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

Blood. 1997 Jul 15;90(2):549-61.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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