Efficacy of pp65-specific TCR-T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation.
Guangna LiuHua ChenXingyu CaoLemei JiaWei RuiHongli ZhengDaosheng HuangFang LiuYue LiuXueqiang ZhaoKai-Yan LiuXin LinPublished in: American journal of hematology (2022)
Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV-specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T-cell receptor (TCR)-T cell therapy offers a promising option to treat CMV infections. Here, using tetramer-based screening and single-cell TCR cloning technologies, we identified various CMV antigen-specific TCRs from healthy donors, and generated TCR-T cells targeting multiple pp65 epitopes corresponding to three major HLA-A alleles. The TCR-T cells showed efficient cytotoxicity toward epitope-expressing target cells in vitro. After transfer into immune-deficient mice bearing pp65 + HLA + tumor cells, TCR-T cells induced dramatic tumor regression and exhibited long-term persistence. In a phase I clinical trial (NCT04153279), CMV TCR-T cells were applied to treat patients with CMV reactivation after HSCT. Except one patient who withdrew at early treatment stage, all other six patients were well-tolerated and achieved complete response (CR), no more than grade 2 cytokine release syndrome (CRS) and other adverse events were observed. CMV TCR-T cells persisted up to 3 months. Among them, two patients have survived for more than 1 year. This study demonstrates the great potential in the treatment and prevention of CMV infection following HSCT or other organ transplantation.
Keyphrases
- cell therapy
- regulatory t cells
- end stage renal disease
- clinical trial
- ejection fraction
- newly diagnosed
- chronic kidney disease
- stem cells
- prognostic factors
- mesenchymal stem cells
- randomized controlled trial
- peritoneal dialysis
- immune response
- dendritic cells
- patient reported outcomes
- oxidative stress
- epstein barr virus
- cancer therapy
- induced apoptosis
- case report
- drug induced
- high glucose
- patient reported
- smoking cessation
- combination therapy