Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity

Hombach, Andreas; Kofler, David M.; Rappl, Gunter; Abken, Hinrich

doi:10.1038/gt.2009.75

Cited by 65 publications

(46 citation statements)

References 27 publications

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“…At least when T regs were coinjected with effector T cells in an animal model the tumor growth was clearly accelerated by T regs in the presence of a bispecific co-ligating ab and not improved [133]. Moreover, T regs transduced with a chimeric antigen receptor were also capable to restore tumor growth [137]. Thus, according to these studies it appears rather unlikely that T regs have a major contribution in killing of tumor cells after cross-linkage via bispecific abs.…”

Section: Mechanism Of Action Of the Bispecific Antibodiesmentioning

confidence: 85%

Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs

Stamova¹,

Koristka²,

Keil³

et al. 2012

Antibodies

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Immunotherapy has emerged as an alternative strategy to treat malignancies in addition to conventional radio- and chemotherapy. There has been a plethora of evidence that the immune system is able to control tumor outgrowth and a number of strategies have been put forward to utilize this ability for immunotherapy. However, some of these strategies have not been very efficient and their success has been limited by tumor evasion mechanisms. A promising approach to engage effector cells of the immune system overcoming some of the escape mechanisms has been introduced more than two decades ago. This approach is based on bispecific antibodies. Here we summarize the evolution of bispecific antibodies, their improvement, remaining obstacles and some controversial reports.

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Section: Mechanism Of Action Of the Bispecific Antibodiesmentioning

confidence: 85%

Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs

Stamova¹,

Koristka²,

Keil³

et al. 2012

Antibodies

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“…Actually, this novel finding of conditional regulation by Tregs in our model fits well with unexplained and apparently conflicting observations in previous studies. For instance, in several solid tumor models, where tumors usually reside outside the bone marrow, Tregs were consistently shown to hamper antitumor immunity (9)(10)(11)30). In contrast, in murine allo-transplantation models, in which hematologic tumors often reside in the bone marrow, Tregs did not hamper the GVT effect (7,8).…”

Section: Discussionmentioning

confidence: 99%

Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells

Guichelaar

Emmelot

Rozemuller

et al. 2013

Clinical Cancer Research

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Purpose: Regulatory T cells (Tregs) are potent tools to prevent graft-versus-host disease (GVHD) induced after allogeneic stem cell transplantation or donor lymphocyte infusions. Toward clinical application of Tregs for GVHD treatment, we investigated the impact of Tregs on the therapeutic graft-versus-tumor (GVT) effect against human multiple myeloma tumors with various immunogenicities, progression rates, and localizations in a humanized murine model.Experimental Design: Immunodeficient Rag2 À/À gc À/À mice, bearing various human multiple myeloma tumors, were treated with human peripheral blood mononuclear cell (PBMC) alone or together with autologous ex vivo cultured Tregs. Mice were analyzed for the in vivo engraftment, homing of T-cell subsets, development of GVHD and GVT. In additional in vitro assays, Tregs that were cultured together with bone marrow stromal cells were analyzed for phenotype and functions.Results: Treatment with PBMC alone induced variable degrees of antitumor response, depending on the immunogenicity and the growth rate of the tumor. Coinfusion of Tregs did not impair the antitumor response against tumors residing within the bone marrow, irrespective of their immunogenicity or growth rates. In contrast, Tregs readily inhibited the antitumor effect against tumors growing outside the bone marrow. Exploring this remarkable phenomenon, we discovered that bone marrow stroma neutralizes the suppressive activity of Tregs in part via production of interleukin (IL)-1b/IL-6. We furthermore found in vitro and in vivo evidence of conversion of Tregs into IL-17-producing T cells in the bone marrow environment.Conclusions: These results provide new insights into the Treg immunobiology and indicate the conditional benefits of future Treg-based therapies.

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“…One possible approach is the generation of genetically modified Tregs, which express an artificial TCR against a desired Ag (e.g., Refs. 19,41,42). Still, the most efficient methods for the genetic manipulation of T cells make use of virus-mediated gene transfer, which bears the risk of effecting the expression of oncogenes or tumor-suppressor genes (43).…”

Section: Discussionmentioning

confidence: 99%

Retargeting of Human Regulatory T Cells by Single-Chain Bispecific Antibodies

Koristka

Cartellieri

Theil

et al. 2012

The Journal of Immunology

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Bispecific Abs hold great potential for immunotherapy of malignant diseases. Because the first components of this new drug class are now entering clinical trials, all aspects of their mode of action should be well understood. Several studies proved that CD8+ and CD4+ effector T cells can be successfully redirected and activated against tumor cells by bispecific Abs both in vitro and in vivo. To our knowledge, this study provides the first evidence that bispecific Abs can also redirect and activate regulatory T cells against a surface Ag, independently of their TCR specificity. After cross-linking, via a bispecific Ab, redirected regulatory T cells upregulate the activation markers CD69 and CD25, as well as regulatory T cell-associated markers, like CTLA-4 and FOXP3. The activated regulatory T cells secrete the immunosuppressive cytokine IL-10, but, in contrast to CD8+ and CD4+ effector T cells, almost no inflammatory cytokines. In addition, the redirected regulatory T cells are able to suppress effector functions of activated autologous CD4+ T cells both in vitro and in vivo. Therefore, the potential risk for activation of regulatory T cells should be taken into consideration when bispecific Abs are applied for the treatment of malignant diseases. In contrast, an Ag/tissue-specific redirection of regulatory T cells with bispecific Abs holds great potential for the treatment of autoimmune diseases and graft rejection.

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Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity

Cited by 65 publications

References 27 publications

Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs

Cancer Immunotherapy by Retargeting of Immune Effector Cells via Recombinant Bispecific Antibody Constructs

Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells

Retargeting of Human Regulatory T Cells by Single-Chain Bispecific Antibodies

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