Tregs activated by bispecific antibodies

Koristka, Stefanie; Cartellieri, Marc; Arndt, Claudia; Feldmann, Anja; Seliger, Barbara; Ehninger, Gerhard; Bachmann, Michael

doi:10.4161/2162402x.2014.994441

Cited by 9 publications

(5 citation statements)

References 10 publications

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“…Considering the clinical safety observed following systemic γδ T-cell activation and γδ T ACT, specific engagement of γδ T-cells using γδ bsTCEs might have an improved safety profile due to their tumor selectivity compared to CD3-bsTCEs. By avoiding detrimental co-activation of regulatory CD3 + T-cells observed with CD3 pan T-cell engagers ( 93 ) and their ability to bridge and engage components of both the innate and adaptive immune system, γδ bsTCEs could potentially result in increased antitumor activity.…”

Section: Present and Future Studies Involving γδ T-cellsmentioning

confidence: 99%

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

et al. 2022

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γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.

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Section: Present and Future Studies Involving γδ T-cellsmentioning

confidence: 99%

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

et al. 2022

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“…In this work, we have extended our QSP model by adding a module describing TCE immunotherapy and applied it to colorectal cancer in human. As an important feature of TCEs, the activation of both effector T cells (Teffs) and regulatory T cells (Tregs) is included in this model (25). Taken together, this extended model aims to provide understanding of the complex processes and identify important biomarkers associated with the outcomes of TCE treatment.…”

Section: Introductionmentioning

confidence: 99%

A Quantitative Systems Pharmacology Model of T Cell Engager Applied to Solid Tumor

Wang

Sové

et al. 2020

AAPS J

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Cancer immunotherapy has recently drawn remarkable attention as promising results in the clinic have shown its ability to improve the overall survival, and T cells are considered to be one of the primary effectors for cancer immunotherapy. Enhanced and restored T cell tumoricidal activity has shown great potential for killing cancer cells. Bispecific T cell engagers (TCEs) are a growing class of molecules that are designed to bind two different antigens on the surface of T cells and cancer cells to bring them in close proximity and selectively activate effector T cells to kill target cancer cells. New T cell engagers are being investigated for the treatment of solid tumors. The activity of newly developed T cell engagers showed a strong correlation with tumor target antigen expression. However, the correlation between tumor-associated antigen expression and overall response of cancer patients is poorly understood. In this study, we used a well-calibrated quantitative systems pharmacology (QSP) model extended to bispecific T cell engagers to explore their efficacy and identify potential biomarkers. In principle, patient-specific response can be predicted through this model according to each patient’s individual characteristics. This extended QSP model has been calibrated with available experimental data and provides predictions of patients’ response to TCE treatment.

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“…42 However, their cytotoxic potential remains controversial, as another group observed no direct cytotoxicity by human CD4 + CD25 + CD127 low cells. 43,44 Even if T-BsAb-activated Treg cells have cytotoxic potential, either by TCR-mediated killing or by death receptor-ligand interaction, their immunosuppressive activity would outweigh their tumoricidal activity, as supported by our results showing the benefit of transient ablation of Treg cells in the preclinical model. For therapeutically targeting Treg cells, anti-CD38 monoclonal antibodies (daratumumab and isatuximab) have the ability to deplete CD38 + Treg cells, 14,17 although the expression of CD38 can also be upregulated on activated effector lymphocytes.…”

Section: Discussionmentioning

confidence: 53%

Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy

Casey,

Lee,

Kwok

et al. 2023

haematol

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T cell-engaging bispecific antibodies (T-BsAbs) have shown impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that the complex interplay between immune cells and tumor cells is implicated in the mechanism of action, and thus, understanding immune regulatory mechanisms might provide a clue for improving the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In the myeloma preclinical model, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-BCMA T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to IL-10 production and inhibition of T-BsAb-mediated CD8 T cell responses. The activation of Treg cells was also seen in myeloma patients-derived bone marrow samples after ex vivo treatment with T-BsAb, further supporting the impact of T-BsAb on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, therapy-induced activation of Treg cells critically regulates antitumor immunity elicited by T-BsAb therapy, providing important implications for improving the efficacy.

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Tregs activated by bispecific antibodies

Cited by 9 publications

References 10 publications

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

A Quantitative Systems Pharmacology Model of T Cell Engager Applied to Solid Tumor

Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy

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