Mutation-specific control of BCR-ABL T315I positive leukemia with a recombinant yeast-based therapeutic vaccine in a murine model.
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.
Bui
Melanie R
MR
University of Colorado Denver School of Medicine, Aurora, CO, USA.
Hodson
Victoria
V
King
Tom
T
Leopold
Derek
D
Dai
Shaodong
S
Fiolkoski
Valerie
V
Oakes
Sarah
S
Duke
Richard
R
Apelian
David
D
Franzusoff
Alex
A
DeGregori
James
J
D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D018572:Disease-Free Survival; D016044:Fusion Proteins, bcr-abl / Q000276:immunology*; D005805:Genes, MHC Class I; D007167:Immunotherapy; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae; D014614:Vaccines, Synthetic / Q000276:immunology
D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; D016044:Fusion Proteins, bcr-abl