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IMMUNOBIOLOGY
From the Center for Genetic and Cellular Therapies,
Departments of Surgery, Immunology, and Pathology, Duke University
Medical Center, Durham, NC; the Department of Experimental
Transplantation and Immunology, Medicine Branch, Division of Clinical
Sciences, National Cancer Institute, Bethesda, MD; the Hematology
Branch, National Heart, Lung, and Blood Institute, Bethesda, MD; and
the Department of Medicine, University of Arkansas for Medical
Sciences, Little Rock, AK.
Immunoglobulin secreted by myeloma cells contains a unique
antigenic determinant (idiotype [Id]) that may serve as a
tumor-specific antigen. Although Id-protein-specific T-cell responses
have been reported in patients with myeloma, it is not known whether
primary myeloma tumor cells can present naturally processed Id peptides on their surface as a target. We immunized 2 healthy human stem-cell donors with Id proteins from their recipients. T cells from the immunized donors released high levels of T-helper 1-type cytokines in
response to stimulation with myeloma cells from their recipients. The
T-cell-mediated cytokine response to tumor cells was blocked by a
major histocompatibility complex (MHC) class I monoclonal antibody,
whereas the response to soluble Id protein was dependent on MHC class
II. To investigate whether Id-specific CD8+ T cells can
recognize and kill autologous myeloma cells, we generated T cells from
peripheral blood mononuclear cells from a third patient with myeloma by
means of in vitro stimulation with autologous dendritic cells pulsed
with Id protein. Tumor-specific lysis of myeloma cells was demonstrated
by the lack of killing of autologous nonmalignant B cells or natural
killer-sensitive K562 cells. Lysis of autologous myeloma targets was
restricted by MHC class I molecules. These data represent the first
report of class I-restricted T-cell recognition of fresh autologous
myeloma targets and formally demonstrate that human myeloma cells
can serve as targets of an Id-specific T-cell response.
(Blood. 2000;96:2828-2833) Multiple myeloma is a malignant disease
characterized by clonal proliferation of plasma cells in the bone
marrow. The monoclonal immunoglobulin (Ig) secreted by myeloma cells
may serve as a tumor-specific antigen because of the unique antigenic
structure in its variable regions (idiotype [Id]). In several
experimental models, it was shown that active immunization with
tumor-derived Ig induces protection against subsequent tumor
challenge.1-2 A central role for T-cell immunity was
suggested by the finding that the adoptive transfer of Id-specific
CD4+ T-cell clones produced resistance to challenge with
MOPC-315 plasmacytoma.3 In addition to anti-Id antibodies,
both Id-specific CD4 and CD8 T-cell responses have been found in
patients with myeloma.3-7 The feasibility of inducing
Id-specific immune responses by vaccinating patients who have myeloma
or B-cell lymphoma with Ig protein derived from their tumors has also
been demonstrated.8,9 Furthermore, Kwak and
colleagues10 reported that vaccination with Id conjugated
to a carrier resulted in activation of CD4+ T cells in a
bone marrow transplant donor and that such T-cell immunity could be
adoptively transferred to an HLA-matched recipient with myeloma.
However, there is no direct evidence indicating that Id-induced T cells
can directly lyse autologous myeloma cells. The inability to
demonstrate myeloma-specific lysis has been partly due to difficulty in
generating protein-specific cytotoxic T cells (CTLs). This technical
obstacle can now be overcome by using specialized antigen-presenting
cells (APCs) called dendritic cells (DCs) to induce CTLs in vitro.
DCs have attracted attention for use as adjuvants in active
immunotherapy of cancer. They are considered to be the most potent APC
because they express not only a high level of major histocompatibility complex (MHC) class II but also a variety of costimulatory molecules, such as CD80, CD86, CD40, CD58, and intracellular adhesion molecule 1. Furthermore, DCs can take up protein antigens from the extracellular environment and present antigenic peptides by means of both class I and class II pathways, which leads to activation of both CD4 T-helper
and CD8 CTLs.11 Taking advantage of the potency of DCs in
promoting CTL responses, we used DCs pulsed with Id protein as a
stimulator to establish a CTL line from the peripheral blood of a
patient with myeloma.
We here demonstrate the recognition of freshly isolated myeloma targets
by class I-restricted T cells obtained from 2 healthy HLA-matched
donors vaccinated with their recipient's Id protein and
granulocyte-macrophage colony-stimulating factor (GM-CSF) in vivo. We
also report the lysis of myeloma tumor targets by an Id-specific CTL
line generated in vitro in a fully autologous system.
Donors and samples
RE, a healthy, fully HLA-matched, 33-year-old male sibling T-lymphocyte
donor, was immunized against the Id protein purified from his
recipient's plasma after informed consent was obtained. During a
6-month period, he received a series of 4 immunizations with 0.5 mg
purified Ig protein, either free or conjugated with KLH, administered
with GM-CSF (250 µg/m2) daily 4 times. Whole blood
collected before vaccination and 1 month after the final vaccination
was the source of T cells for assays against the recipient's tumor
cells. Tumor cells from the recipient were collected from a bone marrow
aspirate obtained at relapse that consisted of 35% to 50% malignant
plasma cells on morphologic evaluation.
Patients and samples
Myeloma Id proteins
T-cell-mediated tumor-specific cytokine responses PBMC (2.5 × 106) obtained from donors before or after vaccination were cultured for 5 days with either medium (RPMI 1640 with 10% National Cancer Tissue Culture 109, 10% fetal bovine serum, 2 mmol/L glutamine, 50 µmol/L 2-mercaptoethanol, 100 µmol/L nonessential amino acids, 1 mmol/L sodium pyruvate, 100 U/mL penicillin, and 100 mg/mL streptomycin), 5 × 104 plasmacytoma/myeloma tumor cells from the recipient, normal B cells from the recipient isolated from PBMC by FACS using a fluoresceinated monoclonal antibody (MoAb) against the light chain not represented in the Id protein (Caltag, Burlingame, CA), myeloma Id protein from the recipient, or an isotype-matched control Id protein (50 µg/mL each) each in the presence or absence of 50 µg/mL anti-MHC class I
or II (G46-2.6 and Tu39, respectively; PharMingen, San Diego, CA) or
control MoAb (MARG 2c-3; Sigma, St Louis, MO). Tumor cells were
pretreated with the MoAbs for 16 hours before coculturing with PBMC.
Supernatants were harvested, and cytokine release was measured by using
enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems,
Minneapolis, MN).
Generation of DCs DCs from patient HR were generated by following a protocol described previously.12 Briefly, PBMC were plated at 6 × 106 cells/mL in 15 mL serum-free AIM V medium in T75 flasks (Costar, Cambridge, MA). After 2 hours of incubation at 37°C, nonadherent cells were removed by gentle rinsing and cryopreserved for later use as responders in T-cell induction. The remaining adherent cells were cultured in AIM V medium with GM-CSF (800 U/mL) and interleukin (IL)-4 (500 U/mL) (Genzyme, Cambridge, MA) for 6 days at 37°C in 5% carbon dioxide. The resulting cells were harvested and confirmed to be DCs on the basis of their unique morphologic and phenotypic characteristics. The DCs were mainly large cells with cytoplasmic projections, and they often formed clumps. On FACS analysis, they brightly expressed CD11c, CD86, and HLA-DR but were negative for CD14 and other lineage markers.Pulsing of DCs and induction of CTLs DCs were washed twice in serum-free AIM V medium before being pulsed with Id protein from patient HR. DCs (1 × 106) were incubated with the Id protein (100 µg/mL) in 1 mL AIM V medium at 37°C for 6 hours or overnight. For induction of CTLs, DCs (2 × 105/well) pulsed with the protein were cocultured with autologous nonadherent PBMC (5 × 106/well) in complete RPMI 1640 medium containing 10% fetal bovine serum. The T-cell culture was restimulated every 7 to 10 days with the same number of pulsed DCs in the presence of IL-2 (5 U/mL) and IL-7 (10 ng/mL) (Genzyme).T-cell-mediated autologous tumor cytotoxicity Five days after restimulation with DCs pulsed with Id protein, the T cells derived from patient HR were recovered and used as effectors in either a 4-hour chromium 51 (51Cr) release assay or a 12-hour indium 111 (111In) release assay. Unmanipulated autologous plasmacytoma or normal B cells were labeled with either 51Cr (NEN, Boston, MA) or 111In-oxine (MPI Pharmacy/Amersham, Arlington Heights, IL) and plated (5000 cells/well) in triplicate with effector cells in 96-well U-bottom microtiter plates. The plasmacytoma targets were also pretreated with 50 µg/mL anti-MHC class I (G46-2.6) or control MoAb (R2B-8; Sigma) for 2 hours, washed, and then used in the CTL assay described above at various ratios of effector to target (E/T). Data are reported as the mean (± SEM) percentage of specific lysis at each E/T ratio. All SEMs were under 5%. The percentage of specific lysis was calculated as follows: [(experimental release / maximum release) (spontaneous release / maximum release)] × 100. The
spontaneous release was 30% in the 51Cr release assay and
35% and 23%, respectively, in the first and second 111In
release assays.
Analysis of intracellular cytokine and T-cell-phenotype by FastImmune assay After 2 in vitro stimulations with DCs pulsed with Id protein, the antigen specificity and phenotype of the T-cell culture derived from patient HR were analyzed simultaneously by FastImmune assay.13 Briefly, effector cells were coincubated with stimulators at a ratio of 5 to 1 at 37°C. Autologous tumor cells were used as stimulators, and autologous PBMC were used as control stimulators. Two hours later, Brefeldin A (BFA) (Sigma) was added at the final concentration of 10 µg/mL to block secretion of cytokines. Cells were then incubated at 37°C for an additional 3 hours in the presence of BFA, washed, and fixed with 1% paraformaldehyde. Fixed cells were permeabilized and triple stained with conjugated antibodies of CD69-phosphatidylethanolamine, CD4-peridinin chlorophyll protein (PerCP) or CD8-PerCP, and interferon- (IFN-)-fluorescein
isothiocyanate, conjugated (FITC) or tumor necrosis factor-
(TNF-)-FITC (Becton Dickinson, Mountain View, CA). Cell samples
were analyzed by a FACScalibur cytometer (Becton Dickinson). Both
CD4+ and CD8+ T-cell populations were gated on
and examined for their expression of CD69 and intracellular
cytokine (IFN-).
Tumor-specific T cells induced by immunization of HLA-matched donors with myeloma Id in vivo We examined T-cell responses in PBMC isolated directly from healthy, HLA-matched, stem-cell transplant donors who had been vaccinated against their recipient's myeloma Id protein according to a clinical protocol designed to raise and transfer tumor-specific T-cell immunity from healthy donors.10 Figure 1 shows the results for donor SG. As expected, PBMC obtained before vaccination of this donor showed no significant response to stimulation with the recipient's myeloma cells (<15 ng/L IFN-, GM-CSF, and
TNF-). However, after vaccination, PBMC responded to tumor
stimulation with markedly increased production of all 3 cytokines
(IFN-, 49 ng/L; GM-CSF, 680 ng/L; and TNF-, 150 ng/L) compared
with the medium control (Figure 1A). Furthermore, PBMC did not respond to simulation by normal B cells from the recipient, suggesting that
these responses were tumor specific. In addition, the tumor-specific cytokine responses were abrogated by anti-MHC class I MoAb (< 15 ng/L
IFN-, GM-CSF, and TNF-) but not by anti-MHC class II MoAb
(IFN-, 52 ng/L; GM-CSF, 703 ng/L; and TNF-, 210 ng/L), indicating
that T-cell recognition of myeloma tumor cells was restricted by class
I molecules. These results also suggest that the tumor-specific T-cell
response was a direct effect of Id vaccination in vivo, since PBMC
obtained before vaccination failed to produce any cytokine response.
In parallel, PBMC obtained from donor SG after vaccination were tested for response to the immunizing Id protein. The data shown in Figure 1B demonstrate the detection of Id-specific T cells, which responded to stimulation with myeloma Id protein from the recipient but not an isotype-matched myeloma Id protein (control Id). Furthermore, the response to soluble myeloma Id protein was abrogated when an anti-MHC class II MoAb, but not an anti-MHC class I MoAb, was added, suggesting that in contrast to the class I-restricted responses to intact myeloma tumor cells, the Id-specific response was restricted by class II molecules. Comparable results were obtained with T cells derived from a second
immunized donor (RE). Specifically, PBMC obtained after vaccination but
not those obtained before vaccination produced a significant amount of
IFN-
Tumor-specific CTLs induced by DCs pulsed with myeloma Id in a fully autologous system Nonadherent PBMC from patient HR were restimulated in vitro with autologous DCs pulsed with Id protein purified from his plasma. After repeated stimulation, a T-cell line (designated as HR) was established and subsequently tested for cytotoxicity against unmodified, cryopreserved autologous plasmacytoma cells by using either a 51Cr release assay (Figure 3A) or an 111In release assay (Figure 3B). FACS analysis showed that the T-cell line was composed of 74% CD3+ cells, 21% CD8+ cells, and 69% CD4+ cells (data not shown). The T cells effectively lysed autologous tumor cells (51% specific lysis at 25:1 E/T ratio). Natural killer-sensitive K562 cells were lysed only at low levels (Figure 3A). Furthermore, autologous normal B cells were not lysed by the T cells (5% at E/T ratio 25:1; Figure 3B), suggesting that the lysis was tumor specific. Moreover, the cytotoxicity of autologous tumor cells was almost completely blocked by pretreatment with an anti-MHC class I MoAb but not an isotype-matched control MoAb. These results indicate that the tumor-specific cytotoxic activity was mediated by class I-restricted CTLs.
T-cell-mediated autologous tumor-specific cytokine responses The HR T-cell line was also tested for its ability to recognize autologous tumor cells in a cytokine-release assay. TNF- production
was measured by ELISA in the supernatant from the T-cell line
cocultured with autologous tumor cells for 6 days. For unknown reasons,
relatively high levels of cytokine release were observed with both T
cells alone and tumor cells alone. However, compared with T cells or
tumor cells alone, T cells cocultured with the tumor cells produced
significantly higher levels of TNF- (Figure 4). Moreover, this tumor cell-induced
response was inhibited by the addition of an anti-MHC class I
MoAb.
Analysis of intracellular cytokine and T-cell phenotype by FastImmune assay The antigen specificity and T-cell phenotype of the HR T cells were analyzed simultaneously by using a FastImmune assay. Figure 5 shows that autologous tumor cells stimulated a significant percentage of both CD8 and CD4 T cells (13% of the CD8 and CD69 double-positive cell population and 9% of the CD4 and CD69 double-positive cell population, respectively) to secrete IFN-. In contrast, only background levels of CD8+ cells
and CD4+ cells (3.7% and 3.3%, respectively) were
activated by autologous PBMC controls. These results provide
independent evidence that in vitro stimulation of PBMC by DCs pulsed
with Id protein can induce CD8+ T cells that are specific
for autologous myeloma cells.
Successful development of a human tumor-specific antigen as a therapeutic T-cell vaccine requires at least 2 criteria. First, the candidate antigen must be shown to be immunogenic in human patients, either in vitro or in vivo. Equally important, however, is the demonstration that the tumor-cell target is capable of expressing the antigen in the form of peptide bound to MHC molecules at the cell surface. Id protein isolated from patients with myeloma may be considered an ideal antigen for immunotherapy because of the uniqueness of its idiotypic determinants and the fact that sufficient amounts of such proteins are easily obtainable from serum or urine. Previously, we and others showed that myeloma Id can be immunogenic for induction of a T-cell response against idiotypic determinants, either autologously in patients9 or in HLA-matched donors.10 The current study extends the observation of immunogenicity of this tumor antigen in vitro (patient HR) and in vivo (donors SG and RE) and, for the first time, establishes that autologous myeloma cells can serve as targets of a T-cell response directed against this antigen. Specifically, strong tumor-specific and class I-restricted cytokine responses mediated by T cells were detected in PBMC from 2 healthy HLA-matched T-cell donors previously vaccinated in vivo with KLH-conjugated myeloma Id derived from the tumors of their respective recipient and GM-CSF (Figures 1A and 2A). As internal controls, these T cells were shown to recognize the idiotypic determinant of the myeloma Id protein, a response that was blocked by anti-MHC class II antibodies (Figures 1B and 2B). Such class II-restricted T-helper cells may be required for the generation and maintenance of the class I-restricted T-cell response. GM-CSF may be a critical component of this vaccine formulation for generation of CD8+ T-cell immunity. Previous studies in animal models demonstrated the ability of paracrine GM-CSF, either by gene delivery to tumor cells14 or as free cytokine with defined tumor antigens,15 to generate tumor-specific CD8+ T-cell responses. GM-CSF probably acts by recruiting professional APCs, including DCs, which may activate pathways of antigen processing that allow exogenous proteins to be presented by MHC class I molecules. Alternatively, the ability of PBMC from patient HR to develop
autologous tumor cytotoxicity was observed after stimulation with DCs
pulsed with autologous myeloma Id protein ex vivo. Unlike the 2 donors,
patient HR was not deliberately vaccinated with Id protein.
Nevertheless, antigen-specific precursor T cells that could be expanded
in vitro were presumably present. The resulting T cells showed strong
cytotoxicity against autologous tumor cells but no cytotoxicity against
autologous nonneoplastic B cells. The tumor-specific cytotoxicity was
restricted by MHC class I molecules, since it was blocked by anti-MHC
class I MoAbs (Figure 3). The T cells also released type 1 cytokines
(IFN- Although class I-restricted CD8+ T cells played a predominant effector role against tumor cells, CD4+ T-helper cells were also observed in all 3 patients. Although the Id-specific T-helper cells were detected on stimulation with Id protein (Figures 1B and 2B), they were not directly reactive to tumor cells, since the cytokine response to tumor cells was not blocked by anti-MHC class II antibody (Figures 1A and 2A). One explanation for this finding is that Id-specific T-helper cells may play a role in the induction phase but not in the effector phase. For example, in the induction phase, CD4 T cells could facilitate in vivo induction of effector CD8+ T cells by the release of cytokines.16,17 It is also possible that the CD4+ T cells and CD8+ T cells recognize different antigenic epitopes on the Id protein. Similarly, CD4+ T cells that responded to secreted Id protein that was taken up, processed, and presented by APCs in the plasmacytoma tumor mass may have been detected (Figure 5). For a study designed to ask the question of whether the tumor-cell
target expresses the candidate tumor antigen at its surface, 2 potential sources of autologous myeloma cells must be considered. Homogeneous human myeloma cell lines can occasionally be established in
immunodeficient mice by serial passage.16 However, fresh unmanipulated plasmacytoma cells are a better source for determining whether T cells elicited by vaccination in vivo or in vitro can recognize expression of the target antigen in its native form on
autologous tumor cells. For example, the autologous HR tumor targets
used were isolated from a solid plasmacytoma mass composed of at least
50% malignant plasma cells. The precise nature of the target antigen
at the surface of these tumor cells recognized by Id-induced T cells
remains to be elucidated. The neoplastic plasma cells in myeloma
generally do not express intact Ig at the cell surface. Rather, the
consistent observation of the blocking of T-cell recognition of myeloma
cell targets by pretreatment with anti-MHC class I antibodies in all 3 patients studied strongly suggests T-cell recognition of an idiotypic
peptide-MHC class I complex on the surface of the tumor cell.
Consistent with this hypothesis, murine T-cell clones were found to be
specific for a peptide comprising amino acids 91 to 101 of the
CTLs are a critical component of antitumor immunity; therefore, a highly desirable goal of cancer vaccines is to develop novel approaches that will elicit potent, tumor-specific CTLs. DCs are considered to be the most potent APC, and both CD4+ and CD8+ T cells can be induced by antigen-loaded DCs.11 The requirement for T-cell immunity is highlighted in studies of multiple myeloma because any antibody response would be expected to be neutralized by the excess of circulating antigen in vivo. The finding of potent CTLs induced in vitro by stimulation with DCs pulsed with myeloma Id strongly supports the use of DCs as adjuvants in active in vivo immunotherapy with myeloma Id in patients with myeloma. Finally, the demonstration that myeloma tumor cells can express idiotypic determinants in such a way that they can be recognized as targets by Id-specific T cells raises the possibility of adoptive immunotherapy strategies using ex vivo expanded, antigen-specific CTLs from patients with myeloma (autologous CTLs) or from HLA-matched healthy T-cell donors.
We thank Dr Eli Gilboa for helpful discussions and Michelle St. Peter, Jong-Hee Nam, and Kevin Provost for technical assistance.
Submitted November 22, 1999; accepted June 14, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Larry W. Kwak, Building 567, Room 205, National
Cancer Institute
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Y. Deng, Y. Jing, A. E. Campbell, and S. Gravenstein Age-Related Impaired Type 1 T Cell Responses to Influenza: Reduced Activation Ex Vivo, Decreased Expansion in CTL Culture In Vitro, and Blunted Response to Influenza Vaccination In Vivo in the Elderly J. Immunol., March 15, 2004; 172(6): 3437 - 3446. [Abstract] [Full Text] [PDF]
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M. Grube, K. Rezvani, A. Wiestner, H. Fujiwara, G. Sconocchia, J. J. Melenhorst, N. Hensel, G. E. Marti, L. W. Kwak, W. Wilson, et al. Autoreactive, Cytotoxic T Lymphocytes Specific for Peptides Derived from Normal B-Cell Differentiation Antigens in Healthy Individuals and Patients with B-Cell Malignancies Clin. Cancer Res., February 1, 2004; 10(3): 1047 - 1056. [Abstract] [Full Text] [PDF]
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H. K. Lyerly Tackling T-cell tumors Blood, October 1, 2003; 102(7): 2313 - 2313. [Full Text] [PDF]
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L. Hansson, H. Rabbani, J. Fagerberg, A. Osterborg, and H. Mellstedt T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma Blood, June 15, 2003; 101(12): 4930 - 4936. [Abstract] [Full Text] [PDF]
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T. Rasmussen, L. Hansson, A. Osterborg, H. E. Johnsen, and H. Mellstedt Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells Blood, June 1, 2003; 101(11): 4607 - 4610. [Abstract] [Full Text] [PDF]
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E. Orsini, R. Bellucci, E. P. Alyea, R. Schlossman, C. Canning, S. McLaughlin, P. Ghia, K. C. Anderson, and J. Ritz Expansion of Tumor-specific CD8+ T Cell Clones in Patients with Relapsed Myeloma after Donor Lymphocyte Infusion Cancer Res., May 15, 2003; 63(10): 2561 - 2568. [Abstract] [Full Text] [PDF]
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C. Milazzo, V. L. Reichardt, M. R. Muller, F. Grunebach, and P. Brossart Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA Blood, February 1, 2003; 101(3): 977 - 982. [Abstract] [Full Text] [PDF]
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 M. V. Dhodapkar, J. Krasovsky, and K. Olson T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells PNAS, October 1, 2002; 99(20): 13009 - 13013. [Abstract] [Full Text] [PDF]
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G. Dotti, B. Savoldo, P. Yotnda, D. Rill, and M. K. Brenner Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40+ and CD40- plasmacytoma cells Blood, June 17, 2002; 100(1): 200 - 207. [Abstract] [Full Text] [PDF]
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J. Gong, S. Koido, D. Chen, Y. Tanaka, L. Huang, D. Avigan, K. Anderson, T. Ohno, and D. Kufe Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12 Blood, April 1, 2002; 99(7): 2512 - 2517. [Abstract] [Full Text] [PDF]
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M. Gorschluter, C. Ziske, A. Glasmacher, and I. G. H. Schmidt-Wolf Current Clinical and Laboratory Strategies to Augment the Efficacy of Immunotherapy in Multiple Myeloma Clin. Cancer Res., August 1, 2001; 7(8): 2195 - 2204. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
-light chain variable region of MOPC-315 bound to an MHC class II
molecule,