Wilms tumor gent 1 (WT1)-specific adoptive immunotherapy in hematologic diseases

Jiang, Yujie; Lv, Xiao; Ge, Xueling; Qu, Huiting; Zhang, Qian; Lu, Kang; Lu, Yingxue; Xue, Chao; Zhang, Lingyan; Wang, Xin

doi:10.1016/j.intimp.2021.107504

Cited by 7 publications

(6 citation statements)

References 52 publications

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“…However, there are still many issues to be solved to improve avidity and increase killing potential of tumor cells by vaccine activated T cells or infused WT1specific T-cell products. 20 WT1 is expressed during embryogenesis and involved in the embryonic development of kidneys, gonads, and several organs lined by the mesothelium. In adults, WT1 is involved in homeostasis processes for tissue maintenance and recovery, resulting in expression in renal podocytes, epicardial cells, Sertoli cells, granulosa cells, and hematopoietic stem cells.…”

Section: What This Study Addsmentioning

confidence: 99%

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

Amerongen

Hagedoorn

Remst

et al. 2022

J Immunother Cancer

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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.

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Section: What This Study Addsmentioning

confidence: 99%

“…However, there are still many issues to be solved to improve avidity and increase killing potential of tumor cells by vaccine activated T cells or infused WT1-specific T-cell products. 20 …”

Section: Introductionmentioning

confidence: 99%

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

Amerongen

Hagedoorn

Remst

et al. 2022

J Immunother Cancer

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“…Identification of tWT1 only in TCGA-OV may be due to the prevalence of hypoxia in this cancer, as it is often diagnosed late into progression and therefore would have a higher degree of tumor hypoxia, thereby increasing the chances of obtaining biopsies derived from hypoxic microenvironments (78). In conclusion, while further work is needed to elucidate the molecular tWT1 isoforms, its potential as a novel therapeutic target may be of particular interest for immunotherapy as the peptide obtained through translation of the added intronic sequence could provide a cancer-specific cryptic antigen (79).…”

Section: Discussionmentioning

confidence: 99%

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

Quenneville,

Feghaly,

Tual

et al. 2023

Preprint

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The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seenin vivo, to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization, DNA binding, and its human ortholog negatively predicts long-term patient survival. Our study demonstrates the importance of culture conditions that better mimic those observed in cancers, especially with regards to hypoxia, and identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer.

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“…These effector functions include the production of cytotoxic granules that contain granzymes and perforin, causing the target cells to undergo apoptosis. Furthermore, CTLs can induce the expression of death receptors on the surface of cancer cells, which further encourages apoptosis [ 38 ]. WT1 vaccinations elicit an immune response that attempts to create immunological memory in addition to their immediate cytotoxic effects.…”

Section: Reviewmentioning

confidence: 99%

WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review

Gugulothu,

Anvesh Sai,

Suraparaju

et al. 2024

Cureus

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Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.

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Wilms tumor gent 1 (WT1)-specific adoptive immunotherapy in hematologic diseases

Cited by 7 publications

References 52 publications

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

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

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review

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