Work

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

Year: 2019

Type: article

Abstract: Background Early CMV reactivation remains a significant cause of morbidity/mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine based on an HLA-A0201-restricted immune-dominant peptide (pp65 495-503 ). In a randomized Phase 1b trial, CMVPepVax (given on days 28 & 56 post-HCT) demonstrated safety, immunogenicity, and reduced CMV reactivations (Lancet Haem 2017). In the current study, we assessed the detailed phenotypes and time-courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. Patients (pts)/methods Of 18 pts in the vaccine arm (VA) and 18 in the observation arm (OA), 12 VA and 8 OA pts were included for the current study as they developed levels of CMV-specific T cells evaluable for memory phenotyping. Eleven of the 12 VA pts did not reactivate CMV during the 6-month while 5 OA and 1 VA pts developed viremia requiring antiviral treatment. The differentiation status of CMV-specific CD3 + CD8 + T cells, identified by pp65 495-503 dextramers, was determined based on CD28/CD45RA expression using polychromatic flow cytometric panels. CD137 expression assay was used to evaluate T cell responses to pp65 or IE1 peptide library. Results The VA pts more often achieved ³0.2% levels of pp65 495-503 -specific CD8 T cells in the absence of clinically detectable CMV viremia (10 non-reactivating pts of 17 in the VA vs. 1 non-reactivating pts of 12 in the OA, p=0.008). Phenotype proportions are displayed in Figure 1. In contrast, when T cells were stimulated with pp65 or IE1 peptide libraries encoding T cell epitopes specific for a variety of HLA alleles, the T cell responses measured by CD137 expression in both VA and OA pts did not significantly differ. These results suggest that the enhanced pp65 495-503 response measured in the VA pts (without viremia) was likely driven by PepVax. When the differentiation status was analyzed, pp65 495-503 -specific T cells in viremic OA pts had a median % of effector phenotype profiles of 91% (range: 31-99%), similar to those of the evaluable non-viremic VA patients, for whom the median % of effector phenotype profiles was 93% (range: 13-100%). Importantly, 2 weeks after the 2nd PepVax vaccination, >80% of pp65 495-503 -specific T cells were TEM and TEMRA in 9 out of the 10 evaluable VA pts. Thus, in these HCT recipients who did not develop CMV viremia, PepVax rapidly expanded CMV-specific T cells with substantial EM profiles. Figure 2 depicts longitudinal dynamic of pp65 495-503 -specific CD8 T cells and their memory profiles. Conclusion Collectively, our analysis indicates that, in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated effector memory CD8 T cells specific to the vaccine epitope of pp65 495-503 early post-HCT, which may have been key to the favorable outcomes of the CMVPepVax clinical trial.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2018.12.157