Gene therapy of B‐cell lymphoma with cytokine gene‐modified trioma cells

Strehl, John; Selmayr, Michael; Kremer, J.-P.; Hültner, Lothar; Lindhofer, Horst; Mocikat, Ralph

doi:10.1002/(sici)1097-0215(19990924)83:1<113::aid-ijc20>3.3.co;2-a

Cited by 5 publications

(7 citation statements)

References 13 publications

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“…DCs were prepared by culturing bone marrow (BM) precursors from C57BL/6 mice in RPMI 1640 supplemented with 20% FCS, 2 mmol/L L-glutamine, 100 U/mL penicillin and streptomycin, 50 μmol/L 2-mercaptoethanol, sodium pyruvate and nonessential amino acids in the presence of 100 ng/mL granulocytemacrophage colony-stimulating factor (GM-CSF) (18) …”

Section: Cell Lines Preparation Of T Cells and Generation Of Dcsmentioning

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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Section: Cell Lines Preparation Of T Cells and Generation Of Dcsmentioning

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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“…For preparation of DCs, bone marrow cells were harvested from BALB/c wild-type or CD40 Ϫ/Ϫ mice or from C57BL/6 mice and cultured in standard medium in the presence of 100 ng/mL recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF). 29 Medium was replaced every 2 days, and a maturation step was performed at day 8 by adding 1 g/mL lipopolysaccharide (LPS) for 16 hours. If not otherwise indicated, only mature DCs were used in the experiments.…”

mentioning

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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199

180

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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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“…However, for retro-and adenoviral vectors, expression levels considerably varied from cell line to cell line. It was also shown that even minute levels of GM-CSF expression are sufficient to induce effective tumor protection in in vivo model systems, 50,51 which makes GM-CSF one of the most potent immunostimulatory reagents in gene therapy. In melanoma models, GM-CSF evoked highest levels of costimulatory molecules on DCs, indicative of greatly improved functional maturation.…”

Section: Discussionmentioning

confidence: 99%

“…12 In a clinical setting, immunotherapy with GM-CSF genemodified tumor cells has also been evaluated. 49 To our knowledge, B-cell lymphomas with the exception of B-CLL cells have been transduced with GM-CSF and used as cellular vaccines to induce systemic antitumor effects, 50,53 indicating that GM-CSF is beneficial in certain malignancies in which relevant tumorassociated antigens are commonly not known. GM-CSF in our study ranks as a model cytokine demonstrating the efficient, B-cell-specific gene transfer of a potent immunostimulatory gene in conjunction with novel EBV vectors, which underscores the feasibility and proof of our concept.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus vector-mediated gene transfer into human B cells: potential for antitumor vaccination

Hellebrand

Mautner²,

Reisbach

et al. 2005

Gene Ther

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The efficient gene transfer of immunostimulatory cytokines into autologous tumor cells or the transfer of tumor-associated antigens into professional antigen-presenting cells is a prerequisite for many immunotherapeutic approaches. In particular with B cells, the efficiency of gene uptake is one of the limiting factors in cell-based vaccine strategies, since normal and malignant human B cells are commonly refractory to transducing gene vectors. Due to its natural tropism for human B cells, Epstein-Barr virus (EBV), a human herpes virus, might be an option, which we wanted to explore. EBV efficiently infects human B cells and establishes a latent infection, while the viral genome is maintained extrachromosomally. Although these characteristics are attractive, EBV is an oncogenic virus. Here, we present a novel EBV-derived vector, which lacks three EBV genes including two viral oncogenes and an essential lytic gene, and encodes granulocyte-macrophage colony-stimulating factor (GM-CSF) as a cytokine of therapeutic interest. We could show that EBV vectors efficiently transduce different B-cell lines, primary resting B cells, and tumor cells of B-cell lineage. Vectorderived GM-CSF was expressed in sufficient amounts to support the maturation of dendritic cells and their presentation of model antigens to cognate T-cell clones in autologous settings and an allogeneic, HLA-matched assay. We conclude that the EBV vector system might offer an option for ex vivo manipulation of B cells and gene therapy of B-cell lymphomas. Gene Therapy (2006) 13, 150-162.

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Gene therapy of B‐cell lymphoma with cytokine gene‐modified trioma cells

Cited by 5 publications

References 13 publications

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

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

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

Epstein–Barr virus vector-mediated gene transfer into human B cells: potential for antitumor vaccination

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