Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for hematologic malignancies but relapse remains the most common cause of death. Infusion of donor lymphocytes (DLIs) can induce remission and prolong survival by exerting graft-vs.-leukemia (GVL) effects. However, sufficient tumor control cannot be established in all patients and occurrence of graft-vs.-host disease (GVHD) prevents further dose escalation. Previous data indicate that invariant natural killer T (iNKT) cells promote anti-tumor immunity without exacerbating GVHD. In the present study we investigated lysis of leukemic blasts through iNKT cells from donor-derived lymphocytes for leukemia control and found that iNKT cells constitute about 0.12% of cryopreserved donor T cells. Therefore, we established a 2-week cell culture protocol allowing for a robust expansion of iNKT cells from cryopreserved DLIs (DLI-iNKTs) that can be used for further preclinical and clinical applications. Such DLI-iNKTs efficiently lysed leukemia cell lines and primary patient AML blasts ex vivo in a dose- and CD1d-dependent manner. Furthermore, expression of CD1d on target cells was required to release proinflammatory cytokines and proapoptotic effector molecules. Our results suggest that iNKT cells from donor-derived lymphocytes are involved in anti-tumor immunity after allo-HCT and therefore may reduce the risk of relapse and improve progression-free and overall survival.
Highlights
Allogeneic hematopoietic cell transplantation is a curative treatment option for many advanced or high-risk hematologic malignancies like acute myeloid leukemia (AML)
The administration of donor lymphocytes is complicated by the high risk of inducing acute or chronic graft-vs.-host disease (GVHD)
Previous clinical studies showed that higher invariant natural killer T (iNKT)-cell numbers in the graft or peripheral blood post-transplant were associated with a reduced incidence of GVHD [14, 24]
Summary
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for many advanced or high-risk hematologic malignancies like acute myeloid leukemia (AML). Overall survival of such patients has improved over the last decades, but relapse remains the most common cause of death after allo-HCT. DLI-iNKTs Promote GVL Effects were found to further strengthen GVL effects. This was first observed by Hans-Jochem Kolb and co-workers in chronic myeloid leukemia (CML) patients in the 1990s [1]. The administration of donor lymphocytes is complicated by the high risk of inducing acute or chronic graft-vs.-host disease (GVHD)
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