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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1317-1326
GENE THERAPY
Lentiviral vectors for efficient delivery of CD80 and
granulocyte-macrophage- colony-stimulating factor in human acute
lymphoblastic leukemia and acute myeloid leukemia cells
to induce antileukemic immune responses
Renata Stripecke,
Angelo A. Cardoso,
Karen A. Pepper,
Dianne C. Skelton,
Xiao-Jin Yu,
Leo Mascarenhas,
Kenneth I. Weinberg,
Lee M. Nadler, and
Donald B. Kohn
From the Institute for Genetic Medicine, University of
Southern California Keck School of Medicine; the Department of Adult
Oncology, Dana Farber Cancer Institute; and the Divisions of
Research Immunology/Bone Marrow Transplantation and
Hematology/Oncology, Childrens Hospital Los Angeles.
Cell vaccines engineered to express immunomodulators have shown
feasibility in eliminating leukemia in murine models. Vectors for
efficient gene delivery to primary human leukemia cells are required to
translate this approach to clinical trials. In this study,
second-generation lentiviral vectors derived from human immunodeficiency virus 1 were evaluated, with the cytomegalovirus (CMV)
promoter driving expression of
granulocyte-macrophage-colony-stimulating factor (GM-CSF) and CD80 in
separate vectors or in a bicistronic vector. The vectors were
pseudotyped with vesicular stomatitis virus G glycoprotein and
concentrated to high titers (108-109 infective
particles/mL). Human acute lymphoblastic leukemia (ALL), acute myeloid
leukemia (AML), and chronic myeloid leukemia cell lines
transduced with the monocistronic pHR-CD80 vector or the bicistronic
pHR-GM/CD vector became 75% to 95% CD80 positive (CD80+).
More important, transduction of primary human ALL and AML blasts with
high-titer lentiviral vectors was consistently successful (40%-95%
CD80+). The average amount of GM-CSF secretion by the
leukemia cell lines transduced with the pHR-GM-CSF monocistronic vector
was 2182.9 pg/106 cells per 24 hours. Secretion was
markedly lower with the bicistronic pHR-GM/CD vector (average, 225.7 pg/106 cells per 24 hours). Lower amounts of CMV-driven
messenger RNA were detected with the bicistronic vector, which may
account for its poor expression of GM-CSF. Primary ALL cells transduced
to express CD80 stimulated T-cell proliferation in an autologous mixed
lymphocyte reaction. This stimulation was specifically blocked with
monoclonal antibodies reactive against CD80 or by recombinant cytotoxic
T-lymphocyte antigen 4-immunoglobulin fusion protein. These results
show the feasibility of efficiently transducing primary leukemia cells
with lentiviral vectors to express immunomodulators to elicit
antileukemic immune responses.
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