Long-term Efficacy of CMV/EBV Bivirus-Specific T Cells for Viral Co-Reactivation After Stem Cell Transplantation

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Long-term Efficacy of CMV/EBV Bivirus-Specific T Cells for Viral Co-Reactivation After Stem Cell Transplantation

Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) co-reactivation following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a significant clinical challenge, often leading to life-threatening complications such as organ damage, post-transplant lymphoproliferative disorder (PTLD), and increased non-relapse mortality (NRM). Adoptive immunotherapy with virus-specific T lymphocytes (VSTs) has emerged as a promising therapeutic strategy, demonstrating efficacy in controlling single-virus reactivations. However, data on the long-term outcomes of bivirus-specific T-cell therapy for concurrent CMV and EBV infections remain limited. This study evaluates the safety, virological response, and long-term survival associated with donor-derived CMV/EBV bivirus-specific T-cell therapy in patients experiencing viral co-reactivation after haplo-HSCT.

Study Design and Patient Characteristics

The study analyzed 97 patients who underwent haplo-HSCT at Peking University People’s Hospital between 2015 and 2019 and received CMV/EBV bivirus-specific T-cell therapy for co-reactivation of both viruses. The median age at VSTs infusion was 27 years (range: 14–66 years), with a median follow-up duration of 1,494 days (range: 67–2,725 days). Patients received a total of 123 VSTs infusions, with 16 patients requiring two infusions and 5 patients receiving three infusions. Key inclusion criteria involved CMV and/or EBV DNAemia persisting despite standard antiviral therapy (e.g., ganciclovir, foscarnet, or rituximab).

Viral reactivation was monitored via quantitative PCR assays. CMV reactivation occurred at a median of 36 days post-transplant (interquartile range [IQR]: 32–41 days), with a median pre-infusion viremia duration of 21 days (IQR: 15–29 days). EBV reactivation was detected later, at a median of 43 days post-transplant (IQR: 36–52 days), with a median pre-infusion viremia duration of 15 days (IQR: 7–22 days). VSTs were administered at a median of 65 days post-transplant (IQR: 57–82 days).

Safety Profile of Bivirus-Specific T-Cell Therapy

No severe infusion-related adverse events, such as cytokine release syndrome (CRS) or grade 3–4 acute graft-versus-host disease (aGVHD), were observed. Within 6 weeks of infusion, 16 patients (16.5%) developed grade 1–2 aGVHD (95% confidence interval [CI]: 10.0–24.6%). Notably, 13 of these patients had prior aGVHD that was quiescent at the time of VSTs infusion, suggesting that T-cell therapy did not exacerbate pre-existing immune complications. Three patients developed de novo grade 1 skin aGVHD, which resolved with topical corticosteroids.

Virological Response and Clinical Efficacy

Overall Viral Control

Bivirus-specific T-cell therapy induced robust virological responses. Median peak CMV DNA titers decreased from 2.1 × 10³ copies/mL (IQR: 8.0 × 10²–5.5 × 10³) pre-infusion to undetectable levels post-infusion (P < 0.001). Similarly, median EBV DNA titers declined from 4.8 × 10³ copies/mL (IQR: 1.6 × 10³–1.1 × 10⁴) to undetectable levels (P < 0.001). The cumulative complete remission (CR) rate, defined as sustained clearance of both viruses, reached 75.3% (95% CI: 65.3–82.8%) at 4 weeks and 81.4% (95% CI: 72.0–99.0%) at 6 weeks post-infusion. Among 79 responders, 45 patients maintained durable viral control without recurrence, while 31 experienced transient viral rebounds that resolved without additional interventions. Three patients succumbed to refractory CMV pneumonitis or EBV-PTLD.

Subgroup Analysis: Co-Infections vs. Single Infections

A subset of 42 patients presented with uncontrolled CMV and EBV co-infections at the time of VSTs infusion. These patients exhibited lower CR rates compared to those with single-virus reactivation (59.5% vs. 87.3% at 4 weeks; P = 0.001). By 6 weeks, the CR rate in co-infected patients improved to 69.0% (95% CI: 52.3–80.9%) but remained significantly lower than in single-infection cases (87.3%; 95% CI: 75.5–94.0%). Multivariable analysis identified CMV/EBV co-infection as an independent predictor of reduced efficacy (hazard ratio [HR]: 2.31; 95% CI: 1.28–4.18; P = 0.006).

Management of Viral-Associated Diseases

Thirty-five patients developed CMV- or EBV-associated diseases before VSTs infusion, including 10 with biopsy-proven EBV-PTLD, 17 with probable EBV-PTLD, and 12 with CMV-related organ involvement (e.g., enteritis, retinitis, pneumonia). The CR rate in this high-risk subgroup was 64.7% (95% CI: 45.7–78.5%) at 6 weeks, underscoring the therapeutic potential of VSTs even in advanced disease states.

Long-Term Transplant Outcomes

Survival and Non-Relapse Mortality

The 1-year, 3-year, and 5-year overall survival (OS) rates for the entire cohort were 69.1% (95% CI: 60.5–78.9%), 67.0% (95% CI: 58.3–77.1%), and 65.8% (95% CI: 57.0–76.0%), respectively. Non-relapse mortality (NRM) plateaued at 29.9% (95% CI: 21.1–39.2%) by 3 years, with no additional events beyond this timepoint. In the co-infected subgroup, 5-year OS and NRM rates were 63.9% (95% CI: 50.8–80.4%) and 31.0% (95% CI: 17.7–45.2%), respectively, demonstrating comparable long-term outcomes to the overall cohort.

Mechanistic Insights and Clinical Implications

The study highlights two critical findings:

  1. In Vivo Antigenic Competition: The reduced efficacy of VSTs in co-infected patients suggests that simultaneous exposure to CMV and EBV antigens may impair the expansion or functional activity of adoptively transferred T cells. This contrasts with in vitro observations where CMV-dominated antigenic competition can suppress EBV-specific T-cell expansion.
  2. Timing of VSTs Infusion: Patients with unresolved co-infections had prolonged pre-infusion viremia (median CMV duration: 21 days; EBV: 15 days), which may have contributed to T-cell exhaustion or impaired reconstitution. Earlier intervention, before the establishment of dual viremia, could enhance outcomes.

Limitations and Future Directions

While this retrospective analysis provides robust real-world evidence, it has limitations. The lack of immune profiling data precludes mechanistic insights into T-cell reconstitution dynamics. Additionally, the single-center design and heterogeneity in antiviral prophylaxis regimens may limit generalizability. Prospective trials comparing VSTs with standard therapies, incorporating immune monitoring, are warranted to validate these findings.

Conclusion

CMV/EBV bivirus-specific T-cell therapy is a safe and effective strategy for managing viral co-reactivation after haplo-HSCT, offering durable remission in over 80% of patients. However, concurrent CMV and EBV infections at the time of infusion diminish therapeutic efficacy, likely due to in vivo antigenic competition. Clinicians should prioritize early intervention and consider sequential targeting of dominant viruses to optimize outcomes.

doi.org/10.1097/CM9.0000000000003443

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