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V. Wiebking et al.
In order to overcome the challenge of limited donor avail- ability,6 innovative protocols have been developed that allow the use of grafts from haploidentical donors. A suc- cessful strategy for haploidentical transplantation is based on the selective elimination of aβ T cells and CD19+ B cells (aβ haplo-HSCT),7 which is associated with a very low incidence of transplantation-related mortality and GvHD (Figure 1A).8-10 In contrast to CD34+-cell selection, this method of manipulation allows the transfer not only of donor hematopoietic stem cells to the recipient, but also committed hematopoietic progenitors as well as mature natural killer and gδ T cells,11,12 which may provide a protective effect against leukemia relapse and reduce the risk of infectious complications.13 With significant improvement in non-relapse mortality, disease relapse has become the most important cause of treatment failure in patients with malignancies undergoing aβ haplo- HSCT.8 In particular, the outcome of aβ haplo-HSCT in children with leukemia not in complete remission or beyond second complete remission has been poor.9,14 For this reason, it is necessary to develop novel strategies to reduce leukemic relapse after haplo-HSCT, without increasing the incidence of GvHD or transplant-related mortality.
An intriguing approach to reducing leukemic relapse is to follow haplo-HSCT with subsequent anti-leukemic cell therapy15 derived from the stem cell donor (Figure 1A- D), since these cells are from healthy immune systems and are also syngeneic (functionally autologous) to the donor graft, rendering them resistant to immune rejection after transplantation. While the infusion of donor-derived
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T cells (donor lymphocyte infusion) has been used in var- ious contexts to enhance antileukemic efficacy (Figure 1B), it is accompanied by a high risk of severe GvHD.16-22 An improvement over donor lymphocyte infusion is to genetically engineer the donor T cells with a safety switch (suicide gene) such that the cells can be quickly eliminated if severe GvHD occurs (Figure 1C). Early trials have suggested that this strategy does help to prevent relapse and the suicide switch (inducible caspase 9) is effective at eliminating alloreactive cells if GvHD occurs.23-25 Although this strategy allows GvHD to be con- trolled after it occurs, the benefit of the graft-versus- leukemia effect and the risk of GvHD remain linked to each other. It would be an improvement, therefore, to establish an approach that provides anti-leukemic activity without GvHD.
Chimeric antigen receptors (CAR) can redirect T-cell cytotoxicity towards cancer-related antigens and achieve remissions in otherwise refractory hematologic malignan- cies expressing these targets.26,27 Currently, the most com- monly used CAR T-cell products are manufactured from patient-derived autologous T cells that are harvested and transduced with a semi-randomly integrating viral vector for delivery and expression of the CAR gene, and then infused back into the patient after lymphodepleting ther- apy.28 This is associated with high variability in the CAR T-cell product and manufacturing failures. Furthermore, contaminations of the autologous cells with leukemic cells29 and the risk of insertional mutagenesis associated with randomly integrating viral vectors30 are challenges associated with the established approach.
Figure 1. T-cell therapy approaches in combination with T-cell receptor aβ+/CD19+-depleted haploidentical stem cell transplantation aiming to decrease relapse rates. (A) The protocol for haploidentical hematopoietic stem cell transplantation (HSCT) with TCRaβ+/CD19+-depletion, which establishes a backbone for additional cellular immunotherapies. (B) In order to improve immune reconstitution and enhance antileukemic activity, a specified number of T cells is transfused to the patient separate from the graft. (C) In order to retain control over the T cells and be able to intervene in the case of severe graft-versus-host disease (GvHD), the T cells can be transduced with a safeguard system such as herpes simplex virus-derived thymidine kinase or inducible caspase 9. (D) The aβ T cells are removed from the graft before transplantation and can be used as starting material to create genome-edited chimeric antigen receptor (CAR) T cells by targeted integration of a CD19-CAR into the TRAC locus, in order to target residual leukemia after HSCT without causing GvHD. sgRNA: single guide RNA; CAR: chimeric antigen receptor; GvHD: graft- versus-host disease; HSPC: hematopoietic stem and progenitor cells; TCR; T-cell receptor; NK cells: natural killer cells: TRAC: T-cell receptor alpha chain; HLA: human leukocyte antigen.
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haematologica | 2021; 106(3)