CMV-specific T-cell receptor-engineered T-cell therapy as first-line treatment for CMV reactivation after haploidentical hematopoietic stem cell transplantation: a phase 2 trial.

INTRODUCTION

Cytomegalovirus (CMV) reactivation is a major cause of mortality following haploidentical hematopoietic stem cell transplantation (haplo-HSCT). The application of conventional therapies is limited by hematologic and renal toxicities (ganciclovir and foscarnet) or time-consuming preparation (CMV-specific cytotoxic T lymphocytes [CTLs]). We previously demonstrated the efficacy and safety of CMV-specific T-cell receptor-engineered T (TCR-T) cells for treating CMV reactivation post-haplo-HSCT.

METHODS

We conducted a phase 2 trial using the previously established highest dose to evaluate efficacy and safety as first-line therapy in a larger cohort. Patients received CMV TCR-T cell infusions (5 × 105 cells/kg) upon detection of >1 × 103 copies/mL CMV DNA in two consecutive tests or >1 × 104 copies/mL once. A second infusion was administered when TCR-T cell expansion remained undetectable within 7 days, and CMV load remained above 1 × 103 copies/mL. Salvage therapy was initiated when complete remission (CR) was not achieved after 3 weeks. The primary endpoint was the 4-week CR rate. TCR-T cells were derived from healthy donors.

RESULTS

Among 25 patients enrolled, 13 developed CMV reactivation and received TCR-T cell therapy. Twelve (12/13, 92.3%, 95% CI: 66.7%-98.6%) achieved CR by week 4. Eleven (11/12, 91.7%, 95% CI: 64.6%-98.5%) maintained CR without further antiviral therapy, with median follow-up of 1011 (range: 657-1561) days post-infusion. Two cases of grade 1 cytokine release syndrome (CRS) occurred. TCR copy number increased ≥104-fold within 14 days and remained detectable for 4 months.

DISCUSSION: These findings highlight the long-term efficacy and safety of TCR-T cells as first-line therapy for CMV reactivation post-haplo-HSCT.

TRIAL REGISTRATION: www.clinicaltrials.gov, identifier NCT05140187.