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.

Perspectives for the Use of Umbilical Cord Blood in Transplantation and Beyond: Initiatives for an Advanced and Sustainable Public Banking Program in Greece

“…The lack of self-sufficiency despite the increasing number of BM and UCB donors reflects the HLA heterogeneity of the Greek population and highlights the importance of increasing the diversity rather that the size of the national repository [27]. The island of Crete in Greece is an elegant example of a high de population HLA diversity probably associated with the mountainou wealth of historical events that have influenced the genetic history an istics of the population [27][28][29][30][31][32]. Such diversity was recently shown i the Cretan population with donors from various populations register representative European unrelated donor registries, nam Knochenmarkspenderdatei (DKMS) [27].…”

“…In practice, such an approach will develop a model to increas public UCB banks and BM registries based on the population HLA this will be an overarching reference dataset of high-resolution HLA The island of Crete in Greece is an elegant example of a high degree intra-and interpopulation HLA diversity probably associated with the mountainous geography and the wealth of historical events that have influenced the genetic history and cultural characteristics of the population [27][28][29][30][31][32]. Such diversity was recently shown in a study comparing the Cretan population with donors from various populations registered in one of the most representative European unrelated donor registries, namely the Deutsche Knochenmarkspenderdatei (DKMS) [27].…”

“…In immunocompromised individuals, opportunistic infections can also be effectively managed using adoptive immunotherapy with pathogen-specific T-cells. These specific T cells are expanded ex vivo from the memory T-cell compartment of donors who have previously been exposed to the targeted pathogen, and infused to the patient upon reactivation of the infection [30,32]. The feasibility of establishing T-cell immunotherapy banks with "off-the-shelf" products which can serve as an "on demand" treatment for patients sharing a minimum HLA matching with the donors, has been shown for both hematologic malignancies and opportunistic infections, mainly with T-cell products originating from adult subjects [33,34].…”

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

“…Hence, by making Tregs resistant to specific immunosuppressive agents, they may acquire a survival advantage and remain functional even under the unfavorable conditions of intense immunosuppression (Figure 2). In the setting of adoptive T cell therapy with virus-specific T cells, our group has developed steroid-resistant, pathogen-specific T cells by the CRISPR/CAS9 genetic disruption of the glucocorticoid receptor, and other groups have also generated specific T cells with engineered resistance to various immunosuppressive agents [231] (reviewed in [232]). We foresee that this approach could be adopted for the generation of immunosuppressionresistant Treg cell products, which after adoptive transfer into transplanted patients, could remain functional and effective, thus broadening the applicability of immunotherapy with Tregs.…”

Pre-Emptive Use of Rituximab in Epstein–Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes

“…Furthermore, noteworthy advancements have been achieved in the field of adoptive immunotherapies for treating PTLD, particularly regarding in vitro autologous donor T-cells, which is practiced as a clinical study in our center, or HLA-matched banked third-party donor polyclonal EBV-specific cytotoxic T-cells (EBVSTs) [56][57][58][59][60][61]. Additionally, chimeric antigen receptor T-cell (CAR-T) therapy has been proven effective in certain cases [62][63][64][65].…”