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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2459-2466
Idiotype Immunization Combined With Granulocyte-Macrophage
Colony-Stimulating Factor in Myeloma Patients Induced Type I, Major
Histocompatibility Complex-Restricted, CD8- and CD4-Specific T-Cell
Responses
By
Anders Österborg,
Qing Yi,
Lotta Henriksson,
Jan Fagerberg,
Susanne Bergenbrant,
Mahmood Jeddi-Tehrani,
Ulla Rudén,
Ann-Kari Lefvert,
Göran Holm, and
Håkan Mellstedt
From the Departments of Oncology (Radiumhemmet) and Medicine,
Karolinska Hospital, Swedish Institute for Infectious Disease Control,
Stockholm; and the Department of Experimental Oncology, Uppsala
University, Uppsala, Sweden.
 |
ABSTRACT |
Idiotypic structures expressed on the myeloma Ig protein might be
regarded as a tumor-specific antigen. Five patients with IgG myeloma
were immunized with the purified serum M-component by repeated
intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype
(Id)-specific T-cell immunity, defined as blood T cells predominantly
secreting interferon- (IFN-) and interleukin-2 (IL-2) (type I
cells). Id-specific DNA synthesis was induced in one patient.
Delayed-type hypersensitivity against the Id was not evoked. The
specific IFN-/IL-2 T-cell response was inhibited (46% to 100%) by
a major histocompatibility complex (MHC) class I monoclonal antibody
(MoAb) in all five patients. A 5% to 37% inhibition by an MHC class
II MoAb was seen in four patients. CD4+ as well as
CD8+ T cells enriched by magnetic microbeads contained
Id-specific cells. The T cells recognized peptides corresponding to the
complementarity-determining regions 1, 2, and 3 of the heavy chain of
the Id. There was a transient rise of B cells producing IgM
anti-idiotypic antibodies in all patients. The results indicate that
immunization of myeloma patients using the autologous M-component and
soluble GM-CSF may evoke an Id-specific predominantly MHC class
I-restricted type I T-cell response.
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INTRODUCTION |
MULTIPLE MYELOMA (MM) is a
lymphoproliferative disorder characterized by a clonal proliferation of
B cells producing a monoclonal Ig that can be detected in the serum
and/or urine. The unique clonal idiotypic Ig structures are
expressed on the cell surface of the myeloma B cells,1 and
peptides of the idiotypic Ig may be presented in the groove of major
histocompatibility complex (MHC) molecules of the clonal tumor B
cells.2,3 The idiotypic structures may serve as
tumor-specific antigens.4 The surface-localized, tumor-derived idiotypes (Id) may elicit a humoral and cellular anti-idiotypic response5,6 that may control the growth of the myeloma B-cell clone. Active immunization using the autologous monoclonal Ig as a vaccine may confer resistance to tumor cell challenge in murine myeloma and B-cell lymphomas.4,7,8
Exogenous antigens are processed and presented by antigen-presenting
cells (APC). Both the exogenous and endogenous presentation pathways
may be used2 resulting in either MHC class II or I presentation.9 The functional activity of APC may be
augmented by granulocyte-macrophage colony-stimulating factor
(GM-CSF)10,11 In vivo soluble GM-CSF has been shown to
enhance the humoral response against hepatitis B vaccine.12
In a comparative study, tumor cells engineered to secrete GM-CSF were
the most potent stimulators of a specific anti-tumor
immunity.13
In the present study, the autologous myeloma IgG protein purified from
serum, the Id of which may serve as tumor-specific antigens, was used
together with free GM-CSF for immunization of myeloma patients. The
specific humoral and cellular anti-Id immunity as well as clinical
effects were analyzed.
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MATERIALS AND METHODS |
Patients.
Five IgG MM patients were included. The median age was 65 years (range,
48 to 74 years). All patients had clinical stage IIA14 with
a World Health Organization (WHO) performance status of 0 to 1. Three
patients were in a stable partial remission following chemotherapy
(nos. 1 and 4) or local radiotherapy (no. 2) 12 to 48 months earlier.
Two patients (nos. 3 and 5) were previously untreated. Clinical
evaluation of the patients before and after immunization was done
according to standard procedures.15 The study was approved
by the local Ethic's Committee. Written informed consent was obtained
from each patient.
Preparation of monoclonal IgG and F(ab )2 fragments.
The procedure has been described in detail.16 Briefly,
serum was applied to a sterile mabTrapG column (Pharmacia, Uppsala, Sweden). IgG was eluted with 0.1 m glycine-HCl (pH 2.7). Isoelectric focusing (Pharmacia Phast system) estimated that more than 90% of the
IgG was monoclonal. The monoclonal IgG was dialysed against sterile
NaCl followed by filtration through a Millipore filter (0.20 µm).
F(ab)2 fragments were prepared by pepsin digestion. F(ab)2 fragments from monoclonal IgG of other myeloma
patients were used as controls and were prepared in the same way as the autologous IgG.
Production of complementarity-determining region (CDR)
peptides.
Total RNA was extracted from a patient's (no. 4) bone marrow
sample.17 First-strand cDNA was synthesized followed by
polymerase chain reaction (PCR) using family-specific IgH variable gene
framework 1-specific oligonucleotides as 5 primer and an IgH constant
gene-specific 3 primer.18,19 The PCR products were
subjected to fragment analysis20 using an automatic
sequencing machine (ALF, Pharmacia). Based on the fragment analysis
result (single peak), the relevant PCR product was ligated into the
pGEM-T vector (Amersham, Cleveland, OH) and transformed to the
Escherichia coli strain JM109. Ten positive colonies, screened
by PCR, were isolated and plasmids containing the cloned inserts
prepared. They were then sequenced using pGEM-T vector primers (Sp6 and
T7). Ten out of 10 clones showed the same sequence, which confirmed the
monoclonality of the PCR product as suggested by fragment analysis.
This proved that this sequence was carried by the tumor B-cell
population.
The amino acid (aa) sequence of the tumor IgH was deduced from the
nucleotide sequence, and peptides corresponding to the full CDR 1-3 regions including 2-4 flanking aa were synthesized. The length of the
CDR1, 2, and 3 peptides were 15, 20, and 20 aa, respectively.
Solid-phase peptide synthesis was performed with
9-fluorenylmethoxycarbonyl methodology.21
Preparation of Id vaccine.
Equal volumes of sterile filtered monoclonal IgG and alum suspension
(National Bacteriological Lab, Stockholm, Sweden) were mixed under
aseptic conditions and adjusted with sterile 0.9% NaCl to a final IgG
concentration of 1 mg/mL. Tests for sterility, pyrogens, and viruses
were negative.22
Immunization protocol.
Patients were immunized day 1 intradermally with 0.5 mg of the
autologous Id vaccine. Seventy-five µg of GM-CSF (Schering-Plough, Kenilworth, NJ) was injected subcutaneously at the same site daily, days 1 to 4. The complete procedure was repeated after 2, 4, 6, 8, and
14 weeks.
Proliferation assay (DNA synthesis).
The method has been described in detail earlier.23,24
Peripheral blood mononuclear cells (PBMC) were stimulated with purified F(ab)2 fragments of the autologous monoclonal IgG (1 pg/mL to 100 µg/mL) as well as with four allogeneic monoclonal
isotype-matched IgG from other myeloma patients purified in the same
way and cultured for 6 days. [3H]-thymidine was added
during the last 18 hours. ConA (40 µg/mL) and PPD (2.5 µg/mL) were used as positive controls. Tests were run in triplicates,
and mean reactivity was calculated for each triplicate. For each
testing time, the highest mean value of a triplicate obtained from the
five different concentrations of the Id was used. Stimulation index
(SI) was calculated by dividing the mean radioactivity for a triplicate
of stimulated cells by that of unstimulated cells. The test was
performed thrice before the first immunization. The mean + 2 SD
stimulation index of the patients using the four control isotypes was
2.68 (range, 0.76 to 3.04) and of five healthy controls using the five
different monoclonal IgGs 2.15 (range, 0.55 to 2.84). A cut-off level
of less than or equal to 3.20 was used in accordance with previous reports.23,24
Reverse enzyme-linked immunospot (ELISPOT) assay
(interferon- (IFN-), interleukin-2
(IL-2) and IL-4 secreting cells).
The ELISPOT assay for identification of IFN--, IL-2-, or
IL-4-secreting cells was used as described.24,25 Briefly,
PBMC (1 × 105/well) were incubated with
F(ab)2 fragments of the autologous or isotypic
monoclonal IgG (1 pg/mL to 1 µg/mL) or CDR peptides (1 to 10 µg/mL)
for 48 hours in humidified air with 5% CO2 at 37°C. As
previously reported,25,26 10 pg/mL of F(ab)2
fragments was found to be optimal in the ELISPOT assay in all the
patients and used for subsequent experiments. A representative
experiment showing the dose-response relationship of Ig-induced
cytokine secreting cells is depicted in Fig
1. Low concentrations (0.1 to 100 pg/mL) of
the Id induced a specific response, whereas at high concentrations (0.1 to 10 µg/mL) the Id-induced T-cell response was less marked as
indicated by the increasing numbers of cells also stimulated by the
isotypic monoclonal IgG. Cells incubated with medium alone, PPD (2.5 µg/mL) or ConA (10 µg/mL), were used as positive controls. Spots
corresponding to cytokine-secreting cells were counted blindly under a
dissection microscope. All samples were incubated in duplicate wells.
The coefficient of variation between duplicates was 8.5%.
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| Fig 1.
Dose-response relationship of IFN--secreting
cells/105 PBMC after incubation with F(ab)2
fragments of autologous ( ) and isotypic control ( ) monoclonal
IgG.
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The results are expressed as the numbers of stimulated IFN--,
IL-2-, or IL-4-secreting cells/105 PBMC. The stimulated
number of spots (total number of spots minus the number of spots in
cultures with medium only) was determined and is shown. Tests were
performed thrice before the first immunization. The mean number of
mitogen (ConA)-induced spots was, for IFN-, 80 spots (range, 30 to
250); for IL-2, 41 spots (range, 20 to 88), and for IL-4, 32 spots
(range, 20 to 80). The mean + 2 SD stimulated number of spots in
patients using three isotype-matched (control) IgG
F(ab)2 fragments was, for IFN-, 9 spots (range 0 to
14); for IL-2, 7 spots (range, 0 to 14); and for IL-4, 6 spots (range,
0 to 14). As another control for specificity, PBMC from five healthy
controls were stimulated with the five different monoclonal IgGs and
the mean + 2 SD of stimulated number of spots was, for IFN-, 10 spots (range 0 to 12); for IL-2, 4 spots (range, 0 to 9); and for IL-4,
6 spots (range, 0 to 6).
Anti-Id antibody assay.
The ELISPOT assay was also used for detection of B cells secreting IgM
antibodies binding to F(ab)2 fragments of the autologous monoclonal IgG.16 The coefficient of variation between
duplicates was 9%. The mean + 2 SD number of spots for five healthy
donors using 12 different monoclonal IgGs was 5 (range 0 to 6).
MHC-restricted T-cell response.
To study MHC restriction of the specific T-cell response, mouse MoAbs
(IgG2b) against MHC class II molecules (HLA-DR; Immunotec, Marseille,
France) or class I molecules (HLA-ABC; Chemicon International Inc,
Temecula, CA) were added (1 µg/mL) to the ELISPOT assay for the whole
incubation period. One microgram per milliliter of the blocking
antibody was optimal as previously shown.27 As a control, a
nonrelevant mouse IgG2b MoAb (Immunotec) was used. Results
are expressed as percent inhibition compared with cultures without the
addition of MHC MoAbs. The unspecific inhibition was 0% to 15%.
Functional analyses of T-cell subsets.
CD4 and CD8 T cells were enriched from freshly prepared PBMC by
antibody-coated magnetic microbeads (MiniMACS, Miltenyi Biotec GmbH,
Bergisch Gladbach, Germany) according to the manufacturer's recommendation. The purity of the respective CD4+ and
CD8+ T-cell fractions was greater than 95%. Monocytes were
collected by incubation of PBMC in a Petri dish for 30 minutes at
37°C. CD4+ and CD8+ T cells, respectively,
were then cultured with 5% autologous adherent cells with or without
the addition of F(ab)2 fragments of the autologous or
isotypic control IgG and analyzed for cytokine secretion as described
above.
Delayed-type hypersensitivity (DTH).
When a positive in vitro T-cell response was noted, sterile autologous
monoclonal IgG (0.1 mg) and a control human pooled polyclonal IgG
(Gammaglobulin Kabi 165 mg/mL, Pharmacia; 0.1 mg) were injected
intradermally. Induration and erythema were measured 24 to 72 hours
after the injection.23,24
Statistical methods.
The Mann-Whitney U-test was used to compare differences between
data obtained before and during immunization, and between autologous
and isotypic (control) IgG.
| |
RESULTS |
Id-specific T-cell response (DNA synthesis).
One patient (no. 1) developed an Id-specific T-cell response in the
high-dose range (1 to 100 µg/mL of autologous F(ab)2 fragments; Fig 2). The proliferative
response gradually increased until week 14 (SI = 43.0 at the highest
concentration [100 µg/mL] ) but had disappeared at week 16 and
remained then negative. The other patients showed no Id-specific
proliferative response (SI  3.20).
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| Fig 2.
DNA synthesis ([3H]-thymidine
incorporation) in PBMC of patient no. 1 (week 14) stimulated with
F(ab)2 fragments of the autologous monoclonal IgG ( ),
F(ab)2 fragments of isotypic control monoclonal IgG
(), and pooled human polyclonal IgG ( ) (cpm of PBMC cultured in
medium alone was 130). The values for PPD-(2.5 µg/mL) and ConA (40 µg/mL)-stimulated PBMC were 3,933 and 78,865 cpm, respectively.
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Id-specific T-cell response (IFN-, IL-2, IL-4
secretion) (ELISPOT).
Before immunization, all patients had low numbers of Id-induced,
cytokine-secreting T cells. The median number of spots for IFN- was
7 (range 4 to 14); for IL-2 5 (range 3 to 9); and for IL-4, 3 (range 1 to 6). During immunization the numbers of specific IFN--and
IL-2-secreting cells increased in all five patients. The differences
compared with week 0 were statistically significant (P < .05) at three of four points of time (week 4, 8, and
16) for IFN-, and at two of four points (week 8 and 16) for IL-2 (Fig 3A and B). No significant IL-4
response was induced (Fig 3C). The IFN- and IL-2 responses,
respectively, induced by the autologous monoclonal IgG were
statistically significantly higher than those induced by the isotypic
control monoclonal IgG (P < .05) at all points (Figs 3A and
B). There were no significant changes in the number of cells responding
to isotypic control IgG during the immunization period.
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| Fig 3.
Time kinetics of cytokine-secreting cells/105
PBMC. PBMC were stimulated in vitro with F(ab)2
fragments of the autologous () or isotypic control ( ) monoclonal
IgG (10 pg/mL). Number of cells secreting IFN-. (A), IL-2 (B), and
IL-4 (C) was assessed by ELISPOT. Mean ± SEM (n = 5) for each
time point are shown. The numbers of IFN-- and IL-2-secreting
cells induced by the autologous monoclonal IgG was statistically
significantly higher compared with week 0 at different points
(*P < .05, **P < .01). At all points of time
the numbers of IFN- and IL-2, but not IL-4-secreting cells, induced
by the autologous IgG were significantly different compared with the
isotypic control monoclonal IgG (P < .05). Arrows indicate
immunization times.
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The time kinetics pattern of Id-induced, cytokine-secreting cells is
exemplified by patient no. 2 in Fig 4. An
increase in the number of IFN-- and IL-2-secreting cells,
respectively, was seen by repeated immunizations. IL-4-secreting cells
remained low, as did the number of IFN--, IL-2-, and
IL-4-secreting cells induced by the isotypic control monoclonal IgG.
Individual data on IFN-- and IL-4-secreting cells of all patients
are summarized in Table 1. The number of
Id-induced, IFN--producing cells reached a plateau in most patients
after 2 to 4 immunizations. Id-induced, IL-4-secreting cells remained
low except for patient nos. 4 and 5, who showed positive values at the
end of the immunization period/at follow-up. During unmaintained
follow-up, idiotype-specific IFN--secreting cells were detectable
in all patients 1 to 3 months after the last immunization. Only one
patient (no. 2) was followed-up for a long time period, and specific
IFN--secreting cells could be detected 1 year after immunization
was terminated.
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| Fig 4.
Time kinetics of cytokine secreting cells/105
PBMC in patient no. 2. PBMC were stimulated in vitro with
F(ab)2 fragments of the autologous monoclonal IgG (10 pg/mL). Number of cells secreting IFN- (), IL-2 ( ), and IL-4
() was assessed by ELISPOT. Number of cells secreting IFN- (),
IL-2 (), and IL-4 () induced by control monoclonal IgG. Arrows
indicate immunization times.
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Table 1.
Numbers of Idiotype- and Isotype-Stimulated IFN--
and IL-4-Secreting Cells at Different Time Points From Start of
Immunization in Myeloma Patients Immunized With the Autologous
Idiotype
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MHC restriction of the Id-specific T-cell response.
Mouse MoAbs against human MHC class I or II molecules were used to
inhibit the Id-induced T-cell response in vitro. MHC class I MoAb
markedly suppressed the specific IFN- or IL-2 response in four out
of five patients (83% to 98% inhibition; Fig.
5). In the remaining patient (no. 1), MHC
class I MoAb induced an inhibition of 46%. MHC class II MoAb had an
inhibitory effect on IFN- or IL-2 secretion varying between 5% and
37%.
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| Fig 5.
Inhibition of Id-induced IFN- (P1, P2, P4, P5) or IL-2
(P3) cytokine-secreting cells by MHC antibodies (ELISPOT)
(mean + SEM). PBMC were stimulated in vitro by
F(ab)2 fragments of the autologous monoclonal IgG (10 pg/mL) in the presence or absence of mouse MoAbs against human MHC
class II (), MHC class I molecules ( ), or control mouse IgG
2b () (1 µg/mL). The absolute number of cells/105 PBMC after stimulation with the autologous
monoclonal IgG (in the absence of blocking antibodies) for patient nos.
1 through 5 were 18, 30, 22, 16, and 19 cells, respectively. The
corresponding numbers obtained with isotypic control IgG were 3, 1, 4, 2, and 3 cells, respectively. Results are expressed as percent
inhibition compared with cells incubated without the blocking MoAbs.
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Subset restriction of the Id-specific T-cell response.
Enrichment of T-cell subsets by magnetic microbeads was done in two
patients (nos. 1 and 3). The Id-specific IFN- response was confined
to both CD8+ and CD4+ cells (Fig
6).
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| Fig 6.
Stimulated number of Id-induced IFN-
cytokine-secreting cells/105 cells (ELISPOT) in
CD4+ and CD8+ T-cell subpopulations from
patients no. 1 (A) and no. 3 (B), enriched from PBMC by magnetic
microbeads. CD4+ and CD8+ cells,
respectively, were cultured with 5% autologous adherent cells in the
presence of F(ab)2 fragments of the autologous () or
isotype-matched allogeneic ( ) monoclonal IgG (10 pg/mL). Standard error of means are shown on top of each column.
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Epitope mapping of Id-specific T-cell response.
Fifteen to 20 aa long peptides of the heavy chain CDR 1, 2, and 3 regions, respectively, of the monoclonal IgG of patient no. 4 were
synthesized. Corresponding peptides of a control myeloma monoclonal IgG
were also produced. High numbers of IL-2-secreting cells specifically
recognizing the CDR 1, 2, and 3 peptides of the autologous but not the
allogeneic Ids were noted (Fig 7A). The CDR
1-, CDR3-, and F(ab)2 fragment-induced specific
responses were abrogated by MHC class I MoAb but not by MHC class II
MoAb, whereas the CDR2-induced IL-2 response was predominantly class II
restricted. No significant IL-4 response was induced by CDR 1-3 peptides (Fig 7B).
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| Fig 7.
CDR 1-3 peptide-reactive T-cells (ELISPOT) secreting IL-2
(A) and IL-4 (B). PBMC of patient no. 4 were stimulated in vitro with
autologous () or allogeneic () peptides 15-20 aa long
corresponding to the CDR1, 2, and 3 regions of the heavy chain and by
F(ab)2 fragments of the autologous monoclonal IgG ().
The autologous Id-induced response was also assayed in presence of
mouse MoAbs against human MHC class II () or MHC class I ( ) (1 µg/mL) molecules. Standard error of means are shown on top of each
column.
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Id-specific T cells in vivo (DTH).
None of the patients developed a DTH reaction against the autologous
IgG M-component (data not shown).
Anti-idiotypic (IgM) humoral response.
All five patients developed B cells secreting IgM antibodies binding to
F(ab)2 fragments of the autologous monoclonal IgG (Fig
8). The differences between week 0 and
weeks 8 and 10, respectively, were statistically significant
(P < .05 and P < .01). The anti-idiotypic IgM
response induced by the autologous monoclonal IgG was statistically significantly higher than that induced by the isotypic control monoclonal IgG at all points (P < .05). There were no
significant changes in the number of cells reactive with the isotypic
control IgG during the immunization period. The anti-idiotypic IgM
humoral response was transient. In all but one patient (no. 3), the IgM antibody response had diminished by the end of the immunization period.
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| Fig 8.
Anti-idiotypic IgM antibodies. Time kinetics of B cells
secreting IgM antibodies binding to F(ab)2 fragments of
the autologous () or isotypic control () monoclonal IgG were
assessed by ELISPOT. Mean ± SEM (n = 5) for each time point are
shown. The increase in the numbers of IgM-secreting cells binding to
the autologous IgG was statistically significant at week 8 (P < .05) and week 10 (P < .01) compared with
baseline. The difference between autologous and isotypic control
monoclonal IgG was statistically significant (P < .05) at
all points. Arrows indicate immunization times.
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Clinical effects.
All patients had a stable IgG M-component concentration for at least 12 months before study entry and reduced (below the normal range)
background Ig (IgM, IgA) levels. One patient (no. 2) was diagnosed with
myeloma-related osteolytic lesions of the eighth thoracic vertebra and
the eighth left rib. The IgG M-component concentration was 25 g/L. No
increased number of plasma cells in a bone marrow sample (obtained from
the iliac crest) was found. The patient received local radiotherapy (40 Gy) 55 weeks before immunization, and the M-component concentration
then remained stable at 20 g/L until start of immunization. During
immunization, the M-component concentration decreased to 7 g/L. At
follow-up 1 year after commencement of immunization, the M-component
concentration remained at 7 g/L. In parallel, background serum Ig
levels were normalized. IgA concentration increased from 1.3 g/L to 1.9 g/L and IgM concentration from 0.2 g/L to 0.6 g/L. There was no urine excretion of the M-component or light chains during the observation period. The M-component concentration as well as the background serum
Ig levels of the other four patients remained stable (data not shown).
| |
DISCUSSION |
Immunization using the autologous myeloma protein-expressing idiotypic
determinants may induce anti-idiotypic antibodies and anti-idiotypic T
cells in animals and humans.5,22,28 Protective and
therapeutic antitumor immunity were induced in animals with transplantable plasmacytomas.4,7,29 The immune effector functions are, however, not completely understood. Cell-mediated immunity seemed to be of importance,6 but antibodies might also have contributed to the rejection of the plasmacytoma
cells.30,31 Effector cells may belong to the
CD4Th1, CD4Th2, or the classical CD8 CTL
subsets.32,33 Immunization of patients with non-Hodgkin's B-cell lymphoma using the autologous idiotypic Ig coupled to keyhole limpet hemocyanin (KLH)-induced MHC class I-restricted Id-specific CD8+ CTLs, which were associated with a favorable clinical
outcome.34
The present pilot study describes the results of Id immunization in
five myeloma patients using the myeloma protein (serum M-component) as
immunogen and given together with soluble GM-CSF. Id-specific T and B
cells were induced in all patients, and a greater than 50% reduction
of the M-component concentration was noted in one patient. Based on the
cytokine secretion pattern (IFN- and IL-2), the majority of the
Id-specific T cells could be classified as type I (Th1 or Tc1)
cells.35 The main part of the induced T cells appeared to
be MHC class I restricted. This may suggest that the immunization led
to a predominant Id-specific CD8+ T-cell response. The
negative DTH reaction in all patients after challenge with the Id might
support such an assumption. Only one patient developed a transient
idiotype-specific proliferative T-cell response. These results might
be explained by the observation that different T-cell subsets and T
cells of varying maturity may have a varying response
profile.36 In particular, antigen-specific cell
proliferation may not correlate to antigen-specific cytokine production, suggesting that proliferation test only may not be sufficient to reveal an antigen-specific, T-cell
population.37 It seems critically important to use several
read-out systems to detect and characterize an antigen-specific, T-cell
response.
Addition of GM-CSF might be of importance for the enhancement and the
quality of the anti-idiotypic immunity.38,39 In a comparative solid tumor model using cytokine gene-transduced melanoma tumor cells for immunization, GM-CSF was shown to be an efficient cytokine for the induction of a protective anti-tumor immunity involving CD8+ as well as CD4+ T
cells.13 Immunization with GM-CSF-transduced tumor B cells induced an effective anti-tumor immunity in a mouse lymphoma model. The
immunity directed against Id-expressing tumor cells also required CD4+ as well as CD8+ T cells. A humoral
response was not detected.38 Immunization of animals with
an Id-GM-CSF fusion protein was capable of inducing an Id-specific
humoral anti-tumor immunity protecting the animals from a subsequent
challenge with the Id-bearing tumor cells.39 The use of
soluble GM-CSF as an adjuvant induced a more efficient cellular
response against "self" tumor-associated protein antigens including idiotypes than did immunization without the addition of
GM-CSF in animal tumor models.40,41 In colorectal carcinoma patients immunized with recombinant carcinoembryonic antigen (rCEA), the rCEA-specific T- and B-cell responses were statistically
significantly enhanced by adding soluble GM-CSF compared with patients
immunized with rCEA alone.42
GM-CSF most likely acts by increasing the capacity to present tumor
antigens.43,44 GM-CSF is a major cytokine for stimulation of dendritic cells (DC). DC pulsed ex vivo with tumor-derived idiotypic
protein induced a cellular immune response and tumor regression in
patients with B-cell lymphomas.45 DC used as APC could
prime a strong CD8 CTL response in lymphocyte populations extensively
depleted of CD4+ T cells.46,47 Exogenous
antigens may use endogenous MHC class I antigen
presentation,9,48-50 and GM-CSF might activate a pathway of
antigen processing allowing exogenous soluble proteins to be presented
by MHC class I molecules.51 Thus, GM-CSF in addition to
augmenting antigen presentation might also contribute to the induction
of an MHC class I-restricted response as noted in our study. Moreover,
myeloma patients in clinical stages I and II seemed to exhibit an auto
T-cell immunity against the Id,23 part of which response
was confined to CD8 cells.52,53 Such a cellular immunity
might preferentially be boosted by immunization with the Id together
with GM-CSF.
In a previous study using the Id alone, 3 out of 5 patients mounted
only a weak transient anti-idiotypic T-cell response with no clinical
effects.22 In the present study, the induced T-cell immunity appeared to be long lasting, and in one of the patients a
reduction of the M-component concentration was noted. The reason(s) for
this single clinical effect is not known. A spontaneous regression, occuring simultaneously at the time of immunization, cannot be completely ruled out, although a reduction of the M-component concentration of such a magnitude and unrelated to treatment should be
a very rare event in multiple myeloma. Notably, this particular patient
developed upon immunization a gradually increasing and marked MHC class
I-restricted type I T-cell response, which persisted for 1 year during
unmaintained follow-up. Although a clinical effect in one single
individual needs to be confirmed, it seems however less likely that the
reduction of M-component concentration could be ascribed to GM-CSF.
GM-CSF has been reported to act as a growth factor for myeloma cell
lines in vitro,54 a notion which may be supported by
occasional clinical observations.55
Based on the present results, further studies on the clinical effects
of Id immunization in myeloma patients are warranted. It remains to be
shown whether human myeloma cells, in accordance to what has been shown
in B-cell lymphomas,2,3 can present endogenously derived
idiotypic peptides in the context of MHC molecules for recognition by T
cells. As immunogen the complete myeloma protein, single chain FV
personal molecules,56 or CDR peptides might be used as the
Id-specific T cell reactivity might preferentially be
located to CDR regions. The prefered clinical situation should be
monoclonal gammopathy of undetermined significance at risk, myeloma
stage I, or after chemotherapy with the intention to eradicate minimal
residual disease.
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FOOTNOTES |
Submitted February 19, 1997;
accepted November 16, 1997.
Supported by grants from the Cancer Society in Stockholm, the Swedish
Cancer Society, the King Gustav V Jubilee Fund, the Åke Winberg
Foundation, the Karolinska Institute Foundation, and the Swedish
Society for Cancer and Traffic Injuries.
Address reprint requests to Anders Österborg, MD, PhD,
Associate Professor, Department of Oncology (Radiumhemmet), Karolinska Hospital, S-171 76 Stockholm, Sweden.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
Wen He and Ingrid Eriksson are greatly acknowledged for expert
technical assistance and Lena Gahne for excellent typing of the
manuscript.
| |
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Abstract
Introduction
Abstract