Wilms’ tumor 1 (WT1)

Understanding WT1 as a potential target

WT1 is a uniquely immunostimulatory cancer antigen that is disproportionately expressed in various hematologic malignancies and solid tumors.1-4 This makes WT1 an attractive target for cancer immunotherapies.5-7

WT1 expression in cancer

The WT1 protein is expressed in various hematologic malignancies and solid tumors, including glioblastoma.1 WT1 has been shown to enable tumor invasion, metastasis, and to promote resistance to radiation and standard chemotherapies.8,9 These factors, along with its functional absence in normal tissues, led the National Cancer Institute to designate WT1 as the number 1 prioritized cancer antigen* for therapeutic targeting among the 75 antigens that were evaluated.10,11

Immunotherapy in WT1-positive tumors

WT1 as a tumor antigen has multiple immunogenic epitopes capable of eliciting host immune system antitumor activity.2-4 These epitopes could be useful for immunotherapeutic strategies. In prior studies, WT1-specific immunologic responses generated by antigen-directed therapies have correlated with longer survival in patients with tumor types expressing WT1.5-7

*Criteria to prioritize cancer antigens: 1. therapeutic function, 2. immunogenicity, 3. role of the antigen in oncogenicity, 4. specificity, 5. expression level and percent of antigen-positive cells, 6. stem cell expression, 7. number of patients with antigen-positive cancers, 8. number of antigenic epitopes, 9. cellular location of antigen expression.10

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References:

  1. Kijima N, Hashimoto N, Chiba Y, Fujimoto Y, Sugiyama H, Yoshimine T. Functional roles of Wilms’ tumor 1 (WT1) in malignant brain tumors. In: van den Heuvel-Eibrink M, ed. Wilms Tumor. Brisbane, Australia: Codon Publications; 2016:261-272.
  2. Sugiyama H. Wilms' tumor gene WT1: its oncogenic function and clinical application. Int J Hematol. 2001;73(2):177-187.
  3. Sugiyama H. WT1 (Wilms' tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol. 2010;40(5):377-387.
  4. Doubrovina E, Carpenter T, Pankov D, Selvakumar A, Hasan A, O'Reilly RJ. Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1(+) leukemias. Blood. 2012;120(8):1633-1646.
  5. Oka Y, Tsuboi A, Nakata J, et al. Wilms' tumor gene 1 (WT1) peptide vaccine therapy for hematological malignancies: from CTL epitope identification to recent progress in clinical studies including a cure-oriented strategy. Oncol Res Treat. 2017;40(11):682-690.
  6. Tsuboi A, Hashimoto N, Fujiki F, et al. A phase I clinical study of a cocktail vaccine of Wilms' tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma. Cancer Immunol Immunother. 2019;68(2):331-340.
  7. Yanagisawa R, Koizumi T, Koya T, et al. WT1-pulsed dendritic cell vaccine combined with chemotherapy for resected pancreatic cancer in a phase I study. Anticancer Res. 2018;38(4):2217-2225.
  8. Qi XW, Zhang F, Wu H, et al. Wilms' tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis. Sci Rep. 2015;5(8924).
  9. Chidambaram A, Fillmore HL, Van Meter TE, Dumur CI, Broaddus WC. Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness. J Neurosurg. 2012;116(4):843-853.
  10. Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323-5337.
  11. Chen MY, Clark AJ, Chan DC, et al. Wilms' tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression. J Neurooncol. 2011;103(1):87-102.