WT1-specific TCRs directed against newly identified peptides install antitumor reactivity against acute myeloid leukemia and ovarian carcinoma

Abstract

BackgroundTranscription factor Wilms’ tumor gene 1 (WT1) is an ideal tumor target based on its expression in a wide range of tumors, low-level expression in normal tissues and promoting role in cancer progression. In clinical trials, WT1 is targeted using peptide-based or dendritic cell-based vaccines and T-cell receptor (TCR)-based therapies. Antitumor reactivities were reported, but T-cell reactivity is hampered by self-tolerance to WT1 and limited number of WT1 peptides, which were thus far selected based on HLA peptide binding algorithms.MethodsIn this study, we have overcome both limitations by searching in the allogeneic T-cell repertoire of healthy donors for high-avidity WT1-specific T cells, specific for WT1 peptides derived from the HLA class I associated ligandome of primary leukemia and ovarian carcinoma samples.ResultsUsing broad panels of malignant cells and healthy cell subsets, T-cell clones were selected that demonstrated potent and specific anti-WT1 T-cell reactivity against five of the eight newly identified WT1 peptides. Notably, T-cell clones for WT1 peptides previously used in clinical trials lacked reactivity against tumor cells, suggesting limited processing and presentation of these peptides. The TCR sequences of four T-cell clones were analyzed and TCR gene transfer into CD8+ T cells installed antitumor reactivity against WT1-expressing solid tumor cell lines, primary acute myeloid leukemia (AML) blasts, and ovarian carcinoma patient samples.ConclusionsOur approach resulted in a set of naturally expressed WT1 peptides and four TCRs that are promising candidates for TCR gene transfer strategies in patients with WT1-expressing tumors, including AML and ovarian carcinoma.

Human iPSC-derived preclinical models to identify toxicity of tumor-specific T cells with clinical potential

“…Previously, all T cell products demonstrated antigen-specific cytotoxicity of tumor cells. 17 , 19 , 20 , 24 In summary, these data confirm the antigen specificity and functionality of the six T cell products included in the screenings of the hiPSC-derived preclinical models.…”

“…Two of the TCRs are currently investigated in phase I/II clinical studies, one targeting the minor histocompatibility antigen (MiHA) HA-1H, 16 encoded by the HMHA1 gene, and the other targeting tumor-associated antigen PRAME. 17 , 18 TCRs targeting B cell specific antigen CD20 19 or T cells targeting tumor-associated antigen WT1, 20 which are still in preclinical phase, were also used. Based on previous extensive in vitro and in vivo studies, these T cells were considered highly potent and antigen-specific.…”

“… 19 WT1 T cell clone WT1 ALLPAVPSL 22.1H1 van Amerongen et al. 20 For each T cell type the targeted gene, targeted peptide, and the name of the initial T cell clone are listed. The references refer to the articles in which the T cell clones were initially identified.…”

“… 38 The tumor-specific T cells included in our study were already extensively screened for potential off-target toxicities against a large panel of different healthy cell subsets, but were not tested before against cardiomyocytes, epicardial cells, and kidney organoids. 17 , 19 , 20 , 24 …”

A library of cancer testis specific T cell receptors for T cell receptor gene therapy

“…The TCR selection strategy from the T cell repertoire of HLA-mismatched individuals enables the selection of potent TCRs specific for self-antigens and can be used for variety of different targets. 26 , 27 Our identified TCRs could potentially be included in an “off-the-shelf” library of TCRs. However, the use of allogeneic “off-the-shelf” TCRs for TCR gene therapy also comes with a toxicity risk.…”