CMV-Specific T-Cell Therapy Improves Immune Reconstitution Following Unrelated Donor HSCT: Results of a Randomized Controlled Trial

Introduction: Qualitative and quantitative deficiencies in T-cell mediated immunity following allogeneic HSCT are associated with a high incidence of cytomegalovirus (CMV) infection, which remains a major cause of morbidity and cost, and a significant indirect cause of mortality in this setting. Adoptive cellular therapy (ACT) can potentially expedite reconstitution of virus-specific immunity, minimizing the period of risk. A number of phase I-II studies have demonstrated proof of concept for such strategies, although estimation of efficacy is limited by potential selection bias. We therefore conducted a randomized controlled trial to evaluate immune reconstitution and safety of CMV-specific T-cells (CMV-ASPECT: ClinicalTrials.gov NCT01220895). 

Methods: The study enrolled CMV-seropositive patients >16 yrs old, undergoing T-cell depleted (alemtuzumab) HSCT from unrelated CMV-seropositive donors in 9 UK centers. Patient and donor were required to share one or more of the following HLA alleles: A*0101, A*0201, A*2402, B*0702 or B*0801; and the donor to demonstrate >0.1% HLA-streptamer positive CMV-specific T-cells. Randomization was then performed 2:1 in favor of the treatment arm. CMV-specific cells were directly selected from an aliquot of the stem cell donation after streptamer-labeling. CMV surveillance was performed using quantitative PCR. Patients with ≥Gd 2 aGvHD or systemic steroid administration at baseline (D28) were withdrawn. CMV-specific T-cells were administered pre-emptively for CMV DNAemia. Both groups received best available antiviral pre-emptive treatment according to standardized intervention criteria. Patients were followed for immune reconstitution (primary endpoint) and safety.      

Results: From Oct 2010 to Jun 2013, 52 patients/donors were enrolled. As of Sep 2013, all subjects had completed immune assessments at 8 weeks post CMV detection and final follow-up visits were underway. The complete study safety and immune reconstitution data will be analyzed January 2014.

Selected Interim Summary Data:

	CMV-specific T-cells (3x104CD3+/kg)	Control
Patient disposition ·         enrolled (withdrawn)	35 (18)	17 (6)
Reasons for withdrawal ·         GvHD or steroids at baseline ·         Insufficient starting material ·         Other	6 8 4	4 - 2
New onset GvHD post visit 2	3 (17.6%)	3 (27.3%)
Fold change from baseline (peak) in CMV specific cells (mean +/- SEM)a	109.1 +/- 42.5	10.5 +/- 7.1
Absolute change from baseline (peak) in CMV specific cells/ml (mean +/- SEM)b	20870 +/- 6766	4867 +/- 2533

^a p = 0.017; ^b p= 0.056

Conclusions: In this first randomized trial of CMV specific T-cells post-HSCT, adoptive cell therapy (Cytovir CMV) proved safe and resulted in earlier and greater durable expansion of CMV-specific T cells and reconstitution of immunity. Further investigation is warranted to determine if the observed increase in CMV-specific cells translates to clinical benefit.