Bone marrow or stem cell transplantation
Acute myeloid leukemia (AML) is the second most common and most difficult to treat pediatric leukemia. Optimal treatment for relapsed and refractory AML is allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, allo-HSCT can result in life-threatening graft-vs-host disease (GvHD), whereby graft-derived T cells attack host tissues.
T regulatory type 1 cells (Tr1) are peripheral regulatory T cells that contribute to antigen-specific tolerance and suppress immune responses through IL-10. Tr1 can also lyse myeloid cells via perforin and granzyme B. We are developing engineered Tr1 suitable for clinical use by lentiviral transduction of IL10 into CD4+ T cells. In AML treated with allo-HSCT, a Tr1 administration could both prevent GvHD through IL-10 secretion and mediate an anti-leukemia effect through killing of residual AML, combating the two major causes of mortality.
To determine if primary pediatric AML blasts were lysed by engineered Tr1, we measured the killing of 23 blasts after co-culture with 4 Tr1 lines. Blasts were either efficiently killed, or displayed several levels of resistance. Comparing the transcriptomes of killing-sensitive and resistant blasts revealed that sensitive blasts express a myeloid activation signature, while the resistant blasts upregulated genes associated with leukemic cell “stemness”. We also identified genes encoding for surface proteins whose expression was significantly upregulated in resistant blasts and negatively correlated with killing. These proteins could be manipulated in vitro to reverse the AML resistance to killing. Altogether, Tr1 can eliminate a subset of pediatric AML blasts, and AML resistance to killing is governed by their underlying molecular signature.