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

• Published in: Blood 1997-07, Vol.90 (2), p.549-561
• Main Authors: CARDOSO, A. A, SEAMON, M. J, AFONSO, H. M, GHIA, P, BOUSSIOTIS, V. A, FREEMAN, G. J, GRIBBEN, J. G, SALLAN, S. E, NADLER, L. M
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - biosynthesis; Antigens, CD - immunology; Antineoplastic agents; Apoptosis; B7-1 Antigen - biosynthesis; B7-1 Antigen - immunology; B7-2 Antigen; Biological and medical sciences; Bone Marrow - immunology; Bone Marrow - pathology; Burkitt Lymphoma - immunology; Burkitt Lymphoma - pathology; Cells, Cultured; CHO Cells; Cricetinae; Dendritic Cells - immunology; DNA Fragmentation; Humans; Immunophenotyping; Immunotherapy; Interferon-gamma - biosynthesis; Leukemia, B-Cell - immunology; Leukemia, B-Cell - pathology; Lymphocyte Culture Test, Mixed; Medical sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - immunology; Pharmacology. Drug treatments; Preleukemia - immunology; Preleukemia - pathology; Recombinant Fusion Proteins - biosynthesis; Reference Values; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v90.2.549

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.