ABSTRACT
Treatment of BCR-ABL1(+) leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR-ABL1(+) acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR-ABL1(+) leukemia cells by blocking both calcineurin/NFAT signaling and BCR-ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA-interference we confirm that calcineurin inhibition sensitizes BCR-ABL1(+) cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co-administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti-leukemia benefit of co-administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Calcineurin Inhibitors , Fusion Proteins, bcr-abl/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adult , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cell Line, Tumor , Cyclosporine/adverse effects , Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Dasatinib , Drug Synergism , Female , Flow Cytometry , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Thiazoles/therapeutic use , Treatment OutcomeABSTRACT
The survival of naive T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naive T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naive B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance.
