Efficacy of pp65‐specific TCR‐T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation

Abstract

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.

ScRNA-seq reveals novel immune-suppressive T cells and investigates CMV-TCR-T cells cytotoxicity against GBM

“…In a phase I clinical trial (NCT04153279), pp65-specific TCR-T cell therapy for CMV infection after hematopoietic stem-cell transplantation was conducted in only seven patients. 44 Previous CMV-specific T-cell therapies using custom CMV peptide pools have shown suboptimal efficacy due to limited antitumor activity and persistence. 45 The exogenous TCR-transduced T cellular therapy demonstrates stronger specificity and sensitivity, and prolonged T-cell persistence for up to 9 months.…”

Analysis and Development of Antigen-specific T Cells Derived from Peripheral Blood Mononuclear Cells of Healthy Donors

“…We analyzed antigen-specific T cells from healthy donor PBMCs and identified 10 CMV-specific TCRs and 1 EBVspecific TCR. CMV-specific TCRs can be used in cell therapy to treat glioblastoma multiforme and prevent CMV infection following hematopoietic stem cell transplantation (HSCT) or other organ transplantation (39,40). EBV-specific TCR can also be used for the treatment of nasopharyngeal carcinoma and post-transplant lymphoproliferative disorder in solid organ and bone marrow transplant recipients (41).…”

Refractory cytomegalovirus infections in Chinese patients receiving allogeneic hematopoietic cell transplantation: a review of the literature

“…Advances in T-cell generation (54, 62, 85) and development of allogeneic CMV-specific cryopreserved cells in an 'off-the-shelf' approach have shown promise to help to mitigate or circumvent T-cell manufacture difficulties and may allow CMV-CTL therapy to become more widely used in future (69). Interestingly, early results from a small Chinese study that generated CMV-specific T cells using T-cell receptors from healthy donors has shown promising anti-CMV efficacy, CMV persistence, and tolerability, and warrants further study in Chinese patients with refractory CMV infection (70). Detailed identification of T-cell populations to expand and potential lessons from the rapidly growing and potentially complementary field of oncology T-cell manufacture may further optimize CMV-CTL processes and enable an increase in the use of CMV-CTL for refractory CMV infection, particularly if allo-HCT is used to consolidate complete response following T-cell therapy (86-89),.…”