CMV~IMPACT: Results of a Randomized Controlled Trial of Immuno-Prophylactic Adoptive Cellular Therapy following Sibling Donor Allogeneic HSCT
Authors: Peggs Karl S , Tholouli Eleni , Chakraverty Ronjon , Nikolousis Emmanouil , Bloor Adrian , Devereux Stephen , Orchard Kim H. , Crawley Charles , Parker Anne , Robinson Stephen P , Chen Frederick , Cook Gordon , Clark Richard E , Thomson Kirsty , Cobb Matthew , Newton Katy , Thomas Simon , Moss Paul 
Published: October 2019

Abstract
Introduction:
Qualitative and quantitative deficiencies in T-cell mediated immunity following allogeneic hematopoietic stem cell transplantation (HSCT) are associated with a high incidence of cytomegalovirus (CMV) infection, which remains an important cause of morbidity and cost, and contributes to mortality. Adoptive cellular therapy (ACT) can potentially expedite reconstitution of CMV-specific immunity and improve outcomes post HSCT. A number of uncontrolled studies have demonstrated proof of concept for such strategies. Previously we presented data from a randomized controlled trial assessing the effect of CMV-specific ACT (Cytovir CMV™) on immune reconstitution following unrelated donor HSCT (CMV~ASPECT). Now we report on a randomized controlled trial to evaluate the incidence of CMV reactivation and safety in a larger cohort of related donor HSCT patients treated with CMV-specific ACT. (CMV~IMPACT: ClinicalTrials.gov NCT 01077908).
Methods:
The study enrolled CMV-seropositive patients >16 years old, undergoing T-cell depleted (alemtuzumab) HSCT from a matched sibling CMV-seropositive donor, in 14 UK transplant centers. Patients and donors were selected using standard criteria. Patients were randomized into either ACT or control arms. CMV-specific cells were manufactured from a dedicated donor apheresis by direct selection at a central facility using either a StreptamerTM or gamma-capture technique (CliniMACS® Cytokine Capture System, IFN-gamma). Products were manufactured using Streptamers if the donor expressed a suitable HLA allele, or using gamma-capture if not. The 14 patients receiving the latter product are not included in this preliminary analysis. CMV surveillance was performed using quantitative PCR. All groups received standardized antiviral pre-emptive treatment. Cells were cryopreserved at a maximum dose of 5x104CD3+/kg and administered to the patient on day 27/28 post-transplant, regardless of CMV surveillance results (prophylactic administration). Patients with ≥ grade 2 acute GvHD or systemic steroid administration at baseline (D27/28) were withdrawn. Patients were assessed for CMV reactivation based on blinded retrospective assessment by the Chief Investigator. Patients were also assessed for evidence of GvHD and CMV-specific immune reconstitution.
Results:
As of August 2014, all but one patient had completed the study. There were no clinically apparent differences in serious adverse event (SAE) or acute GvHD events between the two arms. Notably, the number of patients experiencing >1 treatment episode was considerably lower than had been predicted in the control group (26% vs 60% predicted). There were fewer CMV reactivations in the ACT arm compared to the control arm (0.75 vs 1.0/patient), and fewer patients experiencing >1 treatment episode (15% vs 26%), although neither reached statistical significance. There was a trend toward reduced overall treatment duration in the ACT arm (Table 2, p=0.14). Preliminary data are summarized below. A complete and final analysis will be available at the time of the conference.
Table1: Patient Disposition/Safety ACT Control Enrolled (withdrawn prior to baseline visit) Safety set Per protocol set (no ACT administered in 10 randomized patients) 40 (10) 30 20 35 (4) 31 31 Reasons for withdrawal · GvHD or steroids at baseline · Other 2 8 2 2 No. (%) with new onset acute GvHD (safety set; 100 day follow up) 2 (6.7) 1 (3.2) No. (%) with at least 1 SAE (safety set) 12 (40.0) 10 (32.3)
Table2: Duration of CMV Treatment (days; per protocol set) ACT (n=20) Control (n=31) p Mean (stdv) 19.1 (27.8) 27.3 (31.3) 0.14 Median (min:max) 11 (0 : 114) 25 (0 : 133)
Conclusions:
In this randomized trial of CMV specific T-cells post-HSCT, adoptive cell therapy (Cytovir CMV™) was not associated with a significant increase in safety events, and preliminary analysis indicates Cytovir CMV administration may be associated with lower rates of CMV reactivation and shorter durations of viral treatment, though the lower than predicted reactivation rate in the control group reduced the power of the trial to demonstrate this at a statistically significant level.

Disclosures
Cobb: Cell Medica Ltd: Employment. Newton:Cell Medica Ltd: Employment. Thomas:Cell Medica Ltd: Employment. Moss:Cell Medica Ltd: Membership on an entity's Board of Directors or advisory committees.