LAUSR

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, WT1126–134 (TTCR-C4). 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 WT1126–134. An analysis of a second patient treated with TTCR-C4 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 WT137–45 epitope that was generated by immunoproteasome-deficient cells, including WT1-expressing solid tumor lines. T cells expressing this TCR (TTCR37–45) killed the first patients’ relapsed AML resistant to WT1126–134 targeting, as well as other primary AML, in vitro. TTCR37–45 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. Description Targeting the alternate Wilms’ tumor 1 (WT1) epitope WT137–45 circumvents engineered T cell receptor gene therapy resistance in acute myeloid leukemia. Alternative WT1 targets Adoptive cell therapy using T cell receptor (TCR)–modified T cells has shown clinical success. However, it remains a challenge to find TCRs that respond to shared tumor antigens presented in common human leukocyte antigen molecules. To that end, Ruggiero et al. and Lahman et al. identified and tested TCR constructs targeting alternative epitopes in the Wilms’ tumor antigen 1 (WT1) protein. Ruggiero and colleagues identified WT137–45 as a candidate peptide for TCR-based therapies and used CRISPR-Cas9 editing to target WT137–45-specific TCR sequences to the TRAC locus. Lahman and colleagues showed that, whereas a TCR-targeted WT1 epitope was lost because of immunoproteasome down-regulation, WT137–45 retains its expression and could be targeted by T cells expressing TCRs specific to that epitope, even in cancer cells that lose immunoproteasome activity. In both cases, T cells expressing WT137–45-specific TCRs controlled tumor burden in murine models. Thus, WT137–45 represents a candidate target for TCR-based immunotherapies that is resistant to immunoproteasome down-regulation.