Early Clinical Experience with ALVR109, a Partially HLA-Matched SARS-CoV-2 Specific T-Cell Therapy, in Immunocompromised Patients with COVID-19

Purpose: Therapies for COVID-19 in immunocompromised (IC) patients (pts), including transplant (tx) pts, are limited. We describe our experience with ALVR109, an allogeneic, partially HLA-matched T-cell product, given through emergency investigational new drug (eIND) application to 4 consecutive IC pts with protracted COVID-19. Method(s): To measure SARS-CoV-2 viral loads, SARS-2 RNA was quantified by RT-PCR (N gene) in plasma and saliva. ALVR109 was manufactured for Allovir at Baylor College of Medicine. Result(s): Between May and October 2021, ALVR109 was given to 4 IC pts with COVID-19 (details in Table 1). 2 pts had lymphoma (1 post auto-tx) and 2 had lung tx. All pts had SARS-CoV-2 RNA detected in plasma (viremia) in the weeks leading up to ALVR109 administration. Infusions (20-40 million cells (MC) per dose) were well-tolerated with no adverse events. Prior to ALVR109, pts 1 and 3 had progressive COVID-19 and ongoing SARS-CoV-2 viremia despite monoclonal antibodies (mABs) and remdesivir. Following ALVR109 administration both patients had a decrease in viremia with marked clinical improvement in pt 1, but both eventually died from their underlying disease. Viral loads (plasma/saliva) and functional scores for pt 1 are shown in the figure. Autopsy of pt 3 showed no evidence of SARS-CoV-2 infection by lung in-situ hybridization (ISH). Pts 2 and 4 received ALVR109 as adjunctive therapy to mABs and remdesivir;viremia continued to decline following ALVR109 and both pts survived and were discharged home. Conclusion(s): This initial experience suggests a potential role of ALVR109 in the treatment of IC and tx pts with COVID-19. SARS-CoV-2-specific T-cells appear to be safe and may control viremia in IC pts. Larger studies are needed to confirm this observation, define the best candidates for ALVR109, and determine optimal timing of administration. (Table Presented).

Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

Background The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season. Methods We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for an RTI within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers. In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed. Patients, investigators, and sponsor were masked to treatment assignments. All patients who received at least part of one dose of study drug were included in the primary and safety analyses. The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903, and the phase 3 trial was registered with ANZCTR, ACTRN12619000628145. Findings In the phase 2b trial, we recruited 652 participants in total between May 16, 2017, and Jan 10, 2018, 179 participants to part 1 of the study (randomly assigned 1:1:1 to RTB101 5 mg once daily [61 participants], RTB101 10 mg once daily [58 participants], or matching placebo [60 participants]) and 473 patients to part 2 (randomly assigned 1:1:1:1 to RTB101 10 mg once daily [118 participants], RTB101 10 mg twice daily [120 participants], RTB101 10 mg in combination with everolimus 0.1 mg daily [115 participants] or matching placebo [120 participants]). In our first prespecified statistical analysis of the primary efficacy endpoint for part 2 of the phase 2b trial efficacy of RTB101 10 mg in combination with everolimus 0.1 mg once daily compared with placebo did not meet statistical significance but, in our second prespecified analysis, which included data from part 1 and part 2, we found a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs in the RTB101 10 mg once daily treatment group (34 [19%] of 176) compared with the pooled placebo group (50 [28%] of 180;odds ratio [OR] 0.601 [90% CI 0.391-0.922];p=0.02). In the phase 3 trial, we enrolled 1024 patients between May 7, 2018, and July 19, 2019. 513 (50.1%) participants were randomly assigned to RTB101 10 mg once daily and 510 (49.9%) to placebo. In the full analysis set of the phase 3 trial, RTB101 did not reduce the proportion of patients with clinically symptomatic respiratory illness (134 [26%] of 511 patients in the RTB101 treatment group vs 125 [25%] 510 patients in the placebo treatment group;OR 1.07 [90% CI 0.80-1.42];p=0.65). In both trials, significantly more IFN-induced antiviral genes were upregulated in patients treated with RTB101 as compared with placebo. The study drug was found to be safe and well-tolerated across trials and treatment groups. Only one patient in the placebo group in the phase 3 trial had serious adverse events (nausea, fatigue, hyponatraemia, and arthralgia) which were considered related to study drug treatment. Three patients died in the phase 2b trial and one in the phase 3 trial but no deaths were considered related to study treatment. Interpretation The combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults. Further refinement of clinical trial endpoints and patient populations might be required to identify whether upregulation of IFN responses by mTOR inhibitors consistently decreases the incidence or severity of viral infections in older adults. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

Delivering diabetes care to children and young people during the coronavirus pandemic: Sheffield, UK experience

Introduction: The current Covid-19 pandemic has created unprecedented difficulties in delivering diabetes care and the decision to suspend all non-essential face-to-face patient contacts was made nationally with immediate effect and no specific prior planning. Objectives: To ensure the best possible care to our service users during the pandemic and assess the effect of “lockdown” on HBA1c. Methods: Families were contacted and urged to download their devices and share data wherever possible. For those unable to download, recently diagnosed or requiring an interpreter, face-to-face appointments were offered on our non-acute site with a maximum of one carer per patient using PPE. We also offered “drive-by” device downloading and HBA1c sample collection via an open car window. For those downloading at home we offered the option of returning postal HBA1c samples. Newly diagnosed patients have been admitted and the usual package of in-patient care delivered with subsequent face-to-face and virtual education after discharge. Psychology and Dietetic sessions have continued virtually throughout. Transition of young people to the Young Persons Clinic we share with adult colleagues in an adult setting has been suspended until face-to-face consultations are available in that service Conclusions: Our data so far shows no significant worsening of HBA1c during the first 3 months of the pandemic and we continue to accumulate data and service user feedback on the new ways of working.