Ex vivo generation of human anti-pre-B leukemia-specific autologous cytolytic T cells.

Abstract

In contrast to other neoplasms, antigen-specific autologous cytolytic T cells have not been detected in patients with human pre-B-cell leukemias. The absence of efficient B7 family (B7-1/CD80; B7-2/CD86) -mediated costimulation has been shown to be a major defect in tumor cells' capacity to function as antigen-presenting cells. We show here the generation of autologous anti-pre-B-cell leukemia-specific cytolytic T-cell lines from the marrows of 10 of 15 patients with pre-B-cell malignancies. T-cell costimulation via CD28 is an absolute requirement for the generation of these autologous cytolytic T cells (CTL). Although costimulation could be delivered by either bystander B7 transfectants or professional antigen-presenting cells (indirect costimulation), optimal priming and CTL expansion required that the costimulatory signal was expressed by the tumor cell (direct costimulation). These anti-pre-B-cell leukemia-specific CTL lysed both unstimulated and CD40-stimulated tumor cells from each patient studied but did not lyse either K562 or CD40-stimulated allogeneic B cells. Cytolysis was mediated by the induction of tumor cell apoptosis by CD8+ T cells via the perforin-granzyme pathway. Although we were able to generate anti-leukemia-specific CTL from the bone marrow, we were unable to generate such CTL from the peripheral blood of these patients. These studies show that antigen-specific CTL can be generated from the bone marrow of patients with pre-B-cell leukemias and these findings should facilitate the design of adoptive T-cell-mediated immunotherapy trials for the treatment of patients with B-cell precursor malignancies.

• Authors: A A Cardoso, M J Seamon, H M Afonso, P Ghia, V A Boussiotis, G J Freeman, J G Gribben, S E Sallan, L M Nadler
• Journal: Blood (Blood) Vol. 90 Issue 2 Pg. 549-61 (Jul 15 1997) ISSN: 0006-4971 [Print] United States
• PMID: 9226154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD
• B7-1 Antigen
• B7-2 Antigen
• CD86 protein, human
• Membrane Glycoproteins
• Recombinant Fusion Proteins
• Interferon-gamma

Topics

• Animals
• Antigens, CD (biosynthesis, immunology)
• Apoptosis
• B7-1 Antigen (biosynthesis, immunology)
• B7-2 Antigen
• Bone Marrow (immunology, pathology)
• Burkitt Lymphoma (immunology, pathology)
• CHO Cells
• Cells, Cultured
• Cricetinae
• DNA Fragmentation
• Dendritic Cells (immunology)
• Humans
• Immunophenotyping
• Interferon-gamma (biosynthesis)
• Leukemia, B-Cell (immunology, pathology)
• Lymphocyte Culture Test, Mixed
• Membrane Glycoproteins (biosynthesis, immunology)
• Preleukemia (immunology, pathology)
• Recombinant Fusion Proteins (biosynthesis)
• Reference Values
• T-Lymphocytes (immunology)
• T-Lymphocytes, Cytotoxic (immunology, pathology)
• Tumor Cells, Cultured