Automated CMV-specific CTL infusion cuts reactivation to 36% in HSCT patients ineligible for letermovir
Background
Cytomegalovirus (CMV) infection is a leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), severely impacting patient outcomes. While letermovir prophylaxis has significantly reduced CMV reactivation in seropositive, high-risk patients, a subset remains ineligible for this treatment in certain regions, leaving them vulnerable. Adoptive transfer of donor-derived CMV-specific cytotoxic T lymphocytes (CTLs) presents a promising immunologic strategy to prevent CMV reactivation and accelerate immune reconstitution, addressing this critical unmet need. This approach aims to provide robust, targeted immunity against the virus.
Study Design
This ongoing phase II multicenter study enrolled 14 adult recipients of HLA-identical related HSCT who were ineligible for letermovir prophylaxis. Patients received a single infusion of fresh donor-derived CMV-specific CTLs on day +21 (±7) post-transplant. CTLs were produced under GMP conditions using an automated IFNγ-based selection strategy following CMV pp65 peptide stimulation. The primary endpoint was the incidence of CMV reactivation by day +100 post-transplant, compared with historical controls from the institution. Secondary endpoints included CMV disease, antiviral therapy requirement, and safety.
Results
Prophylactic infusion of donor-derived CMV-specific CTLs significantly reduced CMV reactivation by day +100 post-transplant, occurring in 5 of 14 patients (36%), a notable reduction compared to 53% in the historical cohort.
The median viral load at reactivation was 3,600 IU/mL (range, 240-15,000), with all cases resolving without progression to CMV disease. Safety analysis revealed three patients experienced mild infusion-related reactions, all of which resolved without requiring corticosteroid treatment. The incidence of acute GVHD was similar to the historical control group, suggesting no increased risk from the CTL infusion. Exploratory analyses also evaluated in vivo CTL persistence by IFNγ flow cytometry at 30, 60, and 90 days post-HSCT, indicating sustained immune presence.
Key Findings
- CMV reactivation by day +100 post-transplant occurred in 36% of CTL-treated patients.
- CMV reactivation rate was 53% in the historical control cohort.
- Median viral load at reactivation was 3,600 IU/mL, with all cases resolving without CMV disease.
- Only three patients experienced mild, self-resolving infusion-related reactions.
- Acute GVHD incidence was similar to historical controls, indicating safety.
Why It Matters
This study demonstrates the feasibility and safety of rapid, automated production and prophylactic use of CMV-specific CTLs, offering a vital alternative for HSCT patients unable to receive letermovir. This approach could significantly expand access to effective CMV prophylaxis, reducing morbidity and mortality in a vulnerable population. The automated manufacturing process is a critical advancement, potentially streamlining clinical translation and making this personalized cell therapy more scalable. While further randomized trials are needed, these interim results suggest a promising new protocol for immune reconstitution and viral control post-transplant, potentially integrating into existing HSCT care pathways.
cmv
hsct
t-cell-therapy
immunotherapy
prophylaxis
viral-infection