CMV Specific Immunotherapy: How Many Patients Will Benefit?.
Authors: Garland Russell J. , Diamanti Paraskevi , West Samantha E. , Green Ann , Carrington David , Groves Sarah J. , Winship Kerri L. , Robinson Stephen P. , Oakhill Anthony , Cornish Jacqueline M. , Pamphilon Derwood H. , Marks David I. , Goulden Nicholas J. , Blair Allison G. , Steward Colin G. 
Published: October 2019

Abstract
Cytomegalovirus (CMV) infection is associated with increased transplant related mortality and decreased overall survival after stem cell transplantation (SCT) despite major advances in early detection, prophylaxis and treatment. This effect is most marked in CMV seropositive patients who have a statistically significant decrement in overall or disease free survival of 20–46% when compared to low risk (−/−) transplants (Boeckh Blood 2004 103: 2003–8). Transfer of cellular immunity from a seropositive donor results in reconstitution of T cells to CMV and protection from CMV disease post-SCT, and this underlies the recent development of cellular immunotherapeutic manoeuvres. As a centre looking to develop such therapy, we have carried out a retrospective analysis of a patient cohort in order to estimate how many patients would require this intervention. We used twice weekly quantitative PCR surveillance to analyse the CMV reactivation profiles of 104 recipients of 106 allogeneic SCT, transplanted between April 2002 and April 2004. Hence follow up was 5–27 months. The cohort comprised 41 adults and 65 children. Transplants were from related (42), unrelated (52) and haploidentical donors (12). T cell depletion was performed either (i) in vivo using either CAMPATH-1H (44 transplants) or ATG (5), (ii) ex vivo by either CD34 (8) or CAMPATH-1H in vitro (1), or (iii) by combinations of (i) and (ii) (26). SCTs were for malignancies in 92 cases and non-neoplastic disorders in 14. Many patients were considered high risk, necessitating short search to transplant times. A hierarchy of donor selection factors was considered: HLA matching was the primary determinant, with other factors including stem cell dose, age, gender and CMV status. Seventy-one patients were at risk of CMV reactivation. There were 28 episodes of CMV reactivation in 27 of these patients, with the following Recipient/Donor serostatus combinations: 0 (of 16) −/+, 22 (of 38) +/− and 6 (of 17) +/+. Seven patients (Group A) resolved their infections without intervention. Nine patients (Group B) resolved infections after antiviral drug treatment, whilst the remaining 12 reactivators (Group C) did not clear their CMV DNA load despite antiviral treatment (of whom 3 died, 1 relapsed and the remainder have ongoing CMV PCR positivity). As a minimum a CMV immunotherapy programme should allow prophylaxis or early treatment of all patients in groups B and C. However, using our current selection criteria only 5/21 cases had a CMV seropositive donor. Logistical problems e.g. CTL precursor frequency or availability of an immunodominant tetramer might have rendered some donors inappropriate providers of anti-CMV CTL. Thus a maximum of 5 out of 106 transplanted patients in our unit could have benefited, although this figure could be slightly improved by deliberate selection of CMV positive donors for CMV positive patients. Such numbers should be borne in mind by any centre contemplating the development of antiviral immunotherapy programmes.