Mutation-specific control of BCR-ABL T315I positive leukemia with a recombinant yeast-based therapeutic vaccine in a murine model

Abstract

Chromosomal translocations generating the BCR-ABL oncogene cause chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia. The BCR-ABL(T315I) mutation confers drug resistance to FDA-approved targeted therapeutics imatinib mesylate, dasatinib, and nilotinib. We tested the ability of a recombinant yeast-based vaccine expressing the T315I-mutated BCR-ABL antigen to stimulate an anti-BCR-ABL(T315I) immune response. The yeast-based immunotherapy significantly reduced or eliminated BCR-ABL(T315I) leukemia cells from the peripheral blood of immunized animals and extended leukemia-free survival in a murine model of BCR-ABL(+) leukemia compared to animals receiving sham injection or yeast expressing ovalbumin. With immunization, leukemic cells harboring BCR-ABL(T315I) were selectively eliminated after challenge with a mixed population of BCR-ABL and BCR-ABL(T315I) leukemias. In summary, yeast-based immunotherapy represents a novel approach against the emergence of cancer drug resistance by the pre-emptive targeted ablation of tumor escape mutants.