Fusion genes produced by chromosomal translocations in core-binding factor (CBF) acute myeloid leukemia (AML) are critical leukemia initiating events. A fusion between CBFB and MYH11 genes occurs in approximately half of patients with CBF AML. Amongst patients with these fusions, 80-90% share the type A CBFB-MYH11 fusion variant. Despite being classified as a favorable risk AML subtype, only 50-60% of patients with CBFB-MYH11+ AML are cured with intensive chemotherapy alone. In addition, deep remission remains a challenge. Given that formation of the CBFB-MYH11 fusion is an essential step in leukemia initiation and presence of the fusion is stable across disease course and persistent at relapse, therapies directed against CBFB-MYH11 should prevent escape of leukemia. Researchers at Fred Hutch led by Dr. Bleakley conducted a reverse-immunology strategy to identify high-avidity CD8+ T cells from healthy donors with specificity for a naturally presented epitope from the CBFB-MYH11 type A fusion. This work was the first to discover and characterize the first genuine neoantigen derived from an AML-initiating fusion and demonstrated engineered T-cell receptors for the CBFB-MYH11/B*40:01 epitope confer anti-leukemic activity in vitro.
- Prophylactic and therapeutic treatment of CBF AML and other malignancies expressing the CBFB-MYH11/B*40:01 epitope using engineered TCR- T cell therapy approaches
- Cancer vaccine – alone or in combination with other neoantigens
- Targets a shared neoantigen known to be essential for the initiation of AML
- High-avidity epitope-specific TCR will enable patients to receive a product with a defined specificity and potency
- May be combined with other immunotherapy approaches
Approximately 10% of all AML carries the CBFB-MYH11 fusion. While the percentage of HLA-B*40:01+ individuals varies depending on ethnic background from 4-30%. It is anticipated these HLA- B*40:01+ restricted TCRs could treat 200 patients per year in the US. These findings could be used in concert with other immunotherapy approaches to elicit a robust anti-AML immune response.
- Marie Bleakley, MD - Clinical Research Divisions