WT1-targeted immunotherapy of leukaemia

Area of Science:

• Immunology
• Oncology
• Cellular Therapy

Background:

• Tumor-associated antigens like WT1 are also present in normal tissues, leading to immune tolerance.
• WT1 vaccination in mice often fails to induce robust cytotoxic T cell responses due to this tolerance.
• Existing allorestricted T cell therapies for leukemia require prior stem cell transplantation to manage immune tolerance.

Purpose of the Study:

• To develop a method for generating high-avidity cytotoxic T lymphocytes (CTLs) specific for WT1.
• To overcome immune tolerance against WT1 in leukemia patients.
• To explore T cell receptor (TCR) gene transfer as a strategy for adoptive cellular therapy.

Main Methods:

• Isolation of high-avidity CTLs from HLA-A2-negative donors targeting WT1 epitopes.
• Assessment of allorestricted CTLs' ability to kill HLA-A2-positive leukemia cells and spare normal stem cells.
• Proposal to utilize TCR gene transfer to equip patient CTLs with WT1 specificity.

Main Results:

• Allorestricted CTLs effectively eliminate HLA-A2-positive leukemia cells.
• These CTLs do not target normal CD34+ hematopoietic stem cells.
• TCR gene transfer offers a potential way to transfer anti-leukemia specificity without alloantigens.

Conclusions:

• WT1-specific, allorestricted CTLs show promise for targeting leukemia.
• TCR gene transfer represents a viable strategy to circumvent immune tolerance and alloantigen concerns in adoptive cell therapy for leukemia.