CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

Abstract

We studied the effect of CTLA-4 blockade on graft-versusleukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively hostderived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation

“…Delayed administration of anti-CTLA4 antibody was associated with augmentation of the GVM effect without exacerbation of lethal GVHD in a murine model of MHC-mismatched allo-HCT. 21 In a recent study of a murine model of minor histocompatibility antigen-mismatched allo-HCT, 24 early CTLA4 blockade induced acute GVHD. However, delayed CTLA4 blockade did not result in GVHD, but resulted instead in potentially lethal host-derived autoimmune effects, as well as significant augmentation of resistance to challenge with syngeneic leukemia cells.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…32,46 Another immune-related adverse event of particular interest is the development or worsening of GvHD after allogeneic SCT in a subset of patients. After favorable results from preclinical studies, 82 the idea of applying ICI to enhance graft-versus-tumor effects after allogeneic SCT led to ICI usage in trials and practice. A single dose of ipilimumab in patients who relapsed after allogeneic SCT appeared to be safe with no case of severe GvHD reported among 29 patients.…”

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect

“…In a group of three mice given TBI, all of which developed initial signs of wasting, both leucopenia and thrombocytopenia were documented, whereas hemoglobin and red blood cell count were normal. In other established alloBMT models in our laboratory, 28 we have documented that leucopenia is a common finding in the first 6 weeks after irradiation and alloBMT, whereas neutrophil count, red blood cell count and thrombocyte counts are within the normal range of naive recipient-type mice as early as day 21 after the transplant (unpublished observations). According to the Bethesda guidelines for murine hematological malignancies, 29 these findings are consistent with a murine form of MD/MPS.…”

“…29 Leucopenia and thrombocytopenia may occur as a result of recent irradiation and BMT. In other alloBMT mouse models, 28 we have documented that leucopenia is a common finding in the first 6 weeks after BMT, whereas neutrophil counts, red blood cell counts and thrombocyte counts are within the normal range of naive recipient-type mice within 3 weeks after the transplant (unpublished observations). However, in the current model, the imbalance between an exaggerated myelopoiesis in the spleen and the persistent leucopenia in the periphery reflects the maturation arrest in the myeloid lineage and further supports the diagnosis of myeloproliferation and myelodysplasia.…”