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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3318-3327
Expansion of Philadelphia Chromosome-Negative
CD3+CD56+ Cytotoxic Cells From Chronic
Myeloid Leukemia Patients: In Vitro and In Vivo Efficacy in Severe
Combined Immunodeficiency Disease Mice
Christine Hoyle,
Charles D. Bangs,
Pearl Chang,
Onsi Kamel,
Bela Mehta, and
Robert S. Negrin
From the Division of Bone Marrow Transplantation, Department of
Medicine; the Department of Pathology, Stanford University Medical
School, Stanford; and Becton Dickinson Immunocytometry
Systems, San Jose, CA.
We have developed culture conditions for the efficient expansion of
cytotoxic effector cells from peripheral blood mononuclear cells
(PBMNCs) by the timed addition of interferon- (IFN-), interleukin-2 (IL-2), and the monoclonal antibody (MoAb) OKT3. These
cells, termed cytokine-induced killer (CIK) cells, are composed primarily of T cells, and the population of cells with the greatest cytotoxic activity is an otherwise rare population of
CD3+CD56+ cells that expand dramatically
under these culture conditions. CIK cells were expanded from PBMNCs
from 13 patients with chronic myeloid leukemia (CML). These cultures
contained a variable number of T cells at the start of the culture
(median 44%, range 1% to 64%), yet after 21 to 28 days of culture,
virtually all of the cells were CD3+ T cells (median
97%, range 90% to 99%). The CD3+CD56+
subset of cells expanded significantly (median 25-fold, range 2.2- to
525-fold). CIK cells from all patients showed cytotoxicity against the
tumor cell lines OCI-LY8 and K562. In four patients the expanded CIK
cells suppressed colony growth of autologous CML blast cells and
myeloid progenitor cells. Allogeneic CIK cells from normal donors also
suppressed CML colony growth but did not inhibit growth of normal
hematopoietic colonies. Twelve of the 13 cultures were exclusively
composed of Philadelphia (Ph)-negative cells and one culture had 1 out
of 20 Ph-positive metaphases after 4 weeks in culture. Intracellular
cytokine production was assayed by fluorescence-activated cell sorter
(FACS), and the expanded T-cell cultures produced IL-2, IFN-, and
tumor necrosis factor- (TNF-), but not IL-4. Both the
CD4+ and CD8+ subsets secreted this
cytokine profile. To test the in vivo activity of the expanded CIK
cells, CML was engrafted into severe combined immunodeficiency disease
(SCID) mice using matrigel. After 4 weeks, 4 × 107
autologous CIK cells were injected intravenously by tail vein injection
into groups of mice, and the animals were sacrificed after a total of
18 weeks. Bcr-abl was detected in the bone marrow or spleen of 5 out of
6 control mice and only 2 out of 13 mice who received the autologous
CIK cells (P = .02). In an additional series of animals, the
mice did not engraft with CML but instead developed large human
Epstein-Barr virus-associated lymphomas by 12 weeks. The mice who
received autologous CIK cells at 4 weeks had either no tumor (5) or
small tumors (5), whereas all 10 mice that received CIK cells at week 8 developed lymphomas; however, these were not as large as in the 10 control mice who did not receive CIK cells (P = .03). This
study shows that CIK cells, which are Ph chromosome-negative, can be
expanded from patients with CML and have potent in vitro and in vivo
efficacy against autologous tumor cells.
© 1998 by The American Society of Hematology.
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