Adoptive Transfer of CMV-Specific TCR-T Cells for the Treatment of CMV Infection after Haploidentical Hematopoietic Stem Cell Transplantation

Background: CMV reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Preemptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but its efficacy is quite limited and associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocytes (CTLs) therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need. Methods: A single-arm, open-label Phase I clinical trial evaluating the safety and efficacy of CMV-targeting TCR-T (CMV-TCR-T) cell therapy as the first-line preemptive therapy for patients with CMV reactivation post haploidentical PBSCT was conducted in the Chinese PLA General Hospital (ClinicalTrials.gov Identifier: NCT05140187). Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by 1 to 3 doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×10 3 CMV-TCR-T cells/kg body weight per dose to 5×10 5 CMV-TCR-T cells/kg per dose Results: Except for the Grade 1 CRS observed in one patient and mild fever in 2 patients, no other adverse events were observed. Four patients had complete response within a month after CMV-TCR-T cells infusion without the administration of any antiviral agents. The other two patients who initially didn't completely respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were firstly detected in the peripheral blood of these patients 3 to 7 days after the 1 st dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1~4 months, providing long-term protections against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-GvHD reagents were still being used , further indicating the proliferation potential of CMV-TCR-T cells. Conclusions: Our study firstly showed CMV-targeting TCR-T cell as a highly feasible, safe and effective first-line preemptive treatment for CMV reactivation after haploidentical PBSCT.