Passive and active specific immunotherapy of myeloid leukemias
Fusion Proteins, bcr-abl
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Two approaches are under investigation: Specific passive therapy using genetically engineered humanized monoclonal antibodies reactive with CD33 and active specific immunotherapy (vaccines) reactive with the bcr/ahl fusion protein. Passive therapies: (1) Patients are infused with IJIl-HuM195 to cytoreduce up to a kilogram of leukemia in advance of a conventional bone marrow transplant. 30 patients have been entered on dose escalation trials using M195 orHuM195 followed by busulfanandcytoxan prepared first or second allogeneic bone marrow transplants. No toxicity specific to the addition of the radiolabeled antibody has been defined. There were 2 early deaths: 28 of 30 patients engrafted (median time 14 days). 27 of 30 patients achieved a complete remission. (2) Unlabeled HuM195 is being used in the setting of minimal disease after induction therapy in APL is a model for adjuvant treatment. 5 of the first 8 évaluable patients in complete clinical remission, but with residual leukemia as determined by RTPCR, showed elimination of the RT-PCR signal after HuM195 infusions. (3) Novel constructs using Bismuth-213 bifunctional chelate conjugated HuM195 are under investigation to specifically deliver alpha emitting isotopes that allow single cell kill. Active therapies: The bcr/abl derived fusion protein (P210) provides a unique tumor specific target for active specific immunotherapy. 4 peptides of a series of 76 possible peptides spanning the junction of the B3 A2 or B2A2 p210 junction, showed high or intermediate affinity binding to HLA class 1. Specific human T cell immunity was demonstrated to these peptides in assays for chromium release using peptide loaded HLA matched target CML cells. Specific proliferation of T cells was shown in response to larger B3A2 derived peptides in vitro using autologous antigen presenting cells. The presence of specific CD4 and CDS responses to bcr/abl junctional peptides allows a strategy for vaccination of patients with CML to be developed.