Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses.
Chronic myelogenous leukemia (CML) presents a unique opportunity to develop therapeutic strategies using vaccination against a truly tumor-specific antigen that is also the oncogenic protein required for neoplasia. CML is characterized by the t(9;22) that results in the bcr-abl fusion oncogene and in the expression of a chimeric protein product p210. Previously we have shown that peptides derived from amino acid sequences crossing the b3a2 fusion breakpoint in p210 elicit class I restricted cytotoxic T lymphocytes and class II responses, respectively, in vitro. Such sequences may thus comprise absolutely tumor-specific antigens in a peptide-based vaccine. We evaluated the safety and immunogenicity of a multidose, bcr-abl breakpoint peptide vaccine in 12 adults with chronic-phase CML. Cohorts of 3 patients each received either 50 microg, 150 microg, 500 microg, or 1500 microg total peptide mixed with 100 microg QS-21 as an immunological adjuvant. Delayed-type hypersensitivity (DTH), humoral responses, and unprimed ex vivo autologous proliferation ((3)H-thymidine incorporation) and cytotoxicity (chromium-51 release) responses were measured. All 68 vaccinations were well tolerated without significant adverse effects. In 3 of the 6 patients treated at the 2 highest dose levels of vaccine, peptide-specific, T-cell proliferative responses (n = 3) and/or DTH responses (n = 2) were generated that lasted up to 5 months after vaccination. Cytotoxic T lymphocytes have not been identified. In conclusion, a tumor-specific, bcr-abl derived peptide vaccine can be safely administered to patients with chronic-phase CML and can elicit a bcr-abl peptide-specific immune response despite the presence of active disease in these patients and approximately 10(12) leukemia cells. (Blood. 2000;95:1781-1787)
Pinilla-Ibarz
J
J
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Cathcart
K
K
Korontsvit
T
T
Soignet
S
S
Bocchia
M
M
Caggiano
J
J
Lai
L
L
Jimenez
J
J
Kolitz
J
J
Scheinberg
D A
DA
D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D017635:Clonal Anergy; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007116:Immunization, Passive / Q000009:adverse effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D012449:Safety; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D010446:Peptide Fragments; D016044:Fusion Proteins, bcr-abl