Details

Autor(en) / Beteiligte

• La Rosa, Corinna
• Longmate, Jeffrey
• Lingaraju, Chetan Raj
• Zhou, Qiao
• Kaltcheva, Teodora
• Hardwick, Nicola
• Aldoss, Ibrahim
• Nakamura, Ryotaro
• Diamond, Don J.

Titel

Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Non-Viremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax

Ist Teil von

• Biology of blood and marrow transplantation, 2018-12, Vol.25 (4), p.771-784

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Early cytomegalovirus (CMV) reactivation remains a significant cause of morbidity and mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine designed to control CMV infection in HCT patients seropositive for CMV by stimulating the expansion of T cell subsets that target the CMV tegument protein pp65. In a randomized Phase 1b pilot trial (NCT01588015), two injections of CMVPepVax (at days 28 and 56 post-HCT) demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and usage of antivirals. In the current study, we assess the phenotypes and time-courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have been linked to immune reconstitution profiles characterized predominantly by differentiated effector memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28, and often re-express the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65 495–503 multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in blood specimens from HCT recipients enrolled in the Phase 1b clinical trial. Specimens from the 10 (out of N=18) vaccine patients who had adequate (≥0.2%) multimer binding to allow for memory analysis showed highly differentiated TEM and TEMRA phenotypes for pp65 495–503 -specific CD8 T cells during the first 100 days post-transplant. In particular, by day 70, during the period of highest risk for CMV reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65 495–503 -specific CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the CMVPepVax patients, although their pp65 495–503 -specific CD8 T cell profiles were strikingly similar to those observed in viremic patients, who did not receive the vaccine. Collectively, our analysis indicates that, in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated effector memory pp65 409–503 -specific CD8 T cells early post-HCT. The body of data from this current study indicates that the rapid reconstitution of CMV-specific T cells, with marked levels of effector phenotypes may have been key to the favorable outcomes of the CMVPepVax clinical trial.