Targeting an alternate Wilms’ tumor antigen 1 peptide bypasses immunoproteasome dependency

Abstract

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 126–134 (T TCR-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 WT1 126–134 . An analysis of a second patient treated with T TCR-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 WT1 37–45 epitope that was generated by immunoproteasome-deficient cells, including WT1-expressing solid tumor lines. T cells expressing this TCR (T TCR37–45 ) killed the first patients’ relapsed AML resistant to WT1 126–134 targeting, as well as other primary AML, in vitro. T TCR37–45 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.

Trans-population graph-based coverage optimization of allogeneic cellular therapy

“…A clinical bridge-to-transplant trial is open for patients with relapsed acute leukemias. Following chemotherapy, patients will receive off-the-shelf transduced TCR T-cell products specific for immunogenic leukemia-associated epitopes presented on HLA-A*02:01, such as p 53 R175H ( 52 ) and W T37−45 ( 53 ). The limitations in this scenario are as follows:…”

CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function

“…A TCR targeting the WT1 126–134 , HLA-A*02:01–restricted epitope has been safely tested in clinical trials, but its efficacy has been limited, in part, by its requirement of processing by the immunoproteasome ( 22 , 61 ). In contrast, WT1 37–45 and WT1 −78–64 are naturally processed and presented on the surface of primary blasts harvested from patients with leukemia, as shown by the ability of newly isolated TCRs to efficiently eliminate these targets.…”

Challenges and solutions for therapeuticTCR‐based agents

“…TCR‐engineered T cells are also being investigated for treating hematologic malignancies, particularly for AML/MDS by targeting the differentially expressed TAA WT1 65,311–313 . Interestingly, relapse after WT1 TCR therapy was associated with antigen escape not by WT1 mutation or HLA downregulation but by immunoproteasome regulation, 314 a challenge that can be overcome by informed epitope selection.…”