Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

Abstract

Summary:Dendritic cell (DC) vaccination represents an interesting immunotherapeutic option in the treatment of several malignancies. In multiple myeloma (MM) patients, vaccination with autologous idiotype (Id) protein-pulsed DC is feasible, but their antitumoral effectiveness was rather limited. To improve the therapeutic potential of DC therapy, we studied the immunological effects of syngeneic peripheral blood stem cell transplantation (PBSCT) given in conjunction with Id-loaded DC. Balb/c mice were inoculated i.p. with 5 × 10 5 of HOPC myeloma cells (Balb/c origin). Animals were immunized with three injections of 5 × 10 5 DC pulsed with the IgG2a HOPC or with a control immunoglobulin (Ig control ). Some experimental groups of myeloma-bearing animals received total body irradiation (7.5 Gy) and a subsequent transplant of 2 × 10 7 syngeneic peripheral blood progenitor cells (PBPC) followed by DC therapy beginning at day 10 post transplant. Animals receiving DC therapy or syngeneic PBPCT alone neither induce longterm survival nor tumor-specific CTL reactivity in vitro. In marked contrast, combination of syngeneic PBPC transplantation and subsequent DC therapy resulted in 78% survival after a follow-up of 180 days. In addition, this treatment modality conferred a generation of Id peptide-specific CD8-mediated T cell reactivity. These data provide a rationale for DC-based vaccination in multiple myeloma patients administered post syngeneic transplantation. Multiple myeloma (MM) is a malignant plasma cell disorder derived from a B cell clone. 1 Median survival time of untreated MM patients is less than 1 year. Treatment with alkylating agents induces a clinical response in about 50% of the patients and prolongs survival to a median of approximately 3 years. Although autologous 2,3 or allogeneic stem cell transplantation 4 can improve the outcome in subgroups of patients, the course of MM is still almost invariably fatal. New therapeutic approaches to control or eradicate the malignant clone are definitely needed.The idiotype (Id) that is expressed on the immunoglobulin (Ig) produced by B cell lymphomas and myelomas is clonally restricted to tumour cells and thus can serve as a tumour-specific antigen. Early studies by Sirisinha and Eisen 5 and Lynch et al 6 showed that immunisation with purified Ig derived from a mineral oil-induced plasmacytoma (MOPC) induced anti-idiotypic immunity in syngeneic mice. These findings could be confirmed in several other B cell tumour models. [7][8][9] In most of these studies, anti-Id immunity was dependent on T cells rather than on anti-Id antibodies. Bogen et al have shown that Id-specific CD4 + T cells are essential for tumour protection in the MOPC myeloma model. 9-12 Several experimental and clinical data suggest that dendritic cells (DC) specialised to optimally present antigens can be used to enhance the antitumour T cell response. [13][14][15][16][17][18] In a murine B cell lymphoma model, Flamand et al 16 have shown that a specific anti-Id immunity can be generated in the h...

Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro‐metastasis

“…Although many remedies including alkylating agents, allogeneic stem cell transplantation, and glucocorticosteroids are used, MM in most patients will relapse and its curability is still almost uncertain [39][40][41][42]. New therapeutic approaches to control or eradicate MM are urgently needed.…”

Generation of Cytotoxic Responses in Mice and Human Individuals Against Hematological Malignancies Using Survivin-RNA-Transfected Dendritic Cells

“…For in vitro restimulation, bone marrow-derived DC were used as professional APC and generated as previously described (18). iDC were transfected using 50 g of DOTAP (Roche) and 25 g of in vitro-transcribed RNA or total RNA mixed in 500 l of Opti-MEM.…”

Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies

“…18,19 In brief, the T-cell-enriched nonadherent fraction of PBMCs obtained following the DC plastic adherence step was used for CTL generation. Nonadherent PBMCs were cultured in serum-free medium supplemented with 20 U/mL human IL-2 and 10 ng/mL human IL-7 (CellConcepts).…”