Profile Melanie Bui

Summary of Research:

The emergence of targeted therapy-resistance mutations in BCR-ABL constitutes a significant vulnerability in the clinical treatment of chronic myelogenous leukemia (CML). The most prevalent escape mutation to CML treatment with imatinib mesylate (IM) or second generation tyrosine kinase inhibitor drugs (dasatinib and nilotinib) is a threonine-to-isoleucine mutation at codon 315 of BCR-ABL (T315I mutation). The goal of this study was to test whether yeast-based immunotherapy (TarmogenTM) targeting the T315I epitope triggers the specific elimination and control of leukemic cells driven by BCR-ABL harboring the T315I mutation. Since the BCR-ABLT315I epitope is a true tumor-specific antigen that is either not present or present at low levels prior to IM therapy, tolerance to this epitope should be low. Moreover, the immediate goal is not to eradicate the full leukemic burden, but rather to prevent the outgrowth of drug-resistant leukemic cells, thereby maintaining the effectiveness of current small molecule tyrosine kinase inhibitor therapies targeting the BCR-ABL kinase domain.

Prior to testing the immunotherapeutic approach in a mouse leukemia challenge model, preliminary in silico and in vitro analyses of the feasibility of generating MHC class I T-cell epitopes encompassing the T315I mutation were performed. Overlapping 8-10 amino acid peptides spanning BCR-ABLT315I were analyzed using MHC-binding peptide prediction algorithms, synthesized and evaluated in an in vitro MHC-binding assay. Six candidate T315I H2-Kb binding peptides were identified. Recombinant S. cerevisiae baker’s yeast were then engineered to express ~300 amino acids of the mouse-specific version (2 amino acids different than human ABL sequence) of T315-mutated BCR-ABL (GI-10000 yeast). Mice challenged with 105 mouse leukemia cells whose proliferation is driven by BCR-ABL succumb ~10 days after challenge. Administration of GI-10000 yeast significantly extended survival in two different mouse strains upon challenge with leukemias harboring BCR-ABLT315I but not wild-type BCR-ABL. These results indicate that immune protection was targeted against the single amino acid alteration in the mutated BCR-ABL protein expressed by the leukemia cells. In confirmation of this result, the peripheral circulation of BCR-ABLT315I cells was reduced or eliminated in immunized, but not control, animals. Furthermore, after challenge with a mixed population of wild-type BCR-ABLWT and mutated BCR-ABLT315I leukemias, a more physiologically relevant model, the number of leukemic cells harboring BCR-ABLT315I was significantly reduced relative to cells expressing wild-type BCR-ABLWT in mice vaccinated with the GI-10000 yeast, but not control yeast. In summary, yeast-based immunotherapy targeting drug resistance or escape mutations represents a powerful approach to extend the clinical effectiveness of targeted cancer therapies.

Awards/Publications:

Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology Fellowship (2005, 2006, 2007)

Neuropaty target esterase gene mutations cause motor neuron disease. Rainier S; Bui M; Plein E; Thomas D; Tokarz D; Delaney C; Richardson RJ; Albers JW; Matsunami N; Stevens J; Coon H; Leppert M; Fink JK (2007) In submission.

Control of leukemia driven by T315I escape mutations in BCR-ABL with yeast-based Tarmogen immunotherapy. (2007) Bui M; Hodson VK; Duke RC; Apelian D; Franzusoff A; DeGregori J, Fifteenth International CRI Symposium: Cancer & HIV Vaccines: Shared Lessons Oct; Abstract and Poster.

BCR-ABL Gleevec escape mutant epitope presentation. (2006) Bui M; DeGregori J, Fourteenth International CRI Symposium: Cancer Immunotherapies Oct; Abstract and Poster.

Myofibrillogenesis Regulator 1 Gene Mutations Cause Paroxysmal Dystonic Choreoathetosis. (2004) Rainier S; Thomas D; Tokarz D; Ming L; Bui M; Plein E; Zhao X; Lemons R; Albin R; Delaney C; Alvarado D; Fink JK, Arch Neurol July; 61: 1025-1029.

The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis. (2003) Hedera P, Petty EM, Bui MR, Blaivas M, Fink JK, Arch Neurol. Sep;60(9):1321-5

Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK. (2001) Nat Genet. Nov;29(3):326-31.

Chromosome 15q linked autosomal dominant hereditary spastic paraplegia; new mapping information and candidate gene analysis. SR Rainier, SM Jones, M Bui, JK Fink. (2000) A J Hum Genet, 67:391.

Chromosome 15q linked autosomal dominant hereditary spastic paraplegia. Rainier S, Jones SM, Bui M, Fink JK. Presented at the First International Symposium for Hereditary Spastic Paraplegia, (2000).

Identification of PDC candidate genes via ion channel probes and CBS genome analysis pipeline II. Bui M. Presented at the 46th Annual Student Biomedical Research Forum, (2000).