The cII locus in the Muta™Mouse System Swiger, Roy R.; Cosentino, Lidia; Shima, Naoko ...
Environmental and molecular mutagenesis,
1999, Letnik:
34, Številka:
2-3
Journal Article
Designing effective antileukemic immunotherapy will require understanding mechanisms underlying tumor control or resistance. Here, we report a mechanism of escape from immunologic targeting in an ...acute myeloid leukemia (AML) patient, who relapsed 1 year after immunotherapy with engineered T cells expressing a human leukocyte antigen A*02 (HLA-A2)-restricted T cell receptor (TCR) specific for a Wilms' tumor antigen 1 epitope, WT1
(T
). Resistance occurred despite persistence of functional therapeutic T cells and continuous expression of WT1 and HLA-A2 by the patient's AML cells. Analysis of the recurrent AML revealed expression of the standard proteasome, but limited expression of the immunoproteasome, specifically the beta subunit 1i (β1i), which is required for presentation of WT1
. An analysis of a second patient treated with T
demonstrated specific loss of AML cells coexpressing β1i and WT1. To determine whether the WT1 protein continued to be processed and presented in the absence of immunoproteasome processing, we identified and tested a TCR targeting an alternative, HLA-A2-restricted WT1
epitope that was generated by immunoproteasome-deficient cells, including WT1-expressing solid tumor lines. T cells expressing this TCR (T
) killed the first patients' relapsed AML resistant to WT1
targeting, as well as other primary AML, in vitro. T
controlled solid tumor lines lacking immunoproteasome subunits both in vitro and in an NSG mouse model. As proteasome composition can vary in AML, defining and preferentially targeting these proteasome-independent epitopes may maximize therapeutic efficacy and potentially circumvent AML immune evasion by proteasome-related immunoediting.
ThecII locus in the Muta?Mouse System Swiger, Roy R.; Cosentino, Lidia; Shima, Naoko ...
Environmental and molecular mutagenesis,
1999, Letnik:
34, Številka:
2-3
Journal Article
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