CMV-Specific TCR-T Cells for the Treatment of CMV Reactivation after Allogeneic Hematopoietic Stem-Cell Transplantation

Cytomegalovirus (CMV) reactivation remains the leading cause of death after haploidentical stem cell transplantation (HSCT). Current therapies, including antiviral drugs and relay cell therapy using CMV-specific cytotoxic T lymphocytes (CTLs), have shown only limited benefit to patients, and T-cell receptor (TCR)-T-cell therapy offers a promising option for the treatment of CMV reactivation.

To evaluate the efficacy and safety of CMV-targeted T-cell receptor-engineered T (CMV-TCR-T) cell therapy as a first-line pre-emptive therapy ,we conducted a single-arm, open-label, phase I clinical trial for patients with CMV reactivation after HSCT. Ten patients with CMV reactivation after HSCT were adoptively transferred by one to three doses of HSCT donors-derived CMV-TCR-T cells. Meanwhile, 2 patients who had failed standard antiviral drugs used CMV-TCR-T cells as second-line therapy.

Eight of the first-line treatment patients responded within one month after infusion of CMV-TCR-T cells without administration of any antiviral drugs; the other two patients who initially did not respond to CMV-TCR-T cell therapy were given salvage ganciclovir and phosphonate, followed by rapid clearance of CMV. Second-line treatment patients were controlled with TCR-T cells after 2 weeks of ineffective use of antiviral drugs. CMV-TCR-T cells demonstrated overall robust expansion and persistence in peripheral blood after infusion. CMV-TCR-T cells were first detected in the peripheral blood of these patients 3-7 days after the initial CMV-TCR-T infusion, expanded rapidly and persisted for at least 1-4 months, providing long-term protection against CMV reactivation. In 2 patients, CMV-TCR-T cells began to expand even while anti-graft-versus-host disease reagents were still in use, further demonstrating the proliferative potential of CMV-TCR-T cells. No adverse events were observed except for grade 1 cytokine release syndrome in one patient and mild fever in two patients.

Median follow-up was 318 days. Six patients survived for more than 1 year and 2 patients died (2 in the first-line treatment group and 1 in the second-line treatment group).This study demonstrates the great potential of CMV infection after HSCT or other organ transplantation in terms of treatment and prevention.

No relevant conflicts of interest to declare.