Transient Injection Research Articles

Phase 1b/2, open label, multicenter, study of intratumoral SD-101 in combination with pembrolizumab in anti-PD1 naïve & experienced metastatic melanoma patients.

9550 Background: SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembro is a PD-1 inhibitor approved for the treatment of metastatic melanoma. This study, MEL-01 (NCT02521870), assesses the safety and preliminary efficacy of SD-101 in combination with pembro in stage IIIC-IV melanoma. Methods: A modified 3+3 design was used for SD-101 dose escalation of 1, 2, 4, and 8 mg injected in a single tumor lesion Q1W x 4 then Q3W x 7 in combination with pembro (200 mg IV Q3W). Tumor responses were assessed per investigator using RECIST v1.1. Results: In phase Ib, 22 pts were enrolled: median age 64 y/o, male 68%, white 82%, Stage IV/IIIc 86%/14%, LDH > 1 ULN 27%, ≥ 3 prior lines therapy 36%, anti-PD-1 naïve (n = 9) and experienced (n = 13). There has been no dose limiting toxicity (DLT) to date. The most common (≥20%) treatment-related AEs (TRAEs) were transient low-grade fatigue, myalgia, headache, chills and injection site reactions. Grade ≥ 3 TRAEs were observed in 59.1% pts (most common: myalgia 13.6% and injection site pain 13.6%). Immune-related AEs occurred in 2 pts. One had a G2 pneumonitis on Day 23 resulting in drug withdrawal and the other G3 hypophysitis (85 days after last treatment). No deaths occurred. Responses were observed at all doses in PD-1 inhibitor naïve pts, both at the injected and non-injected lesions. A response was seen at the 8 mg dose in PD-1 inhibitor experienced pts. With median f/u of 97 days (max 382), the ORR was 66.7% in the PD-1 inhibitor naïve patients with best overall response of CR 22.2% (n = 2), PR 44.4% (n = 4), SD 11.1% (n = 1), PD 11.1% (n = 1), and NE 11.1% (n = 1). In the PD-1 inhibitor experienced pts: PR 7.7% (n = 1) and SD 38.5% (n = 5). Conclusions: The combination of SD-101 and pembro was well tolerated and demonstrates no worsening of the expected toxicities of each of the individual monotherapies. These interim data support enhanced activity of adding SD-101 to pembro in anti-PD-1 naive metastatic melanoma as well as potential activity in anti-PD-1 experienced pts. Additional follow up data through May 15, 2017 will be presented. Clinical trial information: NCT02521870.

Vaccine profile of herpes zoster (HZ/su) subunit vaccine

ABSTRACTIntroduction: Herpes zoster (HZ) causes an often severe and painful rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN) and by dissemination in immune-compromised patients. HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age-related or other causes of decreased T cell immunity. A live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 8 years.Areas covered: A new HZ subunit (HZ/su) vaccine combines a key surface VZV glycoprotein (E) with a T cell-boosting adjuvant system (AS01B) and is administered by two intramuscular injections two months apart.Expert commentary: HZ/su showed excellent efficacy of ~90% in immunocompetent adults ≥50 and ≥70 years of age, respectively, in the ZOE-50 and ZOE-70 phase III controlled trials. Efficacy was unaffected by advancing age and persisted for >3 years. Approximately 9.5% of subjects had severe, but transient (1–2 days) injection site pain, swelling or redness. Compliance with both vaccine doses was high (95%). The vaccine will have a major impact on HZ management. Phase I-II trials showed safety and immunogenicity in severely immunocompromised patients. Phase III trial results are expected soon.

Evaluation of transient errors in GPGPUs for safety critical applications: An effective simulation-based fault injection environment

General Purpose Graphics Processing Units (GPGPUs) are increasingly adopted thanks to their high computational capabilities. GPGPUs are preferable to CPUs for a large range of computationally intensive applications, not necessarily related to computer graphics. Within the high performance computing context, GPGPUs must require a large amount of resources and have plenty execution units. GPGPUs are becoming attractive for safety-critical applications where the phenomenon of transient errors is a major concern. In this paper we propose a novel transient error fault injection simulation methodology for the accurate simulation of GPGPUs applications during the occurrence of transient errors. The developed environment allows to inject transient errors within all the memory area of GPGPUs and into not user-accessible resources such as in streaming processors combinational logic and sequential elements. The capability of the fault injection simulation platform has been evaluated testing three benchmark applications including mitigation approaches such as Duplication With Comparison, Triple Modular Redundancy and Algorithm Based Fault Tolerance. The amount of computational costs and time measured is minimal thus enabling the usage of the developed approach for effective transient errors evaluation.

Emulation-based fault analysis on RFID tags for robustness and security evaluation

This paper presents an FPGA (field-programmable gate array) based fault emulation system for analysis of fault impact on security and robustness of RFID (radio frequency identification) tags. This emulation system that deals with any RFID protocol consists of two tag-reader pairs, a fault injection module and an emulation controller all implemented in a single FPGA. The designed approach performs single event upset (SEU) and single event transient (SET) fault injection and permits with high flexibility to set communication scenarios and related parameters. Moreover, we propose a classification of produced errors to evaluate fault impacts and identify most sensitive tag flip-flops causing large number of failures and security concerns. The proposed fault injection approach provides suitable means to increase tags' security and robustness. In our experimentation campaign, an ultra-high frequency (UHF) tag architecture has been exposed to intensive SEU and SET fault injections. The duration of the campaign including results analysis is 30min in where 6,215,316 faults are experimented. Our results have shown that the tag has tolerated 61.82% of SEUs and 67.83% of SETs. The flip-flops that constitute the tag FSM (finite state machine) have been identified as the most sensitive parts causing large number of failures.

WT1 Peptide Vaccine Is Able to Induce WT1-Specifc Immune Response with TCR Clonal Enrichment to Control Minimal Residual Disease in Patients with Myeloid Leukemia

Background: Immunotherapy has the potential for clinical efficacy in patients with myeloid leukemia, especially in the setting of minimal residual disease. WT-1, aberrantly expressed in both myeloid and lymphoid leukemia, is associated with adverse risk in AML. WT1 is highly antigenic and is an attractive target for immunotherapy. The optimal strategy for vaccination to induce CD8+ T cell responses against WT1 is not known.Methods: We performed a pilot randomized study of HLA-A02+ patients to receive vaccination with WT1 126-134 peptide (RMFPNAPYL) in Montanide or in poly ICLC (Hiltonol from Oncovir, a TLR3 agonist) to explore the novel immune adjuvant in patients with myeloid leukemia (NCT01842139). The vaccine was administered q 2 weeks X 6 during the induction phase followed by monthly booster vaccinations X 6 months.Enrollment: Seven patients (4 males, 3 female ages 39 to 73) were randomized. Four patients received WT1 in Montanide (3 AML, 1 CML myeloid blast phase, 2 s/p allo-SCT), and three with WT1 in poly ICLC (2 AML, one MDS RAEB2 s/p allo-SCT). Five patients were in morphologic remission (3 in CR1) and two had very low burden of residual morphologic disease at study entry.Toxicities: All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient post allo-SCT on the Montanide arm developed transverse myelitis with evidence of bacterial meningitis following the first monthly booster vaccination. Another patient on the Montanide arm developed aseptic ulceration at the 12th vaccine site followed by inflammation at the 11th WT1 vaccine site, and persistent erythema at the 1st induction vaccine site about 4 weeks after the completion of all 12 WT1 vaccinations. The aseptic ulcers eventually healed with wound care without antibiotics.Efficacy: Three of 4 patients on the Montanide arm had decease of WT1 qRT-PCR levels after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8+ T cell responses with biased TCR beta chain enrichment. Three patients from who cells were available for TCR alpha and beta CDR3 sequencing had TCR clonal enrichment after WT1 vaccination. In contrast, no obvious WT1-specific immune responses were detected in 2 patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did have a decrease in WT1 qRT-PCR levels and remained in remission 3 years after the initiation of WT1 vaccination. Thus, WT1 peptide in poly ICLC may induce anti-leukemia immune response not detected by our current assays. The third patient on the poly ICLC arm was later found to have A0202 instead of A0201, and thus could serve as negative control. Not surprisingly, this patient did not have a decrease of WT1 qRT-PCR levels nor TCR clonal evolution during vaccination. The patient tolerated the vaccine well without injection reactions and had stable AML for 12 weeks, but the disease progressed before the first monthly WT1 vaccination.Conclusions: WT1 peptide vaccine with Montanide as an adjuvant induces WT1-specific CD8+ T cell responses with TCR clonal and specific TCR beta CDR3 enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Future investigation to combine checkpoint inhibitors with peptide vaccination might further enhance efficacy in patients with myeloid leukemia. DisclosuresLiu:Karyopharm: Research Funding; BMS: Research Funding. Salazar:Oncovir Inc: Employment. Odenike:Suneisis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Geron: Research Funding; CTI/Baxter: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Gajewski:Abbvie: Consultancy; Celldex: Consultancy, Research Funding; Jounce: Consultancy; Incyte: Consultancy, Research Funding; Evelo: Patents & Royalties: Patent application; BMS: Research Funding; Merck: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Bayer: Consultancy; Aduro: Patents & Royalties: Patent application.

Abstract PR02: A personalized neoantigen vaccine in patients with high risk melanoma

Abstract Neoantigens arise from somatic tumor mutations and can encode amino acid changes, generating peptides with the potential to bind to HLA molecules. Since these neoepitopes provide exquisite tumor specificity and are expected to be highly immunogenic as they are not subject to central tolerance, they were long-envisioned as highly valuable tumor antigens. Growing evidence has supported tumor neoepitopes as key antigens triggering immune-mediated tumor killing in vivo across settings of effective cancer immunotherapy, including checkpoint blockade and adoptive transfer with tumor-infiltrating lymphocytes. Vaccination is a potentially effective approach for inducing tumor-specific immune responses, but has been limited by the lack of a sufficiently potent vaccine immunogen. By leveraging next-generation sequencing technologies and new analytical pipelines to systematically identify personal tumor neoantigens, in a phase 1 trial we tested the feasibility, safety, and immunogenicity of a multi-epitope cancer vaccine targeting personal tumor neoantigens in patients with high-risk melanoma. Mutations were identified by DNA and RNA sequencing; epitopes were selected based on class I HLA binding prediction algorithms. The vaccines, comprised of up to 20 long peptides spanning mutated tumor epitopes and admixed with the Toll-Like Receptor 3 agonist poly-ICLC, were administered using a prime-boost approach. Of 12 patients enrolled, the initial 6 patients who received the full set of priming and booster vaccinations experienced only minimal adverse events, consisting of mild and transient injection site reaction, flu-like symptoms, and rash. We identified strong, polyfunctional CD4+ and CD8+ T cell responses against multiple neoepitopes in all dosed patients. Processing and presentation of neoantigens on autologous tumors was confirmed by mass spectrometry and recognition of autologous tumor by vaccine-induced neoantigen-specific T cells was verified. These studies show that a personalized neoantigen vaccine is safe, feasible, and strongly immunogenic in cancer patients. The data should reinvigorate the field of cancer vaccines, providing a rational path for the building of combinatorial approaches to extend their efficacy. Citation Format: Patrick A. Ott, Zhuting Hu, Derin B. Keskin, Sachet A. Shukla, Jing Sun, Ed Fritsch, Nir Hacohen, Catherine J. Wu. A personalized neoantigen vaccine in patients with high risk melanoma [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 PR02.

Shear accumulation as a means for evaluating risk of thromboembolic events in novel endovascular stent graft designs

ObjectiveThis study proposes to establish a simulation-based technique for evaluating shear accumulation in stent grafts and to use the technique to assess the performance of a novel branched stent graft system. MethodsComputational fluid dynamics models, with transient boundary conditions, particle injection, and rigid walls, simplifying assumptions were developed and used to evaluate the shear accumulation in various stent graft configurations with a healthy aorta as comparison. ResultsShear streamlines are presented for the various configurations. Shear accumulation was also calculated for each configuration. The number of particles with shear accumulations >3.5 Pa-s for each configuration was compared with the shear accumulation values of commercially available mechanical aortic valves from the literature. ConclusionsThe stent graft configuration with the diaphragm does have particles with shear accumulation >3.5 Pa-s. However, the percentage of particles with shear accumulation above 3.5 Pa-s is less than the two commercially available mechanical aortic valves, and more surprisingly, is smaller than in the healthy aorta.

Immunity of Automotive Power Line Communication Systems

Power line communication (PLC) could not be established in automotive environments till now due to concerns with the unavoidable electromagnetic disturbances in the vehicle supply nets. Conducted broad band switching noise and field coupled narrow band noise can disturb the communication and prevent higher data rates. The continuously increasing size of the communication cable harnesses in vehicles is very difficult to handle, and PLC could reduce the complexity of the harness. This paper presents an approach to estimate the theoretical limits of PLC in the presence of noise in automobiles. Signal power and bit error rates are computed and discussed, based on electromagnetic compatibility-standards and PLC-parameter sets from older investigations’ noise levels. Commonly used automotive immunity tests are applied to analyze the signal to noise ratio of the PLC in a simulation environment. Therefore, immunity test setup models are introduced in order to analyze the noise injection and coupling characteristics to the PLC receiver. A virtual direct power injection (DPI) test is carried out with narrow band noise and transient pulse injection. For method validation, BCI measurements of a real PLC transceiver were carried out and failure behavior was compared to DPI simulation results. Immunity improvement for single carrier modulation in PLC is proposed. Finally, an analysis of the immunity to pulses is performed and results are discussed.

CT-guided thoracic sympathetic blockade for palmar hyperhidrosis: Immediate results and postoperative quality of life

The purpose of this study was to evaluate the results, complications, and degree of satisfaction among patients who underwent a CT-guided percutaneous puncture thoracic sympathetic blockade. A total of 186 patients underwent CT-guided thoracic sympathetic blockade based on case histories and a prospective pre- and postoperative questionnaire survey. The study sample was composed of 93 patients with an age range from 18 to 34years and a diagnosis with primary palmar hyperhidrosis (severe in some patients). Percutaneous puncture thoracic sympathetic blockade guided by CT was performed under local anesthesia in all patients. Heart rate (HR), non-invasive blood pressure (NIBP), arterial oxygen saturation (SPO2), perfusion index (PI), and palmar temperature (T) were monitored before and after treatment. Follow-up included a questionnaire on life quality and degree of satisfaction. Ten minutes after treatment, the SPO2, PI, and temperature all raised remarkably ([92.75±2.02]% vs. [98.85±1.09]%, [1.55±0.69]% vs. [8.60±0.94]%, [30.95±1.27]°C vs. [35.75±0.55]°C, respectively, P<0.001). The therapeutic success rate was 96.7%. No operative mortality was recorded. No complications were observed, except transient bradycardia in one patient and transient injection site pain in 25 patients. Of the 89 patients who were monitored over a period of 6–12months through follow-up interviews and questionnaires, 46% developed compensatory hyperhidrosis, 87.6% reported improvement in their quality of life. CT-guided percutaneous puncture thoracic sympathetic blockade is a safe, effective, and minimally invasive technique for the treatment of palmar hyperhidrosis. Despite the high rate of compensatory hyperhidrosis, it produces a high rate of patient satisfaction.

Ultra high speed investigation of gaseous jet injected by a single-hole injector and proposing of an analytical method for pressure loss prediction during transient injection

The objective of this study is to investigate the characteristics of a transient gaseous jet produced by a single-hole injector nozzle. High speed schlieren is used to image the jet development process and evaluate time-dependent characteristics of the jet. Both near and far fields have been investigated through two distinct optical configurations. Helium gas was injected at nozzle pressure ratios of 2, 3, 4 and 5 and the effects of nozzle pressure ratio on the jet axial and radial penetrations and tip velocity were investigated. An analytical model is proposed to calculate the pressure drop during transient injection using shock tube theory. Modification of existing predictions with this pressure drop model offered significantly better agreement with the experimental data.

Efficacy and Safety of a Hyaluronic Acid Filler to Correct Aesthetically Detracting or Deficient Features of the Asian Nose: A Prospective, Open-Label, Long-Term Study.

BackgroundThere is increasing interest among patients and plastic surgeons for alternatives to rhinoplasty, a common surgical procedure performed in Asia.ObjectivesTo evaluate the safety, efficacy, and longevity of a hyaluronic acid filler in the correction of aesthetically detracting or deficient features of the Asian nose.MethodsTwenty-nine carefully screened Asian patients had their noses corrected with the study filler (Juvéderm VOLUMA [Allergan plc, Dublin, Ireland] with lidocaine injectable gel), reflecting individualized treatment goals and utilizing a standardized injection procedure, and were followed for over 12 months.ResultsA clinically meaningful correction (≥1 grade improvement on the Assessment of Aesthetic Improvement Scale) was achieved in 27 (93.1%) patients at the first follow-up visit. This was maintained in 28 (96.6%) patients at the final visit, based on the independent assessments of a central non-injecting physician and the patients. At this final visit, 23 (79.3%) patients were satisfied or very satisfied with the study filler and 25 (86.2%) would recommend it to others. In this small series of patients, there were no serious adverse events (AEs), with all treatment-related AEs being mild to moderate, transient injection site reactions, unrelated to the study filler.ConclusionsUsing specific eligibility criteria, individualized treatment goals, and a standardized injection procedure, the study filler corrected aesthetically detracting or deficient features of the Asian nose, with the therapeutic effects lasting for over 12 months, consistent with a high degree of patient satisfaction. This study supports the safety and efficacy of this HA filler for specific nose augmentation procedures in selected Asian patients.Level of Evidence: 3 Therapeutic

Large-volume flux closure during plasmoid-mediated reconnection in coaxial helicity injection

A large-volume flux closure during transient coaxial helicity injection (CHI) in NSTX-U is demonstrated through resistive magnetohydrodynamics (MHD) simulations. Several major improvements, including the improved positioning of the divertor poloidal field coils, are projected to improve the CHI start-up phase in NSTX-U. Simulations in the NSTX-U configuration with constant in time coil currents show that with strong flux shaping the injected open field lines (injector flux) rapidly reconnect and form large volume of closed flux surfaces. This is achieved by driving parallel current in the injector flux coil and oppositely directed currents in the flux shaping coils to form a narrow injector flux footprint and push the injector flux into the vessel. As the helicity and plasma are injected into the device, the oppositely directed field lines in the injector region are forced to reconnect through a local Sweet–Parker type reconnection, or to spontaneously reconnect when the elongated current sheet becomes MHD unstable to form plasmoids. In these simulations for the first time, it is found that the closed flux is over 70% of the initial injector flux used to initiate the discharge. These results could work well for the application of transient CHI in devices that employ super conducting coils to generate and sustain the plasma equilibrium.

The role of temperature, mixture fraction, and scalar dissipation rate on transient methane injection and auto-ignition in a jet in hot coflow burner

The transient injection and subsequent auto-ignition of a methane jet issuing into a laminar coflow of hot exhaust gas from a lean premixed hydrogen air flame was studied using high-speed planar Rayleigh scattering, yielding two-dimensional measurements of mixture fraction, temperature and scalar dissipation rate with high spatio-temporal resolution. The temporal development of the mixing field between the transient fuel jet and the surrounding coflow prior to the occurrence of auto-ignition was examined at a sampling rate of 10kHz. The impact of the transient jet development on numerical modeling of this test case is discussed. It was found that auto-ignition occurred after the jet transitioned from a transient state into the steady state, thus eliminating the need to model the complete transient fuel injection when the primary focus is on the onset of auto-ignition.Simultaneous high-speed OH* chemiluminescence from two viewing angles was applied to gain 3D-information of the ignition kernel location. This information allowed the selection and analysis of ignition events where the initial kernel formed inside the laser light sheet. Detailed analysis of the dynamics of a single ignition event, as well as statistical analysis of multiple ignition events based on a joint probability density approach, indicated that the ignition kernels occurred at very lean mixture fractions and at locations with low scalar dissipation rates.

A Novel Layout-Based Single Event Transient Injection Approach to Evaluate the Soft Error Rate of Large Combinational Circuits in Complimentary Metal-Oxide-Semiconductor Bulk Technology

As the technology scales down, space radiation induced soft errors are becoming a critical issue for the reliability of Integrated Circuits (ICs). In this paper, we propose a novel layout-based Single-Event Transient (SET) injection approach to evaluate the Soft Error Rate (SER) of large combinational circuits in Complementary Metal-Oxide-Semiconductor (CMOS) bulk technology. We consider the effect of ion strike location on the SET pulse width in this approach. Heavy-ion experiments on two different inverter chains are conducted to verify this layout-based SET injection approach. The simulation and experiment results show that this approach can fairly reflect the SET pulse width distribution. Furthermore, we compare the soft error number calculated by our proposed layout-based approach with the normal SET injection approach, and illustrate the detailed circuit response obtained by our proposed approach.

Transient Ion-Pair Separations for Electrospray Mass Spectrometry.

We report a novel ion-pair chromatography (IPC) approach for liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS), where the eluent does not contain any ion-pairing reagent (IPR). The IPR is injected on the column, much like the sample, and moves down the column. Significant amounts of a high retention factor IPR is injected, resulting in a transient but reproducible regional coating that progresses along the column. The sample is injected after a brief interval. The sample components interact with the IPR coated region during their passage; the chosen eluent gradient elutes the analytes of interest into the mass spectrometer before the IPR. Following analyte elution, the gradient is steeply raised, the IPR is washed out, and the effluent is sent to waste via a diverter valve until it is fully removed. As the nature of the analyte retention continuously changes along the column and with time, we call this transient ion-pair separation (TIPS). As the IPR never enters the MS, TIPS addresses two major drawbacks of IPC for ESI-MS: it avoids both ion suppression and ion source contamination. The potential of the generic approach for other modes of separation is discussed. An illustrative separation of two small inorganic ions, iodate and nitrate, is demonstrated on a reverse phase column by a transient prior injection of hexadecyltrimethylammonium chloride as IPR.

Characteristics of Plasma Current Start-Up by Transient Coaxial Helicity Injection on HIST

Transient coaxial helicity injection (T-CHI) was successfully demonstrated in the Helicity Injected Spherical Torus (HIST) device for non-inductive plasma current start-up. The spherical torus (ST) requires no central solenoid coil. The characteristics of the T-CHI start-up discharges on the HIST were investigated in detail. The toroidal plasma current reached 60 - 80 kA, and the current density profile was significantly modified by variations in the bias poloidal coil flux. The Doppler ion temperature and electron temperatures reached 10 - 15 eV, and the electron density of 1 × 1020 m−3, depending on the bias flux. Internal magnetic field measurements using a two-dimensional magnetic probe array verified that closed flux surfaces formed after fast magnetic reconnection during the current rising phase. The amount of closed flux was quantitatively related to the bias flux. We also present the first experimental measurements of helicity balance during the T-CHI process. These results validate the capability of T-CHI for higher current generation in the ST.

Comparison study of ring current simulations with and without bubble injections

AbstractFor many years, stand‐alone ring current models have been successfully producing storm time ring current enhancements without specifying explicit localized transient injections along their outer boundaries. However, both observations and simulations have suggested that the frequent burst flows or bubble injections can contribute substantially to the storm time ring current energy. In this paper, we investigate the difference in the spatial and temporal development of the ring current distribution with and without bubble injections using the Rice Convection Model‐Equilibrium. The comparison study indicates that the simulation with bubble effects smoothed out along geosynchronous orbit can predict approximately the same large‐scale ring current pressure distribution and electric potential pattern as the simulation with bubble effects included. Our results suggest that the increase of the hot plasma population along geosynchronous orbit can be envisaged as an integrated effect of bubble injections from the near‐Earth plasma sheet. However, the observed fluctuations in the plasma population and electric field can only be captured when the mesoscale injections are included in the simulation. We also confirmed again that adiabatic convection of fully populated flux tubes cannot inject the ring current from the middle plasma sheet. The paper provides a justification for using stand‐alone ring current models in the inner magnetosphere to simulate magnetic storms, without explicit consideration of bubbles and magnetic buoyancy effects inside geosynchronous orbit.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation.Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006).Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented.Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. DisclosuresThomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

The Peptidic CXCR4 Antagonist, BL-8040, Significantly Reduces Bone Marrow Immature Leukemia Progenitors By Inducing Differentiation, Apoptosis and Mobilization: Results of the Dose Escalation Clinical Trial in Acute Myeloid Leukemia

Background: The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12; high levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the leukemic blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a short synthetic peptide which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukemic blasts from the bone marrow to the peripheral blood. BL-8040 also inhibits CXCR4/CXCL12 mediated pro-survival ERK/Akt signaling and alters balance of pro/anti-apoptotic Bcl-2 proteins. BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy, and, in contrast to other CXCR4 inhibitors, as a single agent induces apoptosis of leukemia cells ex-vivo in clinical samples. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of adult relapsed/refractory AML patients is currently ongoing (NCT01838395).Objective: To assess the safety, efficacy and pharmacodynamics/pharmacokinetic parameters of BL-8040 in combination with Ara-C in first or second relapse and refractory AML patients.Method: The study includes a dose escalation phase (3+3 design) followed by an expansion phase. Each patient receives a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5 g/m2 for patients ≥60; 3 g/m2 for patients <60) on days 3-7. Five dose levels of BL-8040 (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) have been tested. Extensive pharmacodynamic parameters such as CXCR4 expression on the leukemic cells, receptor occupancy, mobilization of leukemic cells and induction of apoptosis are being assessed after monotherapy with BL-8040 using peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration. Clinical response to treatment is evaluated by BM biopsy on day 30 (-/+ 2).Results: Twenty two patients (median age, 61 y; range, 43-74 y) with relapsed/refractory AML were treated during the escalation phase. BL-8040 was escalated up to 1.5 mg/kg (recommended phase 2 dose) without reaching the MTD. Combination of BL-8040 with Ara-C was safe and well tolerated at all doses tested. Only one SAE (Sweet Syndrome) was reported as possibly related to study drug. The primary treatment related AEs were transient injection site and systemic reactions. The composite complete remission including complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate was 38% in subjects receiving BL-8040 doses of 1 mg/kg and higher (n=16). Two days of BL-8040 monotherapy triggered an average 40.2-fold (range 1.0-350.9) mobilization of immature AML progenitors (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Moreover, a significant apoptotic effect on the immature leukemia progenitors in the BM following 2 days of BL-8040 monotherapy was noted. Flow cytometric evidence of apoptosis by BL-8040 was corroborated by an increase in cleaved caspase 3 positive blasts in day 3 bone marrow biopsies. In addition, BL-8040 treatment resulted in a median decrease of 57.7% (range, -10.4% to -96.2%) in the number of BM Leukemia progenitor cells (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with the baseline biopsy. This decrease was accompanied with a 3.1 fold increase in granulocytes in the day 3 BM biopsy supporting differentiation effect. Finally, long receptor occupancy (up to 24 hours post dosing) was confirmed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed dose incremental BL-8040 exposure with a short plasma half-life.Conclusions: The current data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 has potent anti leukemic activity and in combination with Ara-C may improve the response typically achieved in this advanced AML population. Mechanistically, BL-8040 was able to induce apoptosis of leukemic progenitor cells, overcoming the stroma protection, inducing mobilization and differentiation. DisclosuresRowe:BioLineRx Ltd.: Consultancy; Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Novartis: Research Funding. Altman:Seattle Genetics: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; BMS: Consultancy. Peled:Biokine Ltd.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BiolineRX: Consultancy, Research Funding. Pereg:BioLineRx: Employment. Vainstein:BioLineRx: Employment. Aharon:BioLineRx: Employment. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Mathematical modelling of ICAN-mediated persistent firing in hippocampal neurons

Persistent neural activity has been the focus of neuroscientific research since it was first associated with complex cognitive behaviours. In particular, persistent firing has long been thought to be the neural mechanisms underlying short-term memory encoding and storage [1]. This activity is often elicited by short transient stimuli that have to be retained in memory for long delay periods, in the order of several seconds, after the original stimulus disappeared. In this scenario, the brain stores information for future execution of action depending on that information. Persistent activity elicited in a recurrent network comprising strong excitation in the local circuit has been extensively described in the literature (for a review see [2]). However, recent findings have shown that memory can also be encoded in brain regions which do not display such recurrent connection topology, including the CA1 hippocampal area [3]. Emerging studies are pointing towards intrinsic neural mechanisms independent of synaptic connections, as a complementary mechanism for the maintenance of persistent activity in the hippocampus [4]. These include various cytoplasmic currents flowing through the membrane, characterised by slow ion channel kinetics, and particular neurotransmitter modulation. Our work investigates persistent firing activity in networks of hippocampal neurons, elicited by leveraging intrinsic currents rather than network dynamics. Building on previous findings [5], we model a hippocampal pyramidal neuron using the Hodgkin-Huxley model, with low-threshold Ca2+ currents governing the inward flow of calcium ions in the cell membrane. The intracellular calcium concentration mediates the opening of calcium-activated non-specific (CAN) ion channels [6], which causes an increase in the ionic flow through the cell membrane. Therefore the CAN channels equip the neuron with an after-spike depolarisation mechanism, which enables it to emit action potentials in the absence of external stimulation. Given a transient 250ms 200pA current injection, the neuron is capable of eliciting and maintaining persistent activity with a firing rate of 6Hz for long delay periods (~30s). Moreover, this behaviour is in accord with that displayed in neural recordings of hippocampal slice preparations [4]. Connecting these persistent firing neurons in a network comprising strong local excitation yields a wide range of behaviours depending on the interaction between CAN and synaptic currents. Indeed, our network model is capable of displaying rhythmic behaviour in the form of short synchronised bursts with intra-burst frequencies of 20-40Hz and inter-burst frequencies of 3Hz. These results hint towards a possible mechanism for the generation of memory-related oscillatory activity in the hippocampus.