Abstract
The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3), human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate post-allogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-gamma or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.
MeSH terms
-
Antigen-Presenting Cells / immunology
-
Antigen-Presenting Cells / metabolism
-
Antigen-Presenting Cells / pathology
-
B-Lymphocytes / immunology*
-
B-Lymphocytes / metabolism
-
B-Lymphocytes / pathology
-
CD4-Positive T-Lymphocytes / immunology*
-
CD4-Positive T-Lymphocytes / metabolism
-
CD4-Positive T-Lymphocytes / pathology
-
CD40 Antigens / genetics
-
CD40 Antigens / immunology
-
CD40 Antigens / metabolism
-
CD40 Ligand / genetics
-
CD40 Ligand / immunology*
-
CD40 Ligand / metabolism
-
CD8-Positive T-Lymphocytes / immunology*
-
CD8-Positive T-Lymphocytes / metabolism
-
CD8-Positive T-Lymphocytes / pathology
-
Cathepsin G
-
Cathepsins / genetics
-
Cathepsins / metabolism
-
Cells, Cultured
-
Gene Expression
-
HL-60 Cells
-
Humans
-
Interferon-gamma / immunology
-
Interferon-gamma / metabolism
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Leukemia, Myeloid / genetics
-
Leukemia, Myeloid / immunology*
-
Leukemia, Myeloid / pathology
-
Leukocyte Elastase / genetics
-
Leukocyte Elastase / metabolism
-
Lymphocyte Activation
-
Myeloblastin
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Serine Endopeptidases / genetics
-
Serine Endopeptidases / metabolism
-
Transfection
Substances
-
CD40 Antigens
-
RNA, Messenger
-
CD40 Ligand
-
Interferon-gamma
-
Cathepsins
-
Serine Endopeptidases
-
CTSG protein, human
-
Cathepsin G
-
Leukocyte Elastase
-
Myeloblastin