Haematologica 2003 - Supplements

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To explore the possibility of using myeloma cells, which may contain a multitude of tumor antigens that can stimulate an increased repertoire of anti-tumor T cells, as the source of tumor antigens for immunotherapy, myeloma-specific CTLs were generated from patients by culturing T cells with autologous DCs pulsed with myeloma freeze-and-thaw cell lysate. These CTL lines proliferated in response to autologous primary myeloma cells and DCs pulsed with autologous, but not allogeneic, tumor lysate and secreted predominantly IFN- and TNF-. The CTLs had strong cytotoxic activity against autologous tumor lysate-pulsed DCs and primary myeloma cells. Interestingly, some of the CTLs killed, to a lesser degree, autologous Id-pulsed DCs and allogeneic myeloma cells, suggesting that Id was sometimes a part of tumor antigens present in the tumor lysate and that there were shared tumor antigens between patients. No killing of autologous peripheral blood mononuclear cells, purified B cells, or Epstein-Barr virustransformed B-cell lines was observed. These data demonstrate that CTLs induced by tumor lysate-pulsed DCs specifically kill autologous tumor cells, but not normal blood cells, and provide a rationale for vaccination with tumor cell-pulsed DCs in myeloma patients. To evaluate the anti-myeloma effects of specific CTLs in vivo, a myeloma SCID-hu host was established by inoculation of a myeloma cell line, ARK-RS, into the implanted human bones in the mice. After myeloma was established, defined by the appearance in mouse serum of human Ig secreted by the tumor cells, an ARK-RSspecific CTL line was injected into the tumor sites. Adoptive transfer of specific T cells, but not control CTLs, strongly suppressed tumor growth in vivo. Eight weeks after tumor inoculation, control mice and mice received control CTLs had large tumors (5-10 g) around the implanted human bones, while specific CTL-treated mice had no visible tumor mass or circulating human Ig. Two weeks after the final injection, circulating human T cells were still detected in the circulation, indicating that human T cells survived in the host. These findings indicate that myeloma-specific CTLs can control or even eradicate tumor cells in vivo. In conclusion, our studies demonstrate that Id- and tumor lysatespecific CTLs can be generated from myeloma patients. These CTLs killed specifically primary myeloma cells but not normal blood cells in vitro. Adoptive transfer of myeloma-specific CTLs could eradicate tumor cells in SCID-hu host. Thus, our studies have laid the basis for adoptive immunotherapy in myeloma patients using these CTLs, which may be able to eradicate myeloma cells without causing tissue damage. References Yi Q, Österborg A, Bergenbrant S, Mellstedt H, Holm G, Lefvert AK. Idiotype-reactive T subsets and tumor load in monoclonal gammopathies. Blood 86:3043-3049, 1995. Yi Q, Dabadghao S, Österborg A, Bergenbrant S, Holm G. Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. Blood 90:1960-1967, 1997. Wen YJ, Barlogie B, Yi Q. Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells. Blood 97:1750-1755, 2001. Wen YJ, Min R, Tricot G, Barlogie B, Yi Q. Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy. Blood 99:3280-3285, 2002. Supported by grants from the National Cancer Institute (RO1- CA96569) and Multiple Myeloma Research Foundation and McCarty Cancer Foundation, and by Translational Research Grants from the Leukemia and Lymphoma Society (6548-00 and 6041- 03). P13.5 VACCIBODIES: A NOVEL APPROACH FOR ID VACCINATION Agnete Brunsvik, Inger Sandlie and Bjarne Bogen Institute of Immunology, University of Oslo, Rikshospitalet, 0027 Oslo, Norway. e-mail: bjarne.bogen@labmed.uio.no Bogen lab: http://www.immunol.net/ Immunoglobulins (Ig) have highly diversified variable (V) regions that contain unique antigenic determinants called idiotopes (Id). Idiotype vaccination is promising in treatment of B cell lymphomas and multiple myelomas, and both anti-idiotypic antibodies and Id-specific T cells may be of importance (1). However, Id is a weak self-antigen in its original context (as part of Ig). Therefore, for vaccine purposes, it is important to enhance the immunogenicity of Id. To this end, we have now designed a novel type of recombinant Ig-like molecules called Vaccibodies, which hopefully induce both strong Id-specific Ab and T cell responses. The Vaccibodies consist of two scFv’s derived from the myeloma protein M315 connected through Cγ3 domains and a hinge to two scFv’s with specificity for MHC class II molecules expressed on APC (Fig 1). Fig 1 Legend Fig 1. The structure of the Vaccibody. The two scFvs (top) target the Vaccibody to surface molecules on APC. The two patient-derived M-component scFvs are at the bottom. The two types of Fv are connected by a hinge and C H 3 domains. The hinge contributes to flexibility of the two NH 2 -terminal scFvs relative orientation and offers disulfide bridges between the monomers. The C H 3 domains act as a spacer between the NH 2 and COOH terminal scFvs and participate in the dimerization through hydrophobic interactions. Vaccibodies have been prepared for use in the MOPC315 mouse myeloma model in which Id-specific CD4 + T cells protect mice against myeloma development (2-5). The Vaccibodies have been genetically constructed, and transfected NSO cells produce and secrete the recombinant molecules. The Vaccibodies appear to have a correct structure. In particular, the scFv’s at each end of the Vaccibodies exhibit binding to MHC class II and DNP (specificity of M315), respectively. Thus, the domains retain the same folding pattern as in their original context. The Vaccibodies have been constructed to induce strong T cell responses. The produced Vaccibodies are designed to bind MHC class II + APC and, subsequent to endocytosis and antigen processing, be presented as Id-peptides on class II molecules to Id-specific CD4 + T cells. Furthermore, since they have intact Fv of the M- component, they should bind anti-Id B cells and, with the help of Id-specific T cells, induce differentiation of such B cells into plasma cells that produce anti-Id antibodies. Moreover, the Vaccibodies lack the Cγ2 domains and hence the FcγR binding sites, and should therefore exclusively be taken up by MHC class II and not by FcRs on APC. We have compared class II-specific Vaccibodies with hapten (NIP)-specific Vaccibodies as a negative (nontargeted) control. Initial experiments in BALB/c S86
mice demonstrate that class II-specific Vaccibodies are much more potent at inducing anti-Id 315 antibodies than are NIPspecific Vaccibodies. Moreover, class II-specific Vaccibodies are 100-1000 fold more potent on a per molecule basis at inducing proliferation of Id 315 -specific CD4 + T cells in vitro compared to NIP-specific Vaccibodies. Tumor challenge experiments with MOPC315 are yet to be performed. The plasmids encoding Vaccibodies allow for easy exchange of targeting and patient Fv. Thus, the strategy should be easy to extend to new targeting specificities and new patient Fvs. Refs. 1. King CA, Spellerberg MB, Zhu D, Rice J, Sahota SS, Thompsett AR, Hamblin TJ, Radl J, Stevenson FK (1998). DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat Med 11:1281-6 2. Lauritzsen G.F, Weiss S, Dembic Z, and Bogen B (1994) Naive idiotype-specific CD4 + T cells and immunosurveillance of B cell tumors. Proc Natl Acad Sci USA 91:5700-5704 3. Bogen, B (1996) Peripheral T cell tolerance as a tumor escape mechanism. Deletion of CD4 + T cells specific for a monoclonal Ig idiotype secreted by a plasmacytoma. Eur J Immunol 26:2671 4. Dembic,Z, Schenk, K., Bogen, B (2000). Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate CD4 + T cells. Proc.Natl. Acad. Sci (U.S.A). 97:2697-2702. 5. Dembic, Z., Røttingen, J-A, Dellacasagrande, J. Schenk, K., Bogen, B(2001). Phagocytic dendritic cells from myelomas activate tumor-specific T cells at a single cell level. Blood, 97:2808-2814 S87
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Focussed Symposia Arsenic trioxide
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assess whether such a program will
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The overall response rate was noted
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Figure 5A Table 1: VEL + THAL for R
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naturally occurring OPG. Present tr
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0.505). Finally, the multiple event
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CLINICOPATHOLOGICAL DEFINITION OF W
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Plenary Sessions 1. Development of
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clonotypic IgH VDJ signature confir
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can be considered as two entities,
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immunofluorescence staining for DKK
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P2.3 DEVELOPMENT OF A MULTIPLE MYEL
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P2.5 MOLECULAR CYTOGENETICS OF MYEL
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clear that the biggest challenge fo
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esponse and have demonstrated that
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variable region of the idiotypic im
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4. From MGUS to symptomatic MM Fig.
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(MRI); some have claimed that level
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P4.5 CYTOKINES IN MGUS: THERAPEUTIC
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preventing phosphorylation of p70S6
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transducing component of the interl
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Page 45 and 46: quiescent counterpart, the human um
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Page 49 and 50: manifestations and anomalous protei
Page 51 and 52: P7.4 ROLE OF SERUM FREE LIGHT CHAIN
Page 53 and 54: P7.6 IMMUNOPHENOTYPIC INVESTIGATION
Page 55 and 56: presumably through the circulation,
Page 57 and 58: 9. Chemotherapy, maintenance treatm
Page 59 and 60: stratified according to their antim
Page 61 and 62: explore higher doses of zoledronic
Page 63 and 64: initial therapy. However, the role
Page 65 and 66: P10.2.2 SINGLE VERSUS TANDEM HIGH D
Page 67 and 68: With a median follow-up of 38 month
Page 69 and 70: cells could be harvested following
Page 71 and 72: 11. What is the role of allogeneic
Page 73 and 74: found that 75% of patients who were
Page 75 and 76: patients with responsive disease 3
Page 77 and 78: 9. Giralt S, Estey E, Albitar M, et
Page 79 and 80: Badros A, Barlogie B, Siegel E, et
Page 81 and 82: Figure 3b. Event-free Survival 4-Ye
Page 83 and 84: improve patient outcome in MM. Impo
Page 85 and 86: myeloma and in 40% of previously un
Page 87 and 88: degrade OPG in the same way as myel
Page 89 and 90: P12.2.5 MONOCLONAL ANTIBODY THERAPY
Page 91 and 92: myeloma. Blood 2001; 98:210-216. 6.
Page 93: MHC molecules, in effectively prese
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Page 99 and 100: hypothesis that (1) CCND1 and FGFR3
Page 101 and 102: patient samples. In addition, the p
Page 103 and 104: 016 NEUTRAL ENDOPEPTIDASE (CD10) KN
Page 105 and 106: 2. Genetic heterogeneity in MM: imp
Page 107 and 108: evidence from two t(11;14) cases wh
Page 109 and 110: immunoglobulin heavy chain (IgH) lo
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Page 113 and 114: clusters were found, the first was
Page 115 and 116: MGUS but most likely not crucial fo
Page 117 and 118: Objective: To compare the impact on
Page 119 and 120: 4 patients had MMSET/IgH but did no
Page 121 and 122: and clonal PC from MGUS, MM and PCL
Page 123 and 124: 059 VEGF receptor expresion in Mult
Page 125 and 126: two HLA-A2+ myeloma patients with C
Page 127 and 128: molecules expressed on the surface
Page 129 and 130: Recognition of these antigens appea
Page 131 and 132: Diagnosis requires a single area of
Page 133 and 134: 081 Incidence of solid tumors in co
Page 135 and 136: Growth Factor (VEGF), Hepatocyte Gr
Page 137 and 138: PC-AI levels of MGUS and SMM patien
Page 139 and 140: 093 The predominant pathway of tran
Page 141 and 142: was associated with I.V. line, whil
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5. Signal transduction pathways and
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integrin in IGF-1-triggered MM cell
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118 IL-6- Induced Phosphorylation o
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123 THE IGF/IGF-1R SYSTEM IS A MAJO
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human myeloma cell line (HMCL) to a
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ligation or dexamethasone (Georgii-
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6. Role of microenvironment 6.1 Cel
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141 Human myeloma cells adhere to f
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145 STUDY OF BONE MARROW ANGIOGENES
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patients, the growth of primary mye
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tibia (con=49.1±0.7mg/cm2 vs 5T2=4
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157 The Nitrogen-Containing Bisphos
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7. New prognostic criteria for clas
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atio of >3. This system has subdivi
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Patient 1 (IgG/κ);IgG - 16.5 days,
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176 Pro-inflammatory and angiogenic
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180 Clinical study on the bone lesi
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7.2 Imaging studies 185 99mTc-MIBI
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189 Factors Predicting Occult Spina
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vivo detected resonances was invest
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Support Unit (CTSU) with flexibilit
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(β2m) & C reactive protein (CRP).
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plasmids carrying the clonotypic in
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newly diagnosed multiple myeloma as
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216 Transgenic expression of Myc an
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221 Prolonged survival in the 5T2MM
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9. Chemotherapy, maintenance, treat
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229 EFFECTIVENESS OF STANDARD CHEMO
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234 Melphalan and Dexamethasone- Is
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Methods. We investigated the VECD p
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9.2 Renal complications. 243 MERIT
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cost of SRE-related care was $10,24
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those with Hb >13 g/dL. Analysis of
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sustained response, lasting from 52
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proportion of bone abnormality. IgD
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disease. The lack of response to in
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yielding a median of 3x106/kg CD34
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patients(pts) aged ≥60 yrs. We co
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PBSC mobilizing regimen utilizing C
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their leukocytes and platelets. No
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25 Gy to marrow. The tracer dose wa
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non-CR after the first transplant a
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296 PERIPHERAL BLOOD STEM CELL TRAN
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References Effect of dose-intensive
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with cyclosporine A and methotrexat
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11.Role of novel therapies targetin
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312 Thalidomide as Rescue of Relaps
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patients, light chain in 1 patients
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platelets of 207 (76-402), B2M of 3
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325 Low Dose Thalidomide plus Dexam
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in 5 pts (11%), M protein decreased
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time from diagnosis was 3.7 years a
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339 Thalidomide, Clarithromycin and
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344 COMBINATION OF THALIDOMIDE, DEX
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experienced early death during the
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untreated patients with high tumor
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357 Thalidomide protects endothelia
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362 EOSINOPHILIA IS A VERY COMMON F
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11.5 CC 4047, PS 341 and arsenic tr
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without chromosome 13. Mean IC50 fo
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myeloma patients. Phase I data indi
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11.6 Other drugs 380 EFFECT OF STI5
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significant inhibition of cell prol
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which acts to prevent the synthesis
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of B and its metabolites, however,
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and 10 months after start of therap
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terminal kinase (JNK) pathway which
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lymphocytes was tested by Ellispot.
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411 Dendritic Cell-Based Idiotype V
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Author Index Abe M 74 160 Abelman W
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De La Serna J 291 De Laurenzi A P11
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Hull DR 338 Hullen C P10.2.1 Humes
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Morra E 249 280 359 Morris CM 226 M
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Siegel D 70 115 250 Sierra J 304 30
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