Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial

IntroductionAccumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.Methods and analysisThe study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×106, 1×106, 2×106, 5×106 or 10×106 autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa.Ethics and disseminationThe study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media.Trial registration numberNCT04691232.

Antimicrobial Activity of Stenochlaena palustris and Sauropus androgynus in Staphylococcus aureus, Escherichia coli and Candidia albicans

Stenochlaena palustris and Sauropus androgynus are known to contains antimicrobial substances such as flavonoids, saponins and tannins compounds.The purpose of this study was to analyzes the antimicrobial activity of young and old leaf infusions of S. palustris and S. androgynus leaves against Staphylococcus aureus, Escherichia coli and Candida albicans. Analyze the antibacterial activity of a single preparations with a combination preparation of S.palustris (SP) and S.androgynus (SA) leaves infusion against S.aureus, E.coli and C.albicans. Leaves of S.palustris young part (SP1) taken 0-10 cm from shoots and old parts (SP2) 11-20 cm from shoots, while leaves of S.androgynus young part (SA1) leaves number 1 - 10 from the top and the old part (SA2) leaves number 11-20 from the top. The results showed that a single infusion of SP1 75% and SP2 75%, SA1 90% and SA2 90%, and a combination of SP1 75% and SA1 75%, SP2 75% and SA2 75% have the same activity as ampicillin in S.aureus. Single infusion of SP1 90% and SP2 90%, SA1 90% and SA2 90%, combination of SP1 75% and SA1 80% and the combination of SP2 80% and SA2 60% have the same activity as ciprofloxacin in E. coli. Single infusion of SP1 90% and SP2 90%, and a combination of SP1 80% and SA1 80%, SP2 80% and SA2 80% have the same activity as ketoconazole in C.albicans. The difference in activity due to differences in leaf parts used only occurred in E. coli, whereas in S.aureus and C.albicans (p <0.05).

Brexucabtagene Autoleucel (Tecartus)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses Brexucabtagene autoleucel (Tecartus) cell suspension in a patient-specific single infusion bag for IV use at a target dose of 2 × 106 chimeric antigen receptor T cells per kilogram Indication: Tecartus is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for: The treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after 2 or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

A randomized, double-blind, single-dose study (LAVENDER) to assess the safety, tolerability, pharmacokinetics, and immunogenicity of a combined infusion of ABP 980 and pertuzumab in healthy subjects

Purpose ABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects. Methods This randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing. Results A total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study. Conclusions This study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab. Clinical trial listing EudraCT 2018-002903-33.

Twenty-Four-Hour Heart Rate Is a Trait but Not State Marker for Depression in a Pilot Randomized Controlled Trial With a Single Infusion of Ketamine

Background: Abnormalities of heart rate (HR) and its variability are characteristic of major depressive disorder (MDD). However, circadian rhythm is rarely taken into account when statistically exploring state or trait markers for depression.Methods: A 4-day electrocardiogram was recorded for 16 treatment-resistant patients with MDD and 16 age- and sex-matched controls before, and for the patient group only, after a single treatment with the rapid-acting antidepressant ketamine or placebo (clinical trial registration available on https://www.clinicaltrialsregister.eu/ with EUDRACT number 2016-001715-21). Circadian rhythm differences of HR and the root mean square of successive differences (RMSSD) were compared between groups and were explored for classification purposes. Baseline HR/RMSSD were tested as predictors for treatment response, and physiological measures were assessed as state markers.Results: Patients showed higher HR and lower RMSSD alongside marked reductions in HR amplitude and RMSSD variation throughout the day. Excellent classification accuracy was achieved using HR during the night, particularly between 2 and 3 a.m. (90.6%). A positive association between baseline HR and treatment response (r = 0.55, p = 0.046) pointed toward better treatment outcome in patients with higher HR. Heart rate also decreased significantly following treatment but was not associated with improved mood after a single infusion of ketamine.Limitations: Our study had a limited sample size, and patients were treated with concomitant antidepressant medication.Conclusion: Patients with depression show a markedly reduced amplitude for HR and dysregulated RMSSD fluctuation. Higher HR and lower RMSSD in depression remain intact throughout a 24-h day, with the highest classification accuracy during the night. Baseline HR levels show potential for treatment response prediction but did not show potential as state markers in this study.Clinical trial registration: EUDRACT number 2016-001715-21.

Bisphosphonates after Denosumab withdrawal reduce the vertebral fractures incidence

Objective: Several studies showed the occurrence of vertebral fracture (VFx) in patients discontinuing denosumab (Dmab), suggesting the need of bisphosphonate (BPs) therapy to mitigate this VFx risk increase. However, the morphometric VFx (morphoVFx) incidence after Dmab discontinuation and the BPs effect on VFx risk in this setting are still a matter of debate. Design: Retrospective, monocentric study. Methods: In 120 patients (111 females) discontinuing Dmab, 19 have not been treated (Not-treated Group, 16 females, age 63.5±15.0 years) and 101 patients have been treated (Treated Group, 95 females, age 70.0±10.6 years) with BPs (28 alendronate, ALN; 73 zoledronate, ZOL, single infusion), respectively. We evaluated the incidence of both clinical VFx and morphoVFx in Treated Group and Non-treated Group. Results: Patients in Treated Group showed a 5.5% VFx incidence (n=6, 3 clinical, 3 morpho VFx), which was anyway lower than Not-treated Group patients (n=4, 21.1%, 4 clinical, 3 multiple, p=0.029), despite a comparable FRAX score at the time of Dmab initiation. The logistic regression analysis showed that the VFx incidence was independently associated with the lack of BPs treatment (odds ratio 13.9, 95% confidence interval 1.7-111.1, p=0.014), but not with the number of Dmab injections, age, duration of BPs before Dmab initiation, the BMD at Dmab withdrawal and the prevalence of VFx at Dmab withdrawal. Conclusions: The Dmab withdrawal is associated with an increased risk of clinical but not morphometric VFx. Therapy with ALN or with a single ZOL treatment are partially effective in reducing the increased VFx risk after Dmab withdrawal.

An armored GPC3-directed CAR-T for refractory or relapsed hepatocellular carcinoma in China: A phase I trial.

4095 Background: HCC is a leading cause of cancer-related morbidity and mortality worldwide, of which glypican 3 is a highly specific marker. GPC3-directed CAR-T had shown promising safety but limited efficacy in the treatment of HCC. We developed an armored GPC3-directed CAR-T G3-CAR-ori2 by inserting of a novel and proprietary Ori2 element following the 4-1BB and CD3ζ domains in a second-generation CAR-T. Pre-clinical studies showed a significantly higher memory stem cell ratio and dramatically improved proliferation and persistence, compared with traditional CAR-T, thus offering prolonged efficacy in vitro and in vivo and potentiality leading to improved activity in the clinical setting (ChiCTR1900028121). Methods: This is an open-label, dose-escalation study of G3-CAR-ori2 cell HCC patients in two centers. Eligible patients were aged 18-70 years with histologically confirmed GPC3+ HCC, Child-Pugh score A or B, ECOG≤1, relapsed or refractory to standard therapies. Patients were pre-conditioned with fludarabine (25̃30 mg/m2) and cyclophosphamide (200̃300 mg/m2) daily for 3 days. G3-CAR-Ori2 was administered as a single infusion via intrahepatic or intravenous route with a total dose of 0.9 to 3x10e8 CAR-T. The objective was to assess the safety, preliminary efficacy, persistence and cytokine profiling of G3-CAR-ori2. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 5.0). Tumor responses were evaluated per RECIST (version 1.1). CAR-T cell expansion and persistence were measured by qPCR and flow cytometry. Results: As of Jan 21, 2021, 10 patients had received single infusion, in which 6 received G3-CAR-ori2 via intravenous route and 4 via intrahepatic route. 7 patients received the highest dose level of 3x10e8. 9 patients reached at least 1 month of follow-up and tolerated the treatment well with no dose-limiting toxicity. All patients experienced transient grade 4 decrease in lymphocyte count resulted from the lymphodepletion regimen. Cytokine release syndrome (CRS) was observed in 8 patients, in which 6 at grade 1 or 2 and 2 at grade 4 notably infused with 3 x10e8 both via intravenous route and reversed within 7 days by administering high-dose steroids and tocilizumab. Other grade 4 hematologic toxicities include thrombocytopenia (2/9) and neutropenia (1/9). No neurotoxicity was observed. Two subjects were not evaluable due to early withdrawal from the trial. Among the 7 evaluable subjects, the best responses achieved are 3 PR, 2 SD, 2 PD. The duration of remission of one patient with PR is more than 4 months, follow up is ongoing. CAR-T gene detected by q-PCR provide preliminary indication that G3-CAR-ori2 is able to expand and persist well in the clinical setting. Conclusions: These initial data provide evidence that G3-CAR-ori2 is safe and holds promising antitumor potential, and supports its continuing development in the treatment of r/r GPC3+HCC. Clinical trial information: ChiCTR1900028121.

Long-term follow-up results of a multicenter first-in-human study of the dual BCMA/CD19 Targeted FasT CAR-T GC012F for patients with relapsed/refractory multiple myeloma.

8014 Background: The dual CAR-T GC012F developed on the novel FasT CAR-T platform targeting B cell maturation antigen (BCMA), and CD19 was designed to improve depth of response and overall efficacy for CAR-T as therapy for Multiple Myeloma. Here, we present updated data for study (NCT04236011; NCT04182581) including additional pts treated. Methods: From October 2019 to July 2020, 19 heavily pretreated Relapsed/Refractory Multiple Myeloma (RRMM) pts (age 27-71) with a median of 5 prior lines (range 2-9) received a single infusion of GC012F. 94.7% (18/19) were high risk (HR- defined by mSMART), 5 pts had extramedullary disease, 1 pts presented with plasma cell leukemia, and 15/19 were refractory to last therapy. 4/19 pts had received prior anti- CD38, 18/19 pts prior IMiD. 18/19 pts were refractory to PI, 17 pts to IMiD, 3 pts being primary refractory. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/ m2/d Flu/Cy) CAR-T cells were administered as single infusion at 3 dose levels: 1x105/kg (DL1) n=1, 2x105/kg (DL2) n=9 and 3x105/kg (DL3) n=9. Results: As of Jan 12, 2021 cut-off, 19 pts were evaluated for response. Overall response rate (ORR) was 94.7% - all responses VGPR or better (94.7% - 16/18 sCR, 2/18 VGPR) with all pts MRD- by flow cytometry (10-4-10-6) - earliest response d 28 post infusion. 100% of pts achieved a reduction of paraprotein, 18/19 a 100% reduction. Best response was MRD- sCR in 16/19 patients (84.2%). In DL3 (n=9) 4 additional pts were response evaluable for 6 mth follow-up: 100% (9/9) of pts achieved MRD-sCR as best response, 87.5% (7/8) of response evaluable pts maintained MRD-sCR at landmark analysis of 6 mths. At data cut off, the median time to follow up was 13.8 mths (6.1-16.4) – median duration of response not yet reached. Cytokine Release Syndrome (CRS) and ICANs were graded by ASBMT criteria: grade 1-2 n=16 (84.2%), grade 3 n=2 (10.5%). Median duration of CRS was 4 d (1-8 d). No grade 4/5 CRS or ICANS were observed. 2 deaths occurred on study and were assessed as not related to therapy – one reported previously; one patient was diagnosed with pseudomonas pneumonia on Day 52, refused life-saving treatment and passed. CAR-T median Tmax was 10 d (range 8-14d), median peak copy number (Cmax) was 127548 (16,011-374,346) copies /ug DNA with long duration of persistence of up to 60 weeks at time of data cut off. Patients continue to be monitored for safety and efficacy. Conclusions: BCMA-CD19 dual FasT CAR-T GC012F showed early, deep and durable responses with a high ORR (94.7% - VGPR and better) including a high MRD- sCR rate (DL3=100%, n=9) in high risk RRMM pts including those refractory to anti-CD38, PI and IMIDs with a favorable safety profile consistent with previous findings. BCMA-CD19 dual FasT CAR-T GC012F may present a new treatment approach for patients with RRMM including those with high-risk features refractory to standard of care. Clinical trial information: NCT04236011; NCT04182581.

Casein hydrolyzate for drying-off lactating mammary quarters in cows with chronic mastitis

In this research communication we address the hypothesis that a single intramammary infusion of casein hydrolyzate (CH) would have a similar effect to three intramammary infusions of CH for drying-off quarters with chronic mastitis (CM) during lactation. Sixty cows with CM were selected and randomly distributed into two treatment groups: (a) three intramammary CH infusions (100 mg, 50 ml per infusion, with 24-h intervals) or (b) single intramammary CH infusion (300 mg, 50 ml). Milk samples from the treated and untreated quarters were collected for microbiological culture and somatic cell count (SCC) before and after CH infusions. Milk yield was recorded and a manual pressure index measurement was used to evaluate cessation of lactation. Of the 60 quarters selected, 43 (71.67%) had positive microbiological culture. The quarters treated with three intramammary CH infusions had higher udder pressure index than those treated with single CH infusion. However, the average milk yield and composite SCC of three functional quarters were not different among treatments. Therefore, a single infusion of CH has the potential to be used as an alternative method for drying-off mammary quarters with CM during lactation.

Repeated infusion of mesenchymal stem cells maintain the condition to inhibit deteriorated motor function, leading to an extended lifespan in the SOD1G93A rat model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disorder in which motor neurons within the brain and spinal cord degenerate. A single infusion of mesenchymal stem cells (MSCs) delays disease progression by protecting motor neurons and restoring the blood-spinal cord barrier in the SOD1G93A transgenic ALS rat model. However, the therapeutic effect of a single infusion of MSCs is transient and does not block disease progression. In this study, we demonstrated that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion, after which rats displayed progressive deterioration of hind limb function. We also compared the days until gait ability was lost in rats and found that the repeated-infused group maintained gait ability compared to the single-infusion and vehicle-infusion groups. These results suggest that repeated administration of MSCs may prevent the deterioration of motor function and extend the lifespan in ALS.