Abstract
T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56lowCD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56lowCD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56lowCD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56lowCD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) plays a relevant role in the treatment of many haematological diseases, both malignant and nonmalignant, representing a life-saving procedure [1]
We addressed a possible effect of inducible caspase-9 (iCasp9)-modified donor T cells on early Natural killer (NK) cell reconstitution by monitoring the NK cell frequency and number in both bone marrow (BM) and peripheral blood (PB) for one year by comparing them with age-matched healthy donors (HD)
In line with previous observations, we found a significant increase of NK cell frequency in both PB and BM in the first eight months after transplantation, with a higher NK cell percentage in PB with respect to BM
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) plays a relevant role in the treatment of many haematological diseases, both malignant and nonmalignant, representing a life-saving procedure [1]. The Achilles heel of T-cell-depleted HLA haplo-HSCT is related to the delay in the reconstitution of adaptive immunity that exposes patients to opportunistic infections leading to treatment failure [4]. Donor T cells, administrated simultaneously or post-HSCT, could cause adverse effects, including cytokine release syndrome and GvHD, leading to treatment failure [9]. In order to increase the feasibility of donor T cell adoptive transfer, a safety mechanism to eliminate the infused cells in case of side effects has been developed. In this regard, the transduction of adoptive transfer cells with a safety switch allows us to selectively eliminate only the cells responsible for the unwanted toxicity. In vivo persistence of these safety-switch-modified T cells up to two years post-infusion has been reported, together with a faster recovery of endogenous T cells [12]
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