Anti‐Tumour Activity of Idiotype‐Specific, MHC‐Restricted Th1 and Th2 Clones <i>In Vitro</i> and <i>In Vivo</i>

Lauritzsen, Grete F.; Weiß, Siegfried; Bogen, Bjarne

doi:10.1111/j.1365-3083.1993.tb01668.x

Cited by 37 publications

(29 citation statements)

References 58 publications

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“…The observation is in agreement with some previous studies showing that the Id produced by malignant B cells contains tumor-specific protein sequences that stimulated CD4 ϩ and CD8 ϩ T cells. [23][24][25][26][27][28][29] Furthermore, the cytokine release by the CTLs was analyzed by the ELISPOT assay. The production of a significant amount of IFN-␥ and TNF-␣ was observed when the CTLs were restimulated with Id-pulsed DCs.…”

Section: Discussionmentioning

confidence: 99%

Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells

Wen

Barlogie

2001

Blood

116

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Section: Discussionmentioning

confidence: 99%

Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells

Wen

Barlogie

2001

Blood

116

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“…In the MOPC-315 plasmocytoma model, Bogen and coworkers showed that the adoptive transfer of a CD4 + T cell clone specific for a defined peptide of the -light chain variable region of the Ig MOPC-315 elicited specific antitumoral effects. 12 As expected, Id-primed CD4 + T cells did not exhibit relevant cytotoxicity against the myeloma target in a chromium release assay in our model. It cannot be ruled out that T helper cells support CD8 effector cells by releasing type 1 cytokines (IFN-␥, GM-CSF and TNF-␣) and may act by inflammatory cytokine effects on nonhematopoietic cells, as shown by Qin and Blankenstein.…”

Section: Discussionmentioning

confidence: 61%

“…[9][10][11][12]17 In spite of the fact that the vast majority of myelomas failed to express MHC class II molecules, CD4 + T cells may play an important role in tumour immunity. Qin and Blankenstein 31 recently showed that cellular immunity against MHC class II negative tumours can be mediated by CD4 + T cells through an IFN-␥-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Bogen et al have shown that Id-specific CD4 + T cells are essential for tumour protection in the MOPC myeloma model. [9][10][11][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 host by immunisation with DC loaded in vitro with the Id protein.…”

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confidence: 99%

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

Zeis

Frenzke

Schmitz

et al. 2002

Bone Marrow Transplant

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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...

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“…The first TAA identified was the idiotype (Id) of the immunoglobulin (Ig) expressed in malignant B cells, [1][2][3] and Id vaccination strategies induce specific humoral and cellular immune responses that can lead to tumor regression or rejection. [4][5][6][7][8][9][10] A bioinformatics approach has been applied to the identification of T-cell epitopes from a variety of candidate TAAs, including proteinase 3, 11 MUC-1, 12 melanoma antigen 3, 13 and telomerase, 14 as well as the Id of malignant B cells. 15,16 A conceptual drawback to targeting Id has been the need to create an individualized reagent for each patient.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide

Zirlik

Zahrieh

Neuberg

et al. 2006

Blood

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Heteroclitic peptide modifications increase immunogenicity, allowing generation of cytotoxic T lymphocytes (CTLs) against weakly immunogenic tumor-associated antigens (TAAs). A critical issue is whether T cells generated against heteroclitic peptides retain the ability to recognize and kill tumor cells expressing the original weak TAAs, and whether there is a lower threshold of binding affinity of the native peptides, below which such CTLs can still kill primary tumor cells. To examine this we used a model examining the ability of native and heteroclitic immunoglobulin (Ig)-derived peptides to generate CTLs that can kill chronic lymphocytic leukemia (CLL) cells. We demonstrate that CTLs generated against heteroclitic peptides have enhanced killing of CD40-activated B cells pulsed with either heteroclitic (P < .001) or native peptide (P ‫؍‬ .04) and primary CLL cells (P ‫؍‬ .01). The novel finding reported here is that the rate-limiting factor appears to be the ability to generate CTLs and that once generated, CTL lysis of primary tumor cells is independent of the binding affinity of the native peptide. These findings have implications for vaccination strategies in malignancies and are currently being further examined in vivo in murine models. IntroductionA primary requirement for successful tumor vaccine development is the identification of tumor-associated antigens (TAAs). The first TAA identified was the idiotype (Id) of the immunoglobulin (Ig) expressed in malignant B cells, [1][2][3] and Id vaccination strategies induce specific humoral and cellular immune responses that can lead to tumor regression or rejection. [4][5][6][7][8][9][10] A bioinformatics approach has been applied to the identification of T-cell epitopes from a variety of candidate TAAs, including proteinase 3, 11 MUC-1, 12 melanoma antigen 3, 13 and telomerase, 14 as well as the Id of malignant B cells. 15,16 A conceptual drawback to targeting Id has been the need to create an individualized reagent for each patient. In chronic lymphocytic leukemia (CLL), subsets of patients have been identified with remarkably similar antigen receptors, [17][18][19][20][21][22] and shared Ig framework region (FR)-derived peptides represent important targets for cross-reactive Id therapy, offering the advantage of a less patient-specific immunotherapeutic strategy in B-cell malignancies. 16 A major limitation of this method is the generally low immunogenicity and low binding affinity of these peptides to major histocompatibility complex (MHC) class I and class II molecules. Heteroclitic peptide modifications can increase immunogenicity of low-binding peptides while leaving T-cell recognition residues intact, 23 and these "heteroclitic peptides" lead to improved ability to generate cytotoxic T lymphocyte (CTL) responses against primary tumors. 15,24,25 Heteroclitic modifications as a strategy to enhance immune responses have been tested in several tumor antigens, 26,27 and agonist analogs of subdominant epitopes, once optimized for binding class I molecules, c...

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Anti‐Tumour Activity of Idiotype‐Specific, MHC‐Restricted Th1 and Th2 Clones In Vitro and In Vivo

Cited by 37 publications

References 58 publications

Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells

Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells

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

Cytotoxic T cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide

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