for mammary gland. Here we report on the critical evaluation of NY-BR-1 as a target antigen for CAR-T-cells using bioinformatics, staining procedures and functional CAR tests. While bioinformatic analyses and stainings using the anti-NY-BR-1 monoclonal antibody “clone2” confirmed previous findings, we observed different results when the respective “clone2 scFv” was used. This construct not only shows a higher binding capacity to NY-BR-1 but also a modest but detectable binding to the isoform NY-BR1.1 (ANKRD30B). Additionally, a CAR-construct based on “clone2 scFv” yielded into a cross-reactivity of T cells against NY-BR1.1. Due to the known expression of NY-BR1.1 in normal brain tissue in combination with the also known ability of CAR-T-cells to cross the blood brain barrier, the use of a “clone2 CAR” for the treatment of advanced breast cancer must be judged as dangerous. Our findings show that a critical evaluation of a candidate target antigen for CAR therapy shall be performed by the use of the respective scFv rather than the classical mAb approach.
Citation Format: Patrick Schmidt, Claudia Luckner Minden, Claudia Ziegelmeier, Isabella Gosch, Niels Halama, Frank Momburg, Rosa Eurich, Sarah Schott, Frederik Marmé, Andreas Schneeweiß, Claus Peter Heußel, Dirk Jäger, Inka Zörnig. Evaluation of NY-BR-1 as a suitable antigen for CAR based immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B054.
Abstract B056: Harnessing tissue resident memory T cells to combat solid tumors
Authors: Rosato Pamela C. , Manlove Luke S. , Nelson Christine E. , Pennell Christopher A. , Vezys Vaiva , Masopust David 
Published: November 2016

Abstract
The immunosuppressive tumor microenvironment is a major hurdle to overcome in the development of successful cancer therapies. Newly discovered tissue resident memory CD8+ T cells (TRM) function to create a potent immunostimulatory environment to protect against local reinfection. As TRM are present in abundance in nearly every tissue and can be triggered by cognate peptide alone, without adjuvant, we tested whether we could hijack infection-specific TRM in tumors to reverse the immunosuppressive tumor microenvironment and enhance existing immunotherapies. Mice with established vesicular stomatitis virus (VSV)-specific skin TRM were challenged with the transplantable B16 melanoma cell line. We find VSV-specific CD8+ T cells within established tumors and within 12 hours of cognate peptide delivery, these cells upregulate IFNγ, CD25, and Granzyme B. This led to 1) tumor NK cell activation through Granzyme B upregulation, 2) NK cell recruitment to the tumor, and 3) CD8+ T cell recruitment to the tumor. Ongoing studies are testing whether TRM immunotherapy synergizes with CAR T cell and checkpoint blockade immunotherapies for eradication of recalcitrant tumors. These results demonstrate proof of principal efficacy for exploiting infection-specific TRM as a tumor immunotherapy.
Citation Format: Pamela C. Rosato, Luke S. Manlove, Christine E. Nelson, Christopher A. Pennell, Vaiva Vezys, David Masopust. Harnessing tissue resident memory T cells to combat solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B056.
Abstract B059: Local intratumoral treatment with low-dose CD40 and TLR4 agonists overcomes resistance to PD-1 blockade to regress tumors systemically
Authors: Khalil Danny N. , Campesato Luis Felipe , Li Yanyun , Merghoub Taha , Wolchok Jedd D. 
Published: November 2016

Abstract
Multiple cancers resistant to immune checkpoint blockade (i.e., anti-PD-1, PD-L1, and/or CTLA-4) demonstrate impaired APC activation. We therefore hypothesized that resistance to checkpoint blockade could be overcome with agents selected to enforce APC activation. Using the checkpoint-blockade resistant syngeneic B16 murine model, we screened such agents for their ability to overcome resistance to anti-PD-1 therapy. In the setting of PD-1 blockade, we found that intratumoral treatment with the TLR4 ligand monophosphoryl lipid A (MPL) and low-dose CD40 agonist monoclonal antibody (mAb) primes T cells which infiltrate and regress noninjected tumors at a distant site. Surprisingly, locally injected tumors were heavily infiltrated with neutrophils expressing costimulatory markers within 3 hours of treatment and then rapidly regressed. There was, however, persistence of activated dendritic cells and monocytes in the draining lymph node. Within 1 week, distant tumors were infiltrated with activated CD8 T cells, showed a marked increase in the T effector to T regulatory ratio, and began to regress. The regression of distant tumors was abolished in RAG1-deficient animals lacking lymphocytes. Treatment yielded no discernable toxicity, and cured animals fully resisted tumor re-implantation at 90 days, developing fur depigmentation at both the site of initial treatment, and the untreated tumor reimplantation site, but not elsewhere. Interestingly, systemic administration of MPL and CD40 was less effective than intratumoral treatment despite a 25-fold dose increase. In conclusion, low-dose intratumoral treatment with combined TLR4 and CD40 agonists induces anti-tumor T cells which in turn regress tumors at distant sites and provide durable immunity such that tumor re-implantation is resisted in a highly-specific manner. Given that this regimen relies on agents that are FDA-approved for other indications, or in clinical development, it is potentially translatable across a broad range of malignancies that are currently resistant to immunotherapy.
Citation Format: Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Taha Merghoub, Jedd D. Wolchok. Local intratumoral treatment with low-dose CD40 and TLR4 agonists overcomes resistance to PD-1 blockade to regress tumors systemically [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B059.
Abstract B085: Combining transcriptomic profiling and genome engineering to dissect regulation of tumor immunology
Authors: Cong Le , Singer Meromit , Wang Chao , Kwon John , Anderson Ana , Rozenblatt-Rosen Orit , Kuchroo Vijay , Regev Aviv 
Published: November 2016

Abstract
There is great interest in understanding the dysfunctional state of T-cells during uncontrolled tumor growth, particular regarding the molecular pathways that regulate this functional state for development of potential therapeutic approaches. Here we apply systematic transcriptomic profiling and analysis to dissect the molecular regulation of dysfunctional CD8+ tumor-filtrating lymphocytes (TILs) in a mice melanoma model. We identified key putative regulators and, through combination with precise genome perturbation, established their causal role in driving the dysfunctional phenotype of CD8+ TILs.
Citation Format: Le Cong, Meromit Singer, Chao Wang, John Kwon, Ana Anderson, Orit Rozenblatt-Rosen, Vijay Kuchroo, Aviv Regev. Combining transcriptomic profiling and genome engineering to dissect regulation of tumor immunology [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B085.
Abstract B100: An intrinsic safeguard for chimeric antigen receptor adoptive T-cell immunotherapies
Authors: Valton Julien 
Published: November 2016

Abstract
Adoptive CAR T cell therapies have been reported to be highly efficient at killing tumor cells and are on the verge of revolutionizing the field of cancer treatment. However, there are safety concerns with CAR T cell treatments which would require intervention, including on-target off-tumor effects, on-tumor toxicities such as cytokine release syndrome and tumor lysis syndrome. Avoiding the aformentionned acute and long term adverse events appears to be mandatory to improve the safety of adoptive cell immunotherapies. To address this issue, different teams developed molecular suicide switch systems to remove the transferred cell population. While these different systems are efficient at promoting eradication of adoptively transferred cells, they are expressed independent of the CAR. This could potentially lead to the generation of a CAR T population devoid of the suicide switch system raising concerns about their utility in the clinic. To address this issue, we developed a novel CAR architecture containing an integrated suicide switch component. We demonstrated that this CAR architecture was efficiently depleted by an FDA-approved molecule, retained its cytolytic potential and allowed for universal enrichment and detection of CAR T cells by GMP compatible kit. We will present its development and in-depth characterization.
Note: This abstract was not presented at the conference.
Citation Format: Julien Valton. An intrinsic safeguard for chimeric antigen receptor adoptive T-cell immunotherapies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B100.
Abstract B107: Immunotransplant: Merging checkpoint blockade and T-cell transfer into lymphodepleted recipients
Authors: Marshall Netonia , Marron Thomas , Agudo Judith , Brown Brian , Brody Joshua 
Published: November 2016

Abstract
Lymphomas, with an estimated 80,000 new cases, are the 5th most common cancer in the United States and the majority of lymphoma subtypes are incurable and in need of novel, mechanistically distinct therapies. Two approaches to potently increase the anti-tumor potential of T cells are: checkpoint blockade (e.g. anti-CTLA-4 and anti-PD-1 antibodies) and adoptive T-cell transfer into lympho-depleted recipients. We have developed a novel therapy combining these approaches into ‘checkpoint-blockade-primed immunotransplant’ comprised of: -treatment of tumor-bearing host with anti-CTLA-4 and/or anti-PD-1 antibodies -splenocyte harvest and transfer to lympho-depleted recipient Whereas checkpoint blockade alone has minimal anti-tumor effect in the pre-clinical model, our results show that the combined therapy results in superior anti-tumor immunity as seen by increased production of tumor-reactive IFN γ positive T-cells. Treatment of both tumor-bearing donor and recipient with checkpoint antibodies induces cure of the majority of recipients, in a CD8, NK, and IFNγ-dependent manner. Furthermore, we have demonstrated that CD8 T cells exposed to checkpoint blockade and transfer into the lymphopenic host demonstrate greater: -in vivo serum levels of IL-15 and IL-7 -surface expression levels of IL-15R and IL-7R -in vitro STAT5 phosphorylation in response to common γ-chain cytokines -in vivo proliferation in response to exposure to cognate tumor antigen Ongoing studies will seek to assess the dependence of the above observations (cytokine production, proliferation, anti-tumor effect) on specific common γ-chain cytokines, the role of lymphopenia in inducing T cell trafficking to tumor versus healthy tissue, and guide development of the immunotransplant model to optimize the amplification of anti-tumor immunity for near-term clinical translation.
Citation Format: Netonia Marshall, Thomas Marron, Judith Agudo, Brian Brown, Joshua Brody. Immunotransplant: Merging checkpoint blockade and T-cell transfer into lymphodepleted recipients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B107.
Abstract IA21: Immune mobilizing TCR therapies against cancer (ImmTAC): A novel class of antigen-specific tumor immunotherapy
Authors: Coughlin Christina M. 
Published: November 2016

Abstract
Cancer immunosuppression prevents the effective activation of antigen-specific cytotoxic T cell responses against tumor cells. The activation of tumor-specific responses has the potential to halt the progression of cancer and, in some circumstances, eradicate it. Designing the therapeutic interventions that can achieve this intended mechanism of action (T cell eradication of tumors) aims to harness the known specificity of the T cell: target cell interaction to simultaneously a) lead to death of tumor target cells expressing the antigen and b) to limit surrounding tissue damage and thus manage potential toxicity. Previous design approaches of bispecific therapeutic molecules to redirect T cell responses against cancer cells have utilized antibody binding domains to recognize tumor cell-surface proteins. These first generation bi-specifics have proven efficacy in hematologic malignancies, and novel approaches such as TCR targeting have the goal of enhancing activity in solid tumor settings. The ImmTACs (immune-mobilizing monoclonal TCRs against cancer) are a new class of bispecific therapeutic molecule, utilizing the physiologic antigen recognition system of the T cell, the monoclonal T cell receptor (TCR), as the targeting effector fused to an anti-CD3 domain. The soluble TCRs have been engineered to possess extremely high affinity for their tumor antigen peptide-HLA complex. ImmTACs thus overcome the problem of low affinity tumor-specific T cells imposed by thymic selection, and provide a means to target intracellular tumor antigens not accessible to antibody binding domains. The ImmTACs drive recruitment of polyclonal T cells to the tumor, resulting in potent redirected T cell response and tumor cell destruction in an antigen-specific manner. The first ImmTAC tested in the clinic is IMCgp100, an engineered TCR recognizing the gp100 melanoma antigen in the context of HLA-A2 with promising, preliminary single agent activity in both cutaneous and uveal melanoma.
Citation Format: Christina M. Coughlin. Immune mobilizing TCR therapies against cancer (ImmTAC): A novel class of antigen-specific tumor immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA21.
Low Body Mass Index, Serum Creatinine, and Cause of Death in Patients Undergoing Percutaneous Coronary Intervention
Authors: Goel Kashish , Gulati Rajiv , Reeder Guy S. , Lennon Ryan J. , Lewis Bradley R. , Behfar Atta , Sandhu Gurpreet S. , Rihal Charanjit S. , Singh Mandeep 
Published: November 2016

Background

Low body mass index (
BMI
) and serum creatinine are surrogate markers of frailty and sarcopenia. Their relationship with cause‐specific mortality in elderly patients undergoing percutaneous coronary intervention is not well studied.

Methods and Results

We determined long‐term cardiovascular and noncardiovascular mortality in 9394 consecutive patients aged ≥65 years who underwent percutaneous coronary intervention from 2000 to 2011.
BMI
and serum creatinine were divided into 4 categories. During a median follow‐up of 4.2 years (interquartile range 1.8–7.3 years), 3243 patients (33.4%) died. In the multivariable model, compared with patients with normal
BMI
, patients with low
BMI
had significantly increased all‐cause mortality (hazard ratio [
HR
] 1.4, 95%
CI
1.1–1.7), which was related to both cardiovascular causes (HR 1.4, 95% CI 1.0–1.8) and noncardiovascular causes (HR 1.4, 95% CI 1.06–1.9). Compared with normal
BMI
, significant reduction was noted in patients who were overweight and obese in terms of cardiovascular mortality (overweight: HR 0.77, 95% CI 0.67–0.88; obese: HR 0.80, 95% CI 0.70–0.93) and noncardiovascular mortality (overweight: HR 0.85, 95% CI 0.74–0.97; obese: HR 0.82, 95% CI 0.72–0.95). In a multivariable model, in patients with normal
BMI
, low creatinine (≤0.70 mg/dL) was significantly associated with increased all‐cause mortality (HR 1.8, 95% CI 1.3–2.5) and cardiovascular mortality (HR 2.3, 95% CI 1.4–3.8) compared with patients with normal creatinine (0.71–1.0 mg/dL); however, this was not observed in other
BMI
categories.

Conclusions

We identified a new subgroup of patients with low serum creatinine and normal
BMI
that was associated with increased all‐cause mortality and cardiovascular mortality in elderly patients undergoing percutaneous coronary intervention. Low
BMI
was associated with increased cardiovascular and noncardiovascular mortality. Nutritional support, resistance training, and weight‐gain strategies may have potential roles for these patients undergoing percutaneous coronary intervention.
Short‐Term Risk of Bleeding During Heparin Bridging at Initiation of Vitamin K Antagonist Therapy in More Than 90 000 Patients With Nonvalvular Atrial Fibrillation Managed in Outpatient Care
Authors: Bouillon Kim , Bertrand Marion , Boudali Lotfi , Ducimetière Pierre , Dray‐Spira Rosemary , Zureik Mahmoud 
Published: November 2016

Background
Several studies have recently examined the risks of bleeding and of ischemic stroke and systemic embolism associated with perioperative heparin bridging anticoagulation in patients with nonvalvular atrial fibrillation. However, few studies have investigated bridging risks during vitamin K antagonist initiation in outpatient settings.

Methods and Results

A retrospective cohort study was conducted on individuals starting oral anticoagulation between January 2010 and November 2014 for nonvalvular atrial fibrillation managed in outpatient care and identified from French healthcare insurance. Bleeding and ischemic stroke and systemic embolism events were identified from the hospitalization database. Adjusted hazard ratios with 95%
CI
were estimated using Cox models during the first and 2 following months of anticoagulation. Of 90 826 individuals, 30% had bridging therapy. A total of 318 (0.35%) cases of bleeding and 151 (0.17%) ischemic stroke and systemic embolism cases were identified during the first month of follow‐up and 231 (0.31%) and 122 (0.16%) during the 2 following months, respectively. At 1 month of follow‐up, the incidence of bleeding was higher in the bridged group compared with the nonbridged group (0.47% versus 0.30%;
P
<0.001), and this increased risk persisted after adjustment for covariates (hazard ratio=1.60; 95%
CI
, 1.28–2.01). This difference disappeared after the first month of treatment (0.93; 0.70–1.23). No significant difference in the occurrence of ischemic stroke and systemic embolism was observed either at 1 month of follow‐up or later.

Conclusions
At vitamin K antagonist initiation for nonvalvular atrial fibrillation managed in ambulatory settings, bridging therapy is associated with a higher risk of bleeding and a similar risk of arterial thromboembolism compared with no bridging therapy.
Predictability and Dynamics of Warm-Core Mesoscale Vortex Formation with the 8 May 2009 “Super Derecho” Event
Authors: Grunzke Caleb T. , Evans Clark 
Published: November 2016

The predictability and dynamics of the warm-core mesovortex associated with the northern flank of the 8 May 2009 “super derecho” event are examined by coupling the Advanced Research Weather Research and Forecasting Model with the ensemble adjustment Kalman filter implementation within the Data Assimilation Research Testbed facility. Cycled analysis started at 1200 UTC 2 May 2009, with observations assimilated every 6 h until 1200 UTC 7 May 2009, at which time a 50-member ensemble of 36-h convection-allowing ensemble forecasts were launched. The ensemble forecasts all simulated a mesoscale convective system, but only 7 out of 50 members produced a warm-core mesovortex-like feature similar in intensity to the observed mesovortex. Ensemble sensitivity and composite analyses were conducted to analyze the environmental differences between ensemble members. A more amplified upstream upper-level trough near the time of observed convection initiation is associated with a stronger simulated mesovortex. The amplification of the trough results in increases in the magnitudes of the low-level jet and thermal gradient. Consequently, more moisture is transported poleward into western Kansas, leading to earlier convection initiation in ensemble members with the strongest mesovortices. A circulation budget is performed on the ensemble members with the strongest (member 10) and weakest (member 5) time-averaged circulations. The ascending front-to-rear flow, descending rear-to-front flow, and divergent low-level flow of an MCS are more prominent in member 10, which is hypothesized to allow for the convergence of more background cyclonic absolute vorticity and, thus, facilitating the development of a stronger mesovortex.
Observed and Projected Changes in United States Tornado Exposure
Authors: Strader Stephen M. , Ashley Walker S. , Pingel Thomas J. , Krmenec Andrew J. 
Published: November 2016

AbstractThis study examines how tornado risk and societal exposure interact to create tornado disaster potential in the United States. Finescale historical and projected demographic data are used in a set of region-specific Monte Carlo tornado simulations to reveal how societal development has shaped, and will continue to shape, tornado disaster frequency and consequences. Results illustrate that although the U.S. Midwest contains the greatest built-environment exposure and the central plains experience the most significant tornadoes, the midsouth contains the greatest tornado disaster potential. This finding is attributed to the relatively elevated tornado risk and accelerated growth in developed land area that characterizes the midsouth region. Disaster potential is projected to amplify in the United States due to increasing built-environment development and its spatial footprint in at-risk regions. In the four regions examined, both average annual tornado impacts and associated impact variability are projected to be as much as 6 to 36 times greater in 2100 than 1940. Extreme annual tornado impacts for all at-risk regions are also projected to nearly double during the twenty-first century, signifying the potential for greater tornado disaster potential in the future. The key lesson is that it is the juxtaposition of both risk and societal exposure that drive disaster potential. Mitigation efforts should evaluate changes in tornado hazard risk and societal exposure in light of land-use planning, building codes, and warning dissemination strategies in order to reduce the effects of tornadoes and other environmental hazards.