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In vitro Induction of Myeloid Leukemia–Specific CD4 and CD8 T Cells by CD40 Ligand – Activated B Cells Gene Modified to Express Primary Granule Proteins

Authors' Affiliations: ¹ Stem Cell Allotransplant Section, Hematology Branch, National Heart, Lung, and Blood Institute and ² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland

Requests for reprints: A. John Barrett, Stem Cell Allotransplant Section, Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Building 10/Room 7C103, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-4170; Fax: 301-435-8655; E-mail: barrettj{at}nhlbi.nih.gov.

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 postallogeneic 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- 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.

Key Words: Primary granule proteins • antigen-specific T cells • leukemia immunotherapy • Leukemias and lymphomas • Cellular immunotherapy • Cancer vaccines • Graft versus tumor effect

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