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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2336-2341
Feasibility of Immunotherapy of Relapsed Leukemia With Ex
Vivo-Generated Cytotoxic T Lymphocytes Specific for Hematopoietic
System-Restricted Minor Histocompatibility Antigens
By
Tuna Mutis,
Rob Verdijk,
Ellen Schrama,
Bennie Esendam,
Anneke Brand, and
Els Goulmy
From the Department of Immunohematology and Blood Bank, Leiden
University Medical Center, Leiden, The Netherlands.
 |
ABSTRACT |
Allogeneic bone marrow transplantation (BMT) is a common treatment
of hematologic malignancies. Recurrence of the underlying malignancy is
a major cause of treatment failure. Donor-derived cytotoxic T
lymphocytes (CTLs) specific for patients' minor histocompatibility antigens (mHags) play an important role in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivities. mHags HA-1
and HA-2 induce HLA-A*0201-restricted CTLs in vivo and are exclusively
expressed on hematopoietic cells, including leukemic cells and leukemic
precursors, but not on fibroblasts, keratinocytes, or liver cells. The
chemical nature of the mHags HA-1 and HA-2 is known. We investigated
the feasibility of ex vivo generation of mHag HA-1- and HA-2-specific
CTLs from unprimed mHag HA-1- and/or HA-2-negative healthy blood
donors. HA-1 and HA-2 synthetic peptide-pulsed dendritic cells (DCs)
were used as antigen-presenting cells (APC) to stimulate autologous
unprimed CD8+ T cells. The ex vivo-generated HA-1- and
HA-2-specific CTLs efficiently lyse leukemic cells derived from acute
myeloid leukemia (AML) and acute lymphoid leukemia (ALL) patients. No
lytic reactivity was detected against nonhematopoietic cells.
Sufficient numbers of the CTLs can be obtained for the adoptive
immunotherapy purposes. In conclusion, we present a feasible, novel
therapy for the treatment for relapsed leukemia after BMT with a low
risk of GVHD.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
BONE MARROW transplantation (BMT) is the
present treatment for hematologic malignancies.1,2 One of
the major drawbacks of BMT is leukemia relapse.3,4 Donor
lymphocyte infusions (DLI) as a treatment for relapsed leukemia
appeared successful at least in patients with chronic myeloid leukemia
(CML).5-7 However, DLI therapy is associated with
graft-versus-host disease (GVHD) and is far less effective in acute
lymphoid leukemia (ALL) and acute myeloid leukemia (AML)
patients.6,7 The DLI-induced graft-versus-leukemia (GVL)
effect may result from T-cell responses against minor
histocompatibility antigens (mHags).6,7 Human mHags are
polymorphic antigens that are inherited independent from HLA, show
broad or restricted tissue distribution, and are recognized by
alloreactive T cells.8-15 The mHags HA-1 and HA-2 are
expressed exclusively on hematopoietic cells.9-13
HLA-A*0201-restricted, HA-1-, and HA-2-specific cytotoxic T
lymphocytes (CTLs) effectively lyse leukemic cell precursors and
circulating myeloid and lymphoid leukemic cells,9-12 but
not cells derived from GVHD target organs such as skin fibroblasts,
keratinocytes, or liver cells.13 Because the hematopoietic
cell-restricted and patient-specific target cell damage, HA-1- and
HA-2-specific CTLs can be used to specifically eliminate the leukemia
with a low risk of GVHD. We have recently identified the peptide
sequences of HA-1 and HA-2 antigens.14,15 Here, we
investigated the feasibility of ex vivo generation of mHag HA-1- and
HA-2-specific CTLs from unprimed mHag HA-1- and/or HA-2-negative
healthy blood donors using HA-1 and HA-2 synthetic peptide-pulsed
antigen-presenting cells (APCs).
Dendritic cells (DCs) are specialized APCs for the induction of T-cell
responses from naive T-cell precursors.16 DCs were successfully used to generate human immunodeficiency virus
(HIV)-specific CTLs that lysed peptide-pulsed as well as virally
infected target cells.17,18 In some studies, other types of
APCs, such as unfractionated peripheral blood mononuclear cells (PBMC),
monocytes, or even activated T cells, were used for the in vitro
induction of antigen-specific CTLs.19,20 We aimed at using
HA-1- and HA-2-specific CTLs for the adoptive immunotherapy purposes.
Therefore, we searched for the optimal APC that can be easily obtained,
and can reproducibly induce HA-1- and HA-2-specific CTLs with good
expansion capacity and strong lytic and specific reactivity against
mHag-positive AML and ALL cells.
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MATERIALS AND METHODS |
Peptides.
HA-1 and HA-2 peptides were synthesized using a semiautomatic multiple
peptide synthesizer according to the reported
sequences.14,15 The purity of the peptides was checked by
reverse-phase high-pressure liquid chromatography.
Cellular material.
All cells were obtained from HLA-typed healthy blood bank donors,
volunteers, or healthy bone marrow donors after informed consent.
Peripheral blood was collected with manual leukapheresis. PBMC and bone
marrow mononuclear cells (BMMC) were isolated by Ficoll density
gradient separation.
Monocytes.
Monocytes were isolated by 2-hour plastic adherence from PBMC.
Peripheral blood DC.
Low-density peripheral blood DC (PBDC) were enriched from PBMC as
described earlier.21 Briefly, PBMC were depleted from T
cells by sheep red blood erythrocyte rosetting. Non-T cells were
cultured for 36 hours at 37°C in RPMI plus 10% autologous plasma.
After depleting monocytes, nonadherent cells were layered on 14.5%
metrizamide (Sigma-Aldrich, Zwijndrecht, The Netherlands) gradients and the light-density PBDC were recovered from the interphase after centrifugation at 600g for 10 minutes. PBDC were
identified by fluorescence-activated cell sorting (FACS) being negative
for CD3, CD14, CD16, and CD19, and positive for HLA-DR. The
preparations contained 2 to 6 × 106 cells with a DC
content of 20% to 50%. In some cases, the light-density cells were
further depleted from CD14 and CD19 cells using antibody-coated magnetic beads (DYNAL, Oslo, Norway).
BMDC.
BMDC were differentiated from bone marrow CD34+ cells
(isolated using a CD34+ isolation kit; MACS, Bergisch
Gladbach, Germany) by culturing with 100 ng/mL FLT3 ligand (Genzyme;
Leuven, Belgium), 30 ng/mL interleukin-3 (IL-3), 25 ng/mL stem cell
factor (SCF; Genzyme), 50 U/mL tumor necrosis factor-
(TNF-; Genzyme), and 250 U/mL granulocyte-macrophage
colony-stimulating factor (GM-CSF; Genzyme) for 10 to 14 days. The
cultures contained 20% to 60% DC as detected by high levels of DR and
negative expression of CD3, CD14, CD16, and CD19.
Ex vivo induction of HA-1- and HA-2-specific CTLs.
APC were pulsed with HA-1 or HA-2 peptides (both 10 µg/mL) for 90 minutes at 37°C in serum-free AIM-V medium (GIBCO-BRL,
Breda, The Netherlands). After washing, APC and 10 to 15 × 106 responder cells (CD4-depleted autologous
PBMC) were cultured at different APC:responder cell ratios depending on
the type of APC (5:1, 1:3, and 1:10 for PBMC, monocytes, and DC,
respectively) in 24-well culture plates. Culture medium was
RPMI-supplemented with 10% autologous plasma, 1 U/mL IL-2 (Cetus,
Emeryville, CA), and 1 U/mL IL-12 (Genzyme). The cells
were kept at 37°C in an humidified, 5% CO2 air
mixture. At day 5, 10 U/mL of IL-2 was added. From day 7 on, the T-cell
cultures were restimulated weekly with peptide-pulsed autologous
monocytes. Twenty-four hours after each restimulation, 10 U/mL IL-2 was
added. The T-cell lines were expanded with 10 to 20 U/ml
IL-2-containing culture medium.
In vivo-induced mHag-specific T-cell clones.
In vivo-induced, mHag HA-1- and HA-2-specific CD8+ CTL
clones were isolated from patients peripheral blood post-BMT, and were documented in detail.8,13
Cytotoxicity (chromium-51 release) assays.
Standard, 4-hour 51Cr release assays using
phytohemagglutinin (PHA)-blasts, Epstein-Barr
virus-transformed B-cell lines (EBV-LCL), and fibroblasts and leukemic
cells as target cells were performed as described
previously.13 The percent specific lysis was calculated using the following formula: 100 × (cpm experimental release  cpm spontaneous release)/(cpm maximal release cpm
spontaneous release).
Target cells.
EBV-LCL were cultured in RPMI plus 10% fetal calf serum (FCS).
PHA-activated T-cell blasts (PHA-blasts) were obtained by stimulation of PBMC with 0.1 µg/mL PHA (Murex, Dartford, UK) over 72 hours. PHA-blasts were expanded with medium containing 20 U/mL IL-2. Skin fibroblasts of an HLA-A*0201-positive, HA-1-positive,
HA-2-positive healthy individual were isolated, cultured, and tested
as described previously.13 In short, fibroblasts were
trypsinized and cultured in the wells of 96-well flat-bottomed
microtiter culture plates at a concentration of 3 × 103 cells/well with or without addition of interferon-gamma
(IFN- ) and TNF- (both 300 U/mL) during 72 hours. When indicated,
target cells were pulsed with HA-1 or HA-2 peptides (both 10 µg/mL)
during 51Cr labeling.
Leukemia patients' (AML or ALL) PBMC or bone marrow containing greater
than 95% morphologically recognizable malignant cells were assigned as
leukemic cells. Leukemic cells were thawed and cultured in RPMI plus
10% human serum for 72 hours with or without addition of IFN- and
TNF- (both 300 U/mL) before using as target cells.
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RESULTS |
To define the optimal APC for ex vivo generation of HA-1- and
HA-2-specific CTLs, we prepared PBMC, monocytes, PBDC, or BMDC from 15 HLA-A*0201-positive, HA-1- or HA-2 -negative healthy
individuals. These APCs were pulsed with HA-1 and/or HA-2 synthetic
peptides and used to stimulate autologous unprimed CD8+ T
cells (Fig 1). The attempts to induce HA-1- or
HA-2-specific CTLs using monocytes or PBMC as APC were unsuccessful.
Using PBMC, mHag-specific CTLs could be generated in one of three
attempts only. Monocytes induced HA-1-specific CTLs in two of five
attempts. However, the HA-1-specific CTLs induced by monocytes failed
to lyse HA-1-positive target cells, suggesting that monocytes induced CTLs with low-affinity T-cell receptors for the naturally expressed HA-1 antigen (Fig 1).
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| Fig 1.
Target cell reactivity of HA-1- and HA-2-specific ex
vivo-induced CTLs using various types of APCs pulsed with synthetic
peptides. The type of APC used to induce CTLs is indicated on the
x-axis. Below the x-axis, the number of CTLs generated using the same
type of APC (but in all cases from a different individual) and the
total number of attempts are indicated. Effector-to-target ratio was
20:1.
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PBDC were enriched from in total nine different individuals to induce
HA-1- or HA-2-specific CTLs. In the two of four cases where the DC
preparations had a purity of less than 30%, we induced CTLs that lysed
peptide-pulsed target cells but not mHag-positive target cells (Fig 1).
In contrast, in five cases of five attempts where PBDC purity was 30%
or greater, we generated CTLs that recognized not only peptide-pulsed
target cells, but also mHag-positive EBV-LCL, demonstrating the
recognition of the naturally expressed ligand (Fig 1). Similarly, in
two of two attempts where BMDC were used as APCs, CTLs were induced
that recognized both peptide-pulsed target cells and HA-1-positive
target cells (Fig 1). For six of these ex vivo-generated HA-1- or
HA-2-specific CTLs (HA-1 CTL no. 1 through 4 and HA-2 CTL no. 1 and 2)
using PBDC or BMDC, the actual lytic activity against several
mHag-positive, peptide-pulsed, or unpulsed mHag-negative target cells
is shown in Fig 2. The cytotoxic activity of two in
vivo-generated HA-1- and HA-2-specific CTLs against same targets are
shown as comparison. Similar to the in vivo-generated CTLs, all ex
vivo-generated CTLs showed strong lysis against peptide-pulsed and
mHag-positive target cells. Some CTLs (HA-1 CTL no. 1 and 2, HA-2 CTL
no. 1 and 2) effectively lysed target cells even in effector-to-target
ratios as low as 4:1 (Fig 2). No cytotoxic activity was observed
against autologous PHA-blasts or against several mHag-negative EBV-LCL.
Thus, neither autoreactivity nor "third-party" alloantigen
reactivity could be detected (Fig 2). Several HA-1- or HA-2-specific
CTL clones isolated from these CTLs showed the same target cell
reactivity (data not shown).
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| Fig 2.
CTL activity against peptide-pulsed and mHag-positive
target cells by ex vivo-induced HA-1- and HA-2-specific CTLs. HA-1
CTLs no. 1, 2, 3, and 4 and HA-2 CTLs no. 1 and 2 were generated from
different individuals using PBDC (HA-1 CTLs no. 1, 4 and HA-2 CTLs no.
1, 2) or BMDC (HA-1 CTLs no. 2, 3). The cytotoxic activities of in
vivo-induced HA-1- and HA-2-specific CTLs against the same target
cells are shown as comparison. Target cells: autologous PHA-blasts
( ); autologous PHA-blasts pulsed with peptide ( ; EBV-LCL positive
for HA-1 (n = 4) or HA-2 (n = 3) ( ); EBV-LCL negative for HA-1
(n = 3) or HA-2 (n = 3) ( ); HA-1- or HA-2-negative EBV-LCL
pulsed with HA-1 or HA-2 peptide ( ).
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The ex vivo-induced HA-1- and HA-2-specific CTLs were tested for
their hematopoietic cell restricted reactivity and compared with the in
vivo-induced HA-1- and HA-2-specific CTLs (Fig 3). PHA-blasts, but not fibroblasts (neither after IFN- or after TNF-
stimulation) were recognized by ex vivo (and in vivo)-induced HA-1- and HA-2-specific CTLs. Fibroblasts were only lysed after pulsing with the mHag peptides, demonstrating their susceptibility to
CTL-mediated lysis (Fig 3).
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| Fig 3.
Hematopoietic cell-restricted cytolysis mediated by ex
vivo-induced HA-1- and HA-2-specific CTLs. Data are representative
for all ex vivo-induced CTLs tested. The cytotoxic activities of in
vivo-induced HA-1- and HA-2-specific CTLs against the same target
cell panel are shown for comparison. All target cells used in these
specificity experiments were derived from the same
HLA-A*0201+, HA-1+, HA-2+
healthy volunteer. Target cells: PHA-blasts (); fibroblasts ();
fibroblasts cultured with IFN- + TNF- (both 300 U/mL) ();
fibroblasts cultured with IFN- + TNF- and pulsed with 10 µg/mL peptide ().
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The ex vivo-induced HA-1- and HA-2-specific CTLs were subsequently
analyzed for cytolytic activity against, for this study the most
relevant target cells, leukemic cells from AML and ALL patients. In
vivo-induced HA-1- and HA-2-specific CTLs and an HLA-A*0201-specific alloreactive CTL were used as control effector cells. As shown in Fig 4, AML and ALL cells were lysed
by the HLA-A*0201-specific alloreactive CTL, and by the in
vivo-induced HA-1- and HA-2-specific CTLs, showing that the leukemic
cells were HLA-A*0201-positive and expressed HA-1 or HA-2 antigens. Importantly, the ex vivo-induced CTLs lysed the leukemic cells efficiently and comparable to the control effector cells (Fig 4). The
level of cytotoxicity could be significantly enhanced following IFN-
and TNF- treatment of the leukemic cells, indicating that cytokines
upregulate HLA class I expression on the leukemic cells (Fig 4).
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| Fig 4.
Lysis of HA-1+ or HA-2+
leukemic cells by ex vivo-induced HA-1- and HA-2-specific CTLs. Data
are representative for all ex vivo-induced CTLs. The lysis of same
target cells by in vivo-induced HA-1- and HA-2-specific CTLs, and by
control HLA-A*0201-specific CTL clone are shown for comparison. Target
cells: HA-1 or HA-2 EBV-LCL ( );
HA-1+ or HA-2+ EBV-LCL (); leukemic
cells positive for HA-1 (n = 4) or HA-2 (n = 3) ();
HA-1+ or HA-2+ leukemic cells cultured with
IFN- + TNF- ().
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The feasibility of adoptive immunotherapy with ex vivo-generated CTLs
depends also on their expandability to sufficient numbers. We scored
the expansion rates of HA-1- and HA-2-specific CTLs generated by DC
and calculated the total yield based on the expansion without
cryopreservation (Fig 5). Sufficient
numbers of CTLs for adoptive immunotherapy can be obtained by
initiating the cell cultures with 5 × 107 responder
cells. Figure 5 shows that two HA-2-specific CTLs induced by PBDC
showed expansion rates of greater than 9-, 25-, and 8-fold at the
second, third, and fourth week, respectively, yielding a total of 3 × 109 to 1010 CTLs at the end of the
fourth week. The expansion kinetics of the HA-1-specific CTLs were
slower, but the cells expanded consistently with doubling times of 2 to
3 days during each restimulation. It is estimated that 109
HA-1-specific CTLs can be obtained after 5 weeks of culture (Fig 5).
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| Fig 5.
Expansion of HA-1- and HA-2-specific CTLs. Data
represent a theoretical calculation based on the actual expansion rates
of the CTLs. The expansion rates of the CTLs were calculated as
follows: expansion rate = Total number of the cells after
restimulation/no. of restimulated cells. The initial number of
responder cells was 5 × 107 and the total yield of CTLs
before each restimulation was calculated by multiplying the expansion
rate per week with the number of theoretically restimulated cells.
(,) Two HA-2-specific CTLs induced by PBDC; () HA-1-specific
CTL induced by PBDC; () HA-1-specific CTL induced by BMDC.
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DISCUSSION |
We show that mHag HA-1- and HA-2-specific CTLs can reproducibly be
generated ex vivo from HLA-A*0201-positive, mHag HA-1- and/or
HA-2-negative healthy blood donors using DC pulsed with synthetic
peptides. These CTLs display specific cytotoxic activity against
mHag-positive target cells, including leukemic cells from AML and ALL
patients, but not against nonhematopoietic cells. Sufficient numbers of
CTLs can be generated for adoptive immunotherapy purposes.
To establish the optimal protocol for the ex vivo generation of HA-1-
and HA-2-specific CTLs, we have compared DC, PBMC, and monocytes as
APCs. Only DC induced potent HA-1- and HA-2-specific CTLs. These
results underscore the superior capacity of DC to induce T-cell
responses from naive precursors and confirm the current opinion on the
DC characteristics.16 We observed that monocytes or poorly
enriched DC can also induce mHag peptide-specific CTLs, but these CTLs
fail to recognize the naturally expressed mHag. This finding may have
implications for studies in which the immunogenicity of putative
tumor-associated peptides is tested by loading on PBMC, monocytes, or
on partially maturated monocyte-derived DC. In various studies, CTLs
generated against these putative tumor-associated peptides does not
recognize the tumor cells.22,23 This may suggest that these
putative peptides are not present on the tumor cells, or according to
our findings, only appropriately generated DC are capable of inducing
CTLs recognizing the naturally expressing ligand.
The functional analysis of the HA-1- and HA-2-specific CTLs generated
ex vivo shows (Figs 2 to 4) no autoreactivity, or reactivity to
third-party alloantigens. Thus, these CTLs can be safely transferred to
the patients. Furthermore, the results clearly show that ex vivo-generated CTLs lyse hematopoietic cells effectively, but not the
nonhematopoietic system cells, such as fibroblasts. Adoptive transfer
of HA-1- or HA-2-specific CTLs to HA-1- or HA-2-positive patients
will spare the patient's nonhematopoietic tissues. Thus, upon adoptive
transfer of HA-1- and HA-2-specific CTLs, a low risk of GVHD is
expected. Some precaution may be necessary, since we have previously
demonstrated that HA-1 disparity between patient and donor is
associated with the development of GVHD in adults.24 Therefore, in the clinical trials we will transfer the CTLs not before
50 to 60 days post BMT. It is expected that most recipient hematopoietic cells will then be replaced by HA-1- or HA-2-negative donor cells. Alternatively, one may consider to transduce the HA-1-
and HA-2-specific CTLs with a suicide gene that will make the in vivo
elimination of cells possible if adverse effects occur.25 Most importantly, our study shows that the ex vivo-generated HA-1- and HA-2-specific CTLs effectively lyse leukemic cells derived from
AML and ALL patients, both type of leukemias being resistant to DLI
treatment. The level of cytotoxicity could be significantly enhanced
following IFN- and TNF- treatment of the leukemic cells, indicating that HLA class I antigens are upregulated. HA-1- and HA-2-specific CTL clones produce IFN- and TNF- in vitro
(manuscript in preparation). It is possible that cytokine production by
HA-1- and HA-2-specific CTLs occurs in-vivo as well. Alternatively, the efficacy of adoptive immunotherapy with HA-1- and HA-2-specific CTLs may be enhanced by coadministration of IFN- in resistant cases.
After the successful application of EBV-specific CTLs as specific
adoptive immunotherapy of EBV-related malignancies,26 our
results now open a new possibility for the treatment of relapsed, HA-1- and/or HA-2-positive leukemia patients with HA-1- or
HA-2-specific CTLs induced ex vivo from their HLA-identical,
mHag-negative bone marrow donors.
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ACKNOWLEDGMENT |
We thank Dr M. Oudshoorn for critically reading the manuscript.
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FOOTNOTES |
Submitted October 5, 1998; accepted November 18, 1998.
Supported in part by grants from the Dutch Cancer Foundation (Koningin
Wilhelmina Fonds), Leukemia Society of America, Leiden University
Medical Center, and the J.A. Cohen Institute for Radiopathology and
Radiation Protection. B.E. is a Leukemia Society of America Translational Research Awardee.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Tuna Mutis, MD, PhD,
Department of Immunohematology and Blood Bank, Leiden University
Medical Center, Bldg 1, E3-Q, Box 9600, 2300 RC Leiden, The
Netherlands; e-mail: Mutis{at}rullf2.leidenuniv.nl.
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TOP
ABSTRACT
INTRODUCTION