Adoptive T-cell therapy for B-cell acute lymphoblastic leukemia: preclinical studies.
We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8(+) and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti-leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.
Cardoso
A A
AA
Departments of Adult Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. cardoso@mbcrr.harvard.edu
Veiga
J P
JP
Ghia
P
P
Afonso
H M
HM
Haining
W N
WN
Sallan
S E
SE
Nadler
L M
LM
D001804:Blood Transfusion, Autologous; D001853:Bone Marrow / Q000502:physiology; D002051:Burkitt Lymphoma / Q000628:therapy*; D016827:CD8 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002648:Child; D002675:Child, Preschool; D004727:Endothelium / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D016219:Immunotherapy, Adoptive; D007223:Infant; D007231:Infant, Newborn; D010641:Phenotype; D017154:Stromal Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D016827:CD8 Antigens