Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond

Abstract

Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time- and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context.

Figure 1.

Strategies for adoptive immunotherapy with pSTs. The starting material for the generation of pSTs is the mononuclear cell population isolated from different donor sources. In personalized adoptive immunotherapy, either the patient or the HLA-matched stem cell donor serves as the cell source (autologous or allogeneic, respectively). In off-the-shelf adoptive immunotherapy, pSTs are derived either from cord blood or selected sepositive donor banked blood. T cells can then be stimulated via viral peptide/protein/lysate or antigen-loaded antigen-presenting cells and pSTs are either directly isolated or ex vivo expanded, as natural pSTs (A) or T cells are transduced with a viral vector to express either a transgenic TCR of specific targeting or a CAR redirecting the specificity of T cells against a certain target pathogen. (B) Each either natural or genetically engineered pST cell product can be administered in the transplantation setting to a single, HLA-matched patient (personalized therapy, one donor-one recipient) or multiple, partially HLA-matched patients, within or outside the transplantation context (off-the-shelf therapy, one donor-multiple recipients). CAR = chimeric antigen receptor; pSTs = pathogen-specific T cells; TCR = T-cell receptor.