Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation

ABSTRACT

The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes.

KEYWORDS:

• Immune reconstitution
• hematopoietic stem cell transplantation
• donor leukocyte infusion
• thymus function
• T-cell immunotherapy

Financial & competing interests disclosure

This work was partially supported by grants from AIRC (Associazione Italiana Ricerca sul Cancro, progetto speciale 5xmille), PRIN (Progetti di Rilevante Interesse Nazionale) 2010, MIUR (Ministero dell’Istruzione, Università e della Ricerca), Ministero della Salute (Ricerca Finalizzata 2010), from Regione Lazio, IRCCS Ospedale Pediatrico Bambino Gesù, and the HO2020 project ‘RETHRIM’ (#643580), to F Locatelli. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Immunotherapy approaches aimed at improving immune reconstitution have been largely explored in the past two decades; they are particularly warranted in the T-cell-depleted HLA-haploidentical HSCT setting, since the extensive TCD of the graft used to prevent GvHD translates into delayed immune recovery and, thus, increased infectious-related mortality.

• In allogeneic HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required in order to generate naïve RTEs. These cells account for durable T-cell reconstitution, generating a diverse TCR repertoire and being responsible for robust response to pathogens. Indeed, the thymus is the principal lymphoid organ responsible for generating and supplying naïve T cells, and a broad TCR repertoire, to the periphery.

• After allogeneic HSCT, T-cell recovery is delayed compared to other immune cells. Insufficient recovery in thymopoiesis translates into a predisposition to develop severe infections. SSA, GH, growth factors (KGF and insulin-like growth factor 1, IGF-1), IL-7, and precursor T cells have been explored In order to enhance thymus regeneration.

• Unmanipulated donor lymphocyte infusion (DLI) is the easiest strategy to enhance the pathway of thymus-independent immune reconstitution after allogeneic HSCT, but the risk of provoking GvHD is high and it is increased by the presence of HLA disparity between the donor and the recipient. The infusion of manipulated lymphocytes makes DLI a safer procedure in the haploidentical setting too.

• Adoptive cell therapies with donor-derived alloreactive-depleted T cells, T cells transduced with a suicide gene, T-cell clones or lines directed against life-threatening pathogens, and Treg/Tcon infusion after haploidentical-HSCT can reduce transplantation-related mortality due to infectious complications.

• The results of different trials reported so far are encouraging, but they have been obtained in a limited number of patients. They require confirmation in larger cohorts of patients, homogeneous in terms of disease and treatment, in order to obtain a truly effective comparison among different cell-therapy approaches.

• Future perspectives are focused on the standardization of the manufacturing of cell-therapy products, together with the spread of these techniques, in order to render them more widely available.