Impact of the lymphoma idiotype on in vivo tumor protection in a vaccination model based on targeting antigens to antigen-presenting cells

Kronenberger, Konrad; Dieckmann, Andreas; Selmayr, Michael; Strehl, John; Wahl, Ulrich; Lindhofer, Horst; Kraal, Georg; Mocikat, Ralph

doi:10.1182/blood.v99.4.1327

Cited by 13 publications

(21 citation statements)

References 19 publications

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“…These data indicate that treatment with the trifunctional bsAb mounted a polyvalent cellular response. It has been reported by our group and others that polyvalent antitumor immunity is superior to monoclonal responses (42,45,46). Therefore, the immunizing effect of trifunctional bsAbs provides the invaluable advantage that tumor immune escape, for example, by selection of antigen loss variants, is less likely to occur.…”

Section: Discussionmentioning

confidence: 94%

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

et al. 2012

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A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcg receptors (FcgR), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab 0 ) 2 -counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-g in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab 0 ) 2 -fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity.

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Section: Discussionmentioning

confidence: 94%

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

et al. 2012

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“…33 In our attempt to modify ex vivo-generated DCs to present tumor-derived antigenic peptides, we noticed that syngeneic bone marrow-derived DCs protected 100% of mice against a subsequent challenge with a lethal dose of A20 cells even when the DCs were not loaded with tumor-derived Ags (Figure 1). This robust and reproducible protection was not due to priming against culture medium components and was not observed using the syngeneic lymphoma MPC11 (Figure 1) or the colon carcinoma CT26 (not shown).…”

Section: Unpulsed Dcs Activate Nk Cells To Reject the A20 B-cell Lympmentioning

confidence: 99%

DC-NK cell cross talk as a novel CD4+ T-cell–independent pathway for antitumor CTL induction

Adam¹,

King

Allgeier

et al. 2005

Blood

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It is generally accepted that priming of antitumor CD8 ؉ cytotoxic T lymphocytes (CTLs) needs help that can be provided by CD4 ؉ T cells. We show that interactions between dendritic cells (DCs) and natural killer (NK) cells can bypass the T helper arm in CTL induction. Bone marrow-derived DCs caused rejection of the A20 lymphoma and induced tumor-specific long-term memory, although they were not loaded with tumor-derived antigen. Experiments using CD40 ؊ knock-out mice and cell depletion showed that this effect did not require CD4 ؉ cells. Both primary rejection and long-term CTL memory were the result of NK cell activation by DCs. NK cytotoxicity, which was necessary for primary rejection, was dependent on expression of natural killer group 2 D (NKG2D) ligands on tumor cells. Blocking of these ligands using NKG2D tetramers abrogated tumor killing in vitro and in vivo. The long-term response was due to CTLs directed against antigen(s) expressed on A20 and in vitrodifferentiated DCs. The mechanism leading to CD4 ؉ helper cell-independent CTL responses was elucidated as a cascade that was initiated by NK cell activation. This pathway was dependent on interferon-␥ expression and involved priming endogenous DCs for interleukin-12 production. Our data suggest a novel pathway linking innate and adaptive immunity. ( IntroductionInduction of efficient immune responses requires a coordinated interplay between innate and adaptive immune effector systems. Dendritic cells (DCs) are components of the innate immune system that activate specific effectors of adaptive immunity. 1,2 In an immature state, DCs are able to ingest antigen (Ag). Following a maturation process that involves migration to lymphoid tissues, down-regulation of Ag uptake and upregulation of major histocompatibility complex (MHC) and costimulatory molecules, DCs present antigenic peptides to T lymphocytes. 1 Exogenous proteins are taken up and processed by DCs and presented to CD4 ϩ cells in association with MHC class II molecules, whereas intracellular Ags are presented by MHC class I molecules to CD8 ϩ cytotoxic T lymphocytes (CTLs). There is, however, emerging evidence that exogenous proteins can also be directed to the endogenous presentation pathway, thus leading to CTL induction, a process referred to as cross-presentation. Efficient generation of CTLs from naive CD8 ϩ T cells needs help from CD4 ϩ T cells. [3][4][5] This help involves secretion of cytokines and CD40/CD40L interactions that lead to increased expression of costimulatory molecules on DCs and to induction of interleukin-12 (IL-12). 6 As shown in mouse models, CD4 ϩ T cells are pivotal for protection against tumors and can even mediate tumor rejection independently of CD8 ϩ T lymphocytes, if they are biased toward a T helper 1 (Th1) response. 7 Expression of CD40 by DCs is crucial for the production of Th1 cytokines such as IL-12 and for tumor protection. 7,8 Natural killer (NK) cells are effector cells of the innate immune system that exert direct cytotoxic functions. 9 These are determ...

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“…Numerous antitumor vaccination protocols have been elaborated on the basis of transfer of DCs that were generated in vitro and pulsed with tumor-derived proteins or peptides or transduced with TAA-encoding gene constructs (2)(3)(4). However, immunization against a single antigen can result in selection of antigen loss mutants and is therefore inferior to polyvalent, whole cell-based immunization strategies where even yet-unidentified antigens can be included (5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Potential of the Trifunctional Bispecific Antibody Surek Depends on Dendritic Cells: Rationale for a New Approach of Tumor Immunotherapy

Eißler

Mysliwietz

Deppisch

et al. 2013

Mol Med

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Trifunctional bispecific antibodies (trAbs) used in tumor immunotherapy have the unique ability to recruit T cells toward antigens on the tumor cell surface and, moreover, to activate accessory cells through their immunoglobulin Fc region interacting with activating Fcγ receptors. This scenario gives rise to additional costimulatory signals required for T cell-mediated tumor cell destruction and induction of an immunologic memory. Here we show in an in vitro system that most effective trAb-dependent T-cell activation and tumor cell elimination are achieved in the presence of dendritic cells (DCs). On the basis of these findings, we devise a novel approach of cancer immunotherapy that combines the specific advantages of trAbs with those of DC-based vaccination. Simultaneous delivery of trAbs and in vitro differentiated DCs resulted in a markedly improved tumor rejection in a murine melanoma model compared with monotherapy.

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Impact of the lymphoma idiotype on in vivo tumor protection in a vaccination model based on targeting antigens to antigen-presenting cells

Cited by 13 publications

References 19 publications

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

DC-NK cell cross talk as a novel CD4+ T-cell–independent pathway for antitumor CTL induction

Potential of the Trifunctional Bispecific Antibody Surek Depends on Dendritic Cells: Rationale for a New Approach of Tumor Immunotherapy

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