Harnessing T Cells to Control Infections After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Dramatic progress in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from alternative sources in pediatric patients has been registered over the past decade, providing a chance to cure children and adolescents in need of a transplant. Despite these advances, transplant-related mortality due to infectious complications remains a major problem, principally reflecting the inability of the depressed host immune system to limit infection replication and dissemination. In addition, development of multiple infections, a common occurrence after high-risk allo-HSCT, has important implications for overall survival. Prophylactic and preemptive pharmacotherapy is limited by toxicity and, to some extent, by lack of efficacy in breakthrough infections. T-cell reconstitution is a key requirement for effective infection control after HSCT. Consequently, T-cell immunotherapeutic strategies to boost pathogen-specific immunity may complement or represent an alternative to drug treatments. Pioneering proof of principle studies demonstrated that the administration of donor-derived T cells directed to human herpesviruses, on the basis of viral DNA monitoring, could effectively restore specific immunity and confer protection against viral infections. Since then, the field has evolved with implementation of techniques able to hasten production, allow for selection of specific cell subsets, and target multiple pathogens. This review provides a brief overview of current cellular therapeutic strategies to prevent or treat pathogen-related complications after HSCT, research carried out to increase efficacy and safety, including T-cell production for treatment of infections in patients with virus-naïve donors, results from clinical trials, and future developments to widen adoptive T-cell therapy access in the HSCT setting.

Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021

“…Patrizia Comoli highlighted that some patients need more rapid treatment with CD8+ cells to clear infection quickly and explained that the process to develop cellular infusions can be accelerated using magnetic beads coated with anti‐IFNγ to select CD4+/CD8+ cells and using beads with a streptamer tag to select CD8+ T cells 65,66 . The efficacy observed with these protocols is similar to that seen with cultured cells.…”

“…Cellular therapy for CMV in the HSCT field started 30 years ago, 64 but these therapies are still not being used in routine clinical practice; a situation highlighted by Patrizia Comoli. Cellular therapy triggers the secondary immune response to viruses by stimulating donor cells from HSCT recipients in vitro using infected cells, antigen‐presenting cells (APC) rich in specific peptides, or APCs transduced with vectors carrying relevant antigen products 65 . Polyclonal populations of virus‐specific T cells (VST) are generated that produce high levels of IFNγ, and other cytokines in a process can take between 2 and 8 weeks depending on the protocol used.…”

Is It Feasible to Use CMV-Specific T-Cell Adoptive Transfer as Treatment Against Infection in SOT Recipients?

“…Thus, the development and improvement of new CMV-specific T-cell transfer based therapies could be a useful to adjust the therapeutic interventions (112)(113)(114). However, despite the increasing interest on adoptive CMV specific T-cell transfer, most of the information available comes from studies in HSCT recipients (23,53,115). Only few reports including a small number of SOT recipients have used Tcell adoptive immunotherapy as a treatment of CMV infection or disease (41,43,(46)(47)(48).…”

Immune Prophylaxis and Therapy for Human Cytomegalovirus Infection

“…We will also discuss the role of the vaccines in stimulating protective cell-mediated immune responses, an important component of effective vaccines. However, virus-specific T-cell immunotherapy, recently being tested and showing promise in the prevention and treatment of infections, including CMV in a transplant setting [43,44], is beyond the scope of this paper and will not be discussed. (CMV and HCMV will be used interchangeably for the rest of this review.…”