Page 289 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Cytomegalovirus Triplex vaccine in pediatric hematopoietic stem cell transplant patients at high risk for cytomegalovirus complications: evaluation of vaccine safety, immunogenicity and impact on viremia requiring antivirals
Cytomegalovirus (CMV) reactivation remains a leading clinical concern, contributing to substantial morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT), in both adult and pediatric high- risk CMV-seropositive recipients.1,2 Pre-emptive antiviral therapy (PET) greatly reduces the risk of CMV disease and mortality post-transplant, but it is associated with significant economic burden, toxicity and rates of fail- ure.3,4 In the case or pediatric patients, many PET antivi- rals have intolerable toxicity or have been insufficiently evaluated.5,6 US Food and Drug Administration approved letermovir prophylaxis up day 200 post-transplant7 is ef- fective with minimal myelosuppression, and it is tolerated in pediatric patients.8 Currently its use remains off-label in these patients, pending outcomes of an ongoing phase II trial (clinicaltrials gov. Identifier: NCT03940586). The main drawback of letermovir is the observed increase in clinically significant CMV infection and disease requiring antivirals, when prophylaxis is discontinued.7,9 The de- creased CMV reactivation and the consequent decreased CMV antigen exposure during letermovir prophylaxis may delay CMV-specific immune reconstitution leading to breakthrough CMV viremia requiring antivirals. Notably, polyfunctional T-cell responses specific for CMV pp65 and IE-1 proteins, which are involved in controlling CMV viremia are significantly decreased in HCT patients re- ceiving letermovir prophylaxis, compared with HCT recip- ients receiving PET.10 Additionally, there is no difference in mortality after 1 year between letermovir and PET-treated T-cell replete HCT recipients.9 Infusion of CMV-specific T cells can promote restoration of durable, functional anti- viral immunity. Despite the success of this strategy, ready availability of adoptive T-cell therapy remains difficult to achieve.11 Furthermore, in December 2023 phase III trials of posoleucel,12 an off-the-shelf, multi-virus specific T-cell therapy, including CMV were halted for futility. Conse- quently, immunotherapeutic strategies to suppress both early and late clinical reactivation, through enhancing and sustaining protective immune reconstitution against CMV remain an unmet need in the letermovir era.
Triplex is a modified vaccinia Ankara (MVA) vectored vaccine which expresses three immunodominant CMV proteins; pp65, IE1-exon4, and IE2-exon5. It has been designed to
accelerate reconstitution of protective T-cell CMV-specific immunity. Triplex demonstrated tolerability and immuno- genicity in healthy adults, autologous and allogeneic HCT recipients, in whom it reduced CMV viremia.13 Based on Triplex favorable tolerability, immunogenicity and efficacy outcomes we investigated whether vaccinating HCT pedi- atric recipients, with Triplex safely promoted and expand- ed CMV-specific T cells protecting from clinical viremia requiring PET in the presence of letermovir.
We designed a non-randomized, open label, phase Ib pilot trial to evaluate safety, optimal dose, and immunogenicity of Triplex vaccine in CMV-seropositive pediatric allogeneic HCT recipients. The study was conducted in accordance with the Helsinki Declaration at City of Hope National Med- ical Center (COH), was approved by the local Institutional Review Board, and registered as clinicaltrials gov. Identifier: NCT 03354728.
Fifteen pediatric (age 1-21 years, as defined by the US Federal Food, Drug, and Cosmetic Act) CMV-seropositive allogeneic HCT transplant recipients were consented to be enrolled in the study, from August 2018 through January 2023. Several factors were associated with the trial slow accrual, including reassigning the study to a new principal investigator (PI), as the initial PI transferred to a different Institution; the significant COVID-19 pandemic disruption on cancer clinical trials and constrained financial resources. Clinical characteristics of the study population including Karnofsky performance score, conditioning regimen and stem cell source are described in Table 1. Exclusion criteria for administration of Triplex injection on day 28 post-HCT included: diagnosis of relapse, engraftment failure, acute graft-versus-host disease (GVHD) of grade 3 or 4 (accord- ing to the Keystone Consensus grading system), adminis- tration of steroids with a dosage above 1.0 mg/kg per day within 7 days, ongoing non-hematologic toxicity of grade 3 or higher (according to the Common Terminology Criteria for Adverse Events, version 4.03) and development of CMV viremia with quantitative polymerase chain reaction (qPCR) >500 copies/mL.
Six patients did not meet inclusion and did not receive the planned study intervention (Online Supplementary Figure 1S). Triplex injections were administered to nine eligible recipients on days 28 and 56 post-transplant, consistent
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