Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Baur, Andreas S.; Lutz, Manfred B.; Schierer, Stephan; Beltrame, Luca; Theiner, Gabi; Zinser, Elisabeth; Ostalecki, Christian; Heidkamp, Gordon F.; Haendle, Ina; Erdmann, Michael; Wiesinger, Manuel; Leisgang, Waltraud; Groß, Stefanie; Pommer, Ansgar J.; Kämpgen, Eckhart; Dudziak, Diana; Steinkasserer, Alexander; Cavalieri, Duccio; Schuler‐Thurner, Beatrice; Schuler, Gerold

doi:10.1182/blood-2012-09-456988

Cited by 55 publications

(41 citation statements)

References 47 publications

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“…A recent study even reported induction of tolerance following Ontak therapy. 36 Similar to the observations in the murine studies, results in patients may have been confounded by the co-depletion of tumor-reactive effector T cells.…”

Section: Introductionsupporting

confidence: 62%

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

et al. 2014

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C regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3 C Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8C T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.

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Section: Introductionsupporting

confidence: 62%

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

et al. 2014

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“…Whether β-catenin in DCs adversely affects antitumor efficacy of human DC vaccines has not been investigated. Interestingly, in a clinical trial of a DC cancer vaccine against melanoma in combination with regulatory T-cell depletion with unexpected reduced efficacy, DCs were shown to exhibit increased expression of β-catenin and a tolerogenic phenotype (44), suggesting that activation of β-catenin in human DCs might similarly suppress their function and therefore blocking β-catenin could potentially provide therapeutic benefit. Our findings that β-catenin in DCs exerts opposite functions during different phases of …”

Section: Discussionmentioning

confidence: 99%

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8⁺T cells through regulation of IL-10

Liang

Cui

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4+ and CD8+ T-cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8+ T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8+ T-cell immunity. However, vaccination of DC–β-catenin−/− (CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC–β-catenin−/− mice were deficient in generating CD8+ T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by β-catenin−/− DCs. Deletion of β-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8+ T cells, suggesting that β-catenin in DCs plays a positive role in CD8+ T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for β-catenin–dependent inhibition of cross-priming, but also uncovered an unexpected positive role that β-catenin plays in maintenance of CD8+ T cells. Despite β-catenin’s opposite functions in regulating CD8+ T-cell responses, selectively blocking β-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8+ T-cell immunity and improved antitumor efficacy, suggesting manipulating β-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.

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“…In contrast, Treg-depleting drugs appeared to have paradoxical immunologic effects that could impair the activity of DC vaccination (e.g., depletion of NK cells, induction of tolerogenic DCs, and promotion of nonactivated Treg survival; ref. 69).…”

Section: Combinations To Combat Tolerance Induced By Immunosuppressivmentioning

confidence: 99%

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

Bol

Schreibelt

Gerritsen

et al. 2016

Clinical Cancer Research

312

245

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Dendritic cell (DC) vaccination in cancer patients aims to induce or augment an effective antitumor immune response against tumor antigens and was first explored in a clinical trial in the 1990s. More than two decades later, numerous clinical trials have been performed or are ongoing with a wide variety of DC subsets, culture protocols, and treatment regimens. The safety of DC vaccination and its ability to induce antitumor responses have clearly been established; however, although scattered patients with long-term benefit were reported, DC vaccines have not yet fulfilled their promise, perhaps mainly due to the lack of large-scale well-conducted phase II/III trials. To allow meaningful multicenter phase III trials, the production of DC vaccines should be standardized between centers which is now becoming feasible. To improve the efficacy of DC-based immunotherapy, it could be combined with other treatments.

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Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Abstract: Key Points• ONTAK blocks DC maturation by coreceptor downmodulation and inhibition of Stat3 phosphorylation to induce a tolerogenic phenotype.• ONTAK kills activated CD4T cells but stimulates antiapoptosis in resting T reg by engagement and stimulation through CD25.

Cited by 55 publications

References 47 publications

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8⁺T cells through regulation of IL-10

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

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Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Abstract: Key Points• ONTAK blocks DC maturation by coreceptor downmodulation and inhibition of Stat3 phosphorylation to induce a tolerogenic phenotype.• ONTAK kills activated CD4T cells but stimulates antiapoptosis in resting T reg by engagement and stimulation through CD25.

Cited by 55 publications

References 47 publications

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+T cells through regulation of IL-10

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

Contact Info

Product

Resources

About

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8⁺T cells through regulation of IL-10