T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant

Abstract

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in acute myeloid leukemia (AML) patients entering HCT with poor-risk features. 1-3 When HCT does produce prolonged relapse-free survival (RFS), it commonly reflects graft-versus-leukemia (GVL) effects mediated by donor T cells reactive with antigens on leukemic cells. 4 As graft T cells have not been selected for leukemia-specificity and frequently recognize proteins expressed by many normal host tissues, GVL is often accompanied by morbidity and mortality from graft-versus-host disease (GVHD). 5 Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens. 6 We therefore isolated a high

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

“…In a phase I clinical trial (NCT01640301), 11 patients with high-risk AML were treated prophylactically with WT1 TCR-T cells, and none had relapsed at a median follow-up of 21.3 months after allo-HCT, compared with 27% relapse at 16 months among matched controls. 114,115 No survival advantage over standard of care was seen in patients treated with WT1 TCR-T cells at relapse in preliminary findings. Tawara et al 116 developed a retroviral construct encoding a high-affinity WT1/HLA-A*24:02-specific TCR identified from the peripheral repertoire of a healthy individual, 108 along with siRNAs to eliminate expression of endogenous TCR chains.…”

“…Chapuis et al 114,115 next developed transgenic TCR-T cells directed against an HLA-A*02:01-restricted WT1 epitope for prevention or treatment of AML relapse after allo-HCT. To generate WT1-specific T cells, cytomegalovirus-or Epstein Barr virus-specific T cells from the HCT donor were transduced with a native, high-affinity, WT1-specific TCR identified from the peripheral repertoires of a healthy HLA-A*02:01 + individual.…”

T Cell Receptor Engineered Lymphocytes for Cancer Therapy

“…This creates a disulfide bond and enhances appropriate pairing of the exogenous TCRs while discouraging mispairing with endogenous TCR chains (Chapuis et al, 2019;Cohen et al, 2007;Kuball et al, 2007). h. To increase TCR expression in human T cells, codon-optimize the DNA sequence (except for the CACC start site, Furin cleavage site, GSG linker, and P2A sequences).…”

“…Even in the minor fraction of PDAs that have a high tumor mutational burden and thus likely several neoepitopes (e.g., peptides uniquely expressed by cancer cells), immune-checkpoint inhibition is often insufficient for cure (Hu, Hellmann, et al, 2018;. The infusion of in vitro-expanded T cells that express a tumor-reactive TCR can eliminate solid tumors in advanced cancer patients (Chapuis et al, 2012;Chapuis et al, 2019;Chapuis et al, 2013;Johnson et al, 2009;Rollins et al…”

“…Because TCRs comprise a heterodimer of an alpha and beta chain, both genes have to be cloned from the same T cell. Historically, T cells were cloned from antigen-specific T cell lines, and TCR genes were amplified and cloned from individual T cells (Chapuis et al, 2019;Clay et al, 1999;Hughes et al, 2005;Schmitt et al, 2013;Stromnes et al, 2015). Typically, full-length TCRs were then cloned from the T cell clones using 5 rapid amplification of cDNA ends (RACE)-associated approaches.…”