102,363 research outputs found
Low noise high performance 50nm T-gate metamorphic HEMT with cut-off frequency f<sub>T</sub> of 440 GHz for millimeterwave imaging receivers applications
No full textThe 50 nm m-HEMT exhibits extremely high f<sub>T</sub>, of 440GHz, low F<sub>min</sub> of 0.7 dB, associated gain of 13 dB at 26 GHz with an exceptionally high Id of 200 mA/mm and gm of 950 ms/mm at low noise biased point
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LTBK-01. INO-5401 AND INO-9012 DELIVERED INTRAMUSCULARLY (IM) WITH ELECTROPORATION (EP) IN COMBINATION WITH CEMIPLIMAB (REGN2810) IN NEWLY DIAGNOSED GLIOBLASTOMA
No full textAbstract
BACKGROUND
Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding hTERT, WT-1, PSMA) plus INO-9012 (synthetic DNA plasmid encoding IL-12), and the PD-1 immune checkpoint inhibitor cemiplimab, is given to patients with newly diagnosed GBM to evaluate tolerability, efficacy and immunogenicity.
METHODS
Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). Primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks x 4 doses, then Q9W) is given IM with EP by CELLECTRA® 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), and adjuvantly (Cohort B only).
RESULTS
Fifty-two subjects enrolled: 32 in Cohort A; 20 in Cohort B. 35% women; median age 60 years (19–78 years). The adverse event profile is consistent with single-agent (INO-5401, INO-9012, EP and cemiplimab) reported events. OS at 12 months was 84.4% (Cohort A) and 85% (Cohort B). OS at 18 months in Cohort A is 50% (95% CI 31.9 - 68.1); median OS is 17.9 months (14.5 - NR); Cohort B OS18 and median OS will be presented. Tumor gene transcripts at diagnosis confirmed expression of INO-5401 antigens. Peripheral immune responses following INO-5401 revealed antigen-specific T cell responses by Interferon gamma ELISpot and flow cytometry, including cytokine production and expansion of antigen specific CD8+T cells with lytic potential.
CONCLUSIONS
INO-5401 + INO-9012, a novel DNA plasmid immunotherapy, demonstrates acceptable risk/benefit and generates robust systemic immune responses to encoded tumor antigens when administered with cemiplimab and RT/TMZ in newly diagnosed GBM patients. Overall survival is encouraging. Clinical trial information: NCT03491683
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Effects of INO-1001 treatment on the density of NIIs.
No full text<p>Confocal laser scanning microscopy images of single-label immunofluorescence for NIIs marker EM48 (red), which labels neuronal intranuclear inclusions containing aggregated mutant huntingtin (NIIs) in the striatum of vehicle treated R6/2 (<b>A</b>), or R6/2 mice treated with INO-1001 (<b>B</b>) from 5 weeks of age and counterstained with NeuroTrace fluorescent Nissl (visualized by green fluorescence). (<b>E</b>) Quantification of NIIs in vehicle-or-INO-1001 treated R6/2 mice. There were no NIIs detected in striatum of vehicle-or-INO-1001 treated wild-type mice, so this group was not included in the statistical analysis. A t-test indicated that the density of NIIs in striatum of R6/2 mice treated with INO-1001 was lower than that in R6/2 mice treated with vehicle (<i>P</i><0.05 = 0.0026). Please note the arrow indicates a neuronal cell body with NIIs in the R6/2 mouse treated with saline.</p
Identifying the Neutrino mass Ordering with INO and NOvA
No full textThe relatively large value of established recently by the Daya Bay reactor experiment opens the possibility to determine the neutrino mass ordering with experiments currently under construction. We investigate synergies between the NOvA long-baseline accelerator experiment with atmospheric neutrino data from the India-based Neutrino Observatory (INO). We identify the requirements on energy and direction reconstruction and detector mass for INO necessary for a significant sensitivity. If neutrino energy and direction reconstruction at the level of 10% and 10 degree can be achieved by INO a determination of the neutrino mass ordering seems possible around 2020
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INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (GBM): Interim results
No full text2514 Background: Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding for hTERT, WT-1 and PSMA), plus INO-9012 (synthetic DNA plasmid encoding IL-12), with the PD-1 checkpoint inhibitor cemiplimab, is given to patients with newly-diagnosed GBM to evaluate tolerability, efficacy and immunogenicity of the combination. Methods: Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). The primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks for 4 doses, then Q9W) is given with EP by CELLECTRA 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), followed by maintenance (Cohort B only). Results: Fifty two subjects were enrolled: 32 in Cohort A; 20 in Cohort B. 35% women and 90% white. Median age 60 years (range 19-78 years). Common Grade ≥3 AEs reported were: platelet count decreased (11.5%), tumor inflammation (7.7%), seizure (7.7%), ALT increased (7.7%), lymphocyte count decreased (7.7.%). One Grade 5 unrelated event of urosepsis was reported. Of 69 SAEs reported there was only 1 related to the combination therapy, Grade 1 pyrexia. 48% of subjects reported irAEs, most frequently ALT increased (9.6%), AST increased (7.7%), diarrhea (7.7%), pyrexia (7.7%) and tumor inflammation (7.7%). 71% of the reported SAEs and irAEs occurred within the first 12 weeks of treatment. OS at 12 months was 84.4% (95% CI 67.2, 94.7) in Cohort A; Cohort B will be presented at ASCO. ELISpot assessments demonstrated T cell responses to INO-5401. Flow cytometry demonstrated evidence of activated INO-5401-specific CD8+T cells with lytic potential (CD38+Prf+GrzA+) when compared with baseline, post-treatment in the majority of patients assayed. Conclusions: INO-5401 + INO-9012 in combination with cemiplimab and RT/TMZ has an acceptable safety profile, is immunogenic and may show a survival advantage in patients with newly-diagnosed GBM. OS18 data will be presented later this year. Clinical trial information: NCT03491683
P858 An open-label, multi-center trial of INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab in subjects with newly-diagnosed glioblastoma (GBM)
No full textBackgroundGBM is one of the most deadly cancers and treatment is surgery, followed by radiation (RT) and temozolomide (TMZ) daily during RT followed by cycles of TMZ for select patients.1 New immunotherapies, such as checkpoint inhibition, may benefit patients with GBM. T cell-enabling therapies, in combination with checkpoint inhibition, may improve overall survival (OS). In this study, a novel antigen-specific T cell-generating therapy, INO-5401 (synthetic DNA plasmids encoding for human telomerase [hTERT], Wilms Tumor-1 [WT-1] and prostate specific membrane antigen [PSMA]), plus INO-9012 (synthetic DNA plasmid encoding for IL-12), with the PD-1 checkpoint inhibitor, cemiplimab, was given to patients with newly-diagnosed GBM to evaluate tolerability, immunogenicity and clinical efficacy of the combination.MethodsPhase I/II, single arm, two cohort study (A: MGMT Promoter Unmethylated, B: MGMT Promoter Methylated). The primary objective is to evaluate the safety of INO-5401 and INO-9012 followed by EP with CELLECTRA® 2000 in combination with cemiplimab. Secondary objectives include the evaluation of preliminary clinical efficacy and immunogenicity. Treatment is with 9 mg INO-5401 with 1 mg INO-9012 every three weeks (Q3W) for four doses, then Q9W; and cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over three weeks; TMZ is given concurrent with radiation (Cohorts A and B), followed by maintenance TMZ (Cohort B).Results52 patients were enrolled onto this study; 32 in Cohort A and 20 in Cohort B. 18 were women (35%) and 47 were white (90%). The median age was 60 years (range 19-78 years). The most common Grade ≥3 adverse events were elevations in alanine or aspartate aminotransferase (ALT/AST; 5 patients), and tumor inflammation/edema (5 patients); there was one Grade 5 unrelated event of urosepsis. The only related SAE reported in more than one patient was pyrexia. 22 patients (42%) reported immune-related AEs, with the most common being elevations in ALT or AST (8 patients), and were reported most commonly within the first nine weeks of treatment. The safety profile was consistent with that of patients with GBM and of checkpoint inhibitors. ELISpot assessments performed to date demonstrated the majority of patients have T cell responses to INO-5401. PFS6 was 75% (95% CI 56.6, 88.5) in Cohort A (preliminary; Cohort B pending).ConclusionsINO-5401 + INO-9012 with cemiplimab has an acceptable safety profile, is immunogenic and is potentially efficacious in patients with newly-diagnosed GBM. This combination is promising; survival results will be updated next year.Trial RegistrationNCT03491683.Ethics ApprovalThis study was approved by New York University institution’s Ethics Board; approval number i17-00764.ReferencesStupp R, et al. (2009). Lancet Oncology 10(5): 459–466
Light W-ino dark matter in brane world cosmology
No full textThe thermal relic density of W-ino-like neutralino dark matter in brane world cosmology is studied. The expansion law at a high energy regime in brane world cosmology is modified from the one in standard cosmology, and the resultant relic density can be enhanced if the five-dimensional Planck mass M-5 is low enough. We calculate the W-ino-like neutralino relic density in the anomaly mediated supersymmetry breaking scenario and show that the allowed region is dramatically modified from the one in standard cosmology and the W-ino-like neutralino with mass of order 100 GeV can be a good candidate for dark matter. Since the allowed region disappears eventually as M-5 decreases, we can find a lower bound on M-5 greater than or similar to 100 TeV according to the neutralino dark matter hypothesis, namely, the lower bound in order for the allowed region of neutralino dark matter to exist
DNA immunotherapy for recurrent respiratory papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107
No full textRecurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for efficacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included surgical intervention frequency and change in RRP Severity Score (modified) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction. RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical benefit to HPV-6 and/or HPV-11-associated RRP adults and is well-tolerated. Importantly, treatment-induced peripheral T-cell responses traffic to airway tissue and are associated with clinical response
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DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107.
No full textRecurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for efficacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included surgical intervention frequency and change in RRP Severity Score (modified) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction. RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical benefit to HPV-6 and/or HPV-11-associated RRP adults and is well-tolerated. Importantly, treatment-induced peripheral T-cell responses traffic to airway tissue and are associated with clinical response
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