Page 291 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
lowing Triplex vaccination, which had a similar longitudinal profiles and often surpassed those observed in healthy adults and HCT recipients from previous Triplex vaccina- tion studies13 (Figure 1; Online Supplementary Figure S2). High levels of functional CMV-specific T-cell response were measured in patients treated at both Triplex DL, in both age groups, in transplant recipients with either CMV-sero- positive or CMV-seronegative donors undergoing matched related, unrelated or haploidentical HCT, using bone marrow or peripheral stem cell sources. The elevated response may have contributed to restoring protective antiviral cellular immunity after transplant in the Triplex-vaccinated pedi- atric recipients, who did not receive PET to control CMV reactivation. However, a randomized study is required to confirm such a hypothesis. A possible explanation of the vigorous response to Triplex in pediatric recipients may be linked to the effective activity of the thymus, which is highly functional in children, protecting against serious in- fections and leading to good vaccine responses.15 High-dose post-transplant cyclophosphamide used in haploidentical HCT pediatric recipients to prevent acute GVHD, did not induce CMV-specific T-cell depletion, in agreement with previous studies in adult recipients.16 As often reported in the adult transplant population, use of high dosage cortico- steroids for GVHD reduced CMV-specific T-cell responses3,14 and in COH011 led to late PET treatment. As visualized by the gray bands in Figure 2A, functionally activated pp65, IE1, IE2-specific T cells increased post-transplant during immune-reconstitution. Linear mixed models were used to evaluate the longitudinal changes on log10-transformed
concentration of CMV-specific T cells. The analysis showed a significant increase in pp65-specific T cells/μL (left plot) after day 28 first Triplex injection through day 270 post-HCT (P=0.013). As previously found in healthy adults and in HCT recipients vaccinated with Triplex,13 longitudinal pp65-spe- cific T-cell expansions were the most consistent and the highest in magnitude among the current recipient popu- lation, while enhanced levels of both IE1- and IE2-specfic T cells were observed in some pediatric patients (Figure 1). The memory phenotype analysis (Figure 2B) focused on pp65-specific T-cell responses, and showed that func- tionally activated pp65-specific CD137+CD8+ T cells had a predominant TCM profile early post-transplant, and re- duced naïve T-cell subsets.13 In the vaccinated recipients, pp65-specific CD8 T cells showed a memory phenotype pattern mainly consisting of antigen-experienced TCM, immediately after transplant. By linear mixed models, the TCM subset significantly decreased following Triplex first injection (P=0.043) acquiring enhanced effector (TEMRA + TEM) functions (P=0.026), through day 270 post-HCT. Strong predominance of long-lived and functional effector T cells has been reported during primary CMV infection, since these cells are critical for viremia control.17
This is the first-in-pediatric HCT recipient study of Triplex. The early post-HCT administration of a biologic vaccine has few precedents in pediatric clinical trial history. Though clinical research is of considerable importance in devel- oping safe medications, pediatric trials pose many ethical and clinical challenges. Our pilot trial outcomes are of interest in the transplant context, as they demonstrated
Figure 1. Cytomegalovirus-specific T-cell responses. Longitudinal immune profiles of COH010 and COH014 pediatric haploidentical (Haplo) recipients in response to Triplex vaccination. Cytomegalovirus (CMV)-specific T cells/μL are shown by distinct colors (pp65- , IE1-, and IE-2) and line types (CD4 and CD8), as indicated in legend. Letermovir duration is shown by the black line on plot top (Haplo). BMT: bone marrow transplant; DL: dose level.
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