Abstract 936: Targeting TNFR2 for cancer immunotherapy: Ligand blocking depletors versus receptor agonists

Mårtensson, Linda; Cleary, Kirstie L.S.; Semmrich, Monika; Kovacek, Mathilda; Holmkvist, Petra; Svensson, Caroline; Demiri, Mimoza; Blidberg, Therese; Thornberg, Ulla-Carin; Pitic, Vincentiu; Dadas, Osman; Lim, Sean H.; Beers, Stephen A.; Cragg, Mark S.; Frendéus, Björn; Teige, Ingrid

doi:10.1158/1538-7445.am2020-936

Cited by 6 publications

(10 citation statements)

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“…They reported an antitumor effect on several cancer types using the murine version and found corresponding activity of human agonist TNFR2 antibodies that could be used in patients. • Encouraging unpublished results were also presented at the AACR annual meetings in 2020 and 2021, regarding advances in both agonists and antagonists targeting TNFR2 and tested in the context of cancer (Mårtensson et al, 2020;Chen et al, 2021).…”

Section: Therapeutic Perspectives Current State Of Clinical-grade Therapeutic Toolsmentioning

confidence: 99%

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The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

Moatti

Cohen

2021

Front. Cell Dev. Biol.

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Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.

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Section: Therapeutic Perspectives Current State Of Clinical-grade Therapeutic Toolsmentioning

confidence: 99%

“…Encouraging unpublished results were also presented at the AACR annual meetings in 2020 and 2021, regarding advances in both agonists and antagonists targeting TNFR2 and tested in the context of cancer ( Mårtensson et al, 2020 ; Chen et al, 2021 ).…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

Moatti

Cohen

2021

Front. Cell Dev. Biol.

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“…BI-1910 is another agonist anti-TNFR2 mAb in development following promising results from a surrogate anti-mouse TNFR2 antibody; this mAb induced strong anti-tumor responses in several pre-clinical tumor models and was effectively combined with checkpoint blockade antibodies. The dominant mechanism of action was expansion of CD8 + T cells and improved CD8 + to Treg ratio in the tumor site ( 143 ). BI-1808 is an alternative TNFR2 targeting mAb, classified as a deleting, ligand blocking molecule.…”

Section: Targeting Tnfr2mentioning

confidence: 99%

Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives

2023

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The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients.

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“…In a preclinical study, the anti-TNFR2 antibody BI-1808 demonstrated potent antitumor efficacy in CT26, MC38, and B16 cancer models as a single agent or in combination with an anti-PD-1 antibody. BI-1808 depleted early tumor-infiltrating Tregs and induced promotion of Teffs at the tumor site, which improved the ratio of CD8 + Teffs to Tregs and tumor regression ( 95 ). Currently, BI-1808 is being studied in Phase I/II clinical trials.…”

Section: Antibody-based Immunotherapies Targeting Tumor-infiltrating ...mentioning

confidence: 99%

Antibody-based cancer immunotherapy by targeting regulatory T cells

et al. 2023

Front. Oncol.

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Regulatory T cells (Tregs) are among the most abundant suppressive cells, which infiltrate and accumulate in the tumor microenvironment, leading to tumor escape by inducing anergy and immunosuppression. Their presence has been correlated with tumor progression, invasiveness and metastasis. Targeting tumor-associated Tregs is an effective addition to current immunotherapy approaches, but it may also trigger autoimmune diseases. The major limitation of current therapies targeting Tregs in the tumor microenvironment is the lack of selective targets. Tumor-infiltrating Tregs express high levels of cell surface molecules associated with T-cell activation, such as CTLA4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor superfamily members including 4-1BB, OX40, and GITR. Targeting these molecules often attribute to concurrent depletion of antitumor effector T-cell populations. Therefore, novel approaches need to improve the specificity of targeting Tregs in the tumor microenvironment without affecting peripheral Tregs and effector T cells. In this review, we discuss the immunosuppressive mechanisms of tumor-infiltrating Tregs and the status of antibody-based immunotherapies targeting Tregs.

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Abstract 936: Targeting TNFR2 for cancer immunotherapy: Ligand blocking depletors versus receptor agonists

Cited by 6 publications

References 0 publications

The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives

Antibody-based cancer immunotherapy by targeting regulatory T cells

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