Harnessing co-stimulatory TNF receptors for cancer immunotherapy: Current approaches and future opportunities

Waight, Jeremy D.; Gombos, Randi; Wilson, Nicholas S.

doi:10.3233/hab-160308

Cited by 21 publications

(20 citation statements)

References 216 publications

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“…Therapeutic immunoglobulin (IgG)-based monoclonal antibodies (mAbs) elicit a range of functional activities, many of which can be fine-tuned by optimizing the interaction of the fragment crystallizable gamma receptor (FcγR) region, with FcγRs expressed on immune and non-immune cell populations (Kim and Ashkenazi, 2013; Offringa and Glennie, 2015; Waight et al, 2017). Two broad subclasses of FcγRs, activating and inhibitory, interact with therapeutic mAbs (Nimmerjahn et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

et al. 2018

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SUMMARY The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

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Section: Introductionmentioning

confidence: 99%

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

et al. 2018

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“…However, efficient activation of the receptors often requires receptor clustering induced by binding of more than one ligand displayed on the cell membrane. 10,11 Here, antibodies are limited due to their bivalent binding mode and require binding to nearby Fcγ receptor-bearing cells for clustering and signal induction.…”

Section: Introductionmentioning

confidence: 99%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

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“…In a mouse ovarian tumor model, the combination of GITR ligation and PD1 blockade induced potent antitumor immunity and tumor regression, while anti‐GITR or anti‐PD1 antibodies alone did not have any therapeutic effect . Several clinical studies in cancer patients are currently studying combinatorial targeting of GITR and the PD1/PDL1 pathway . Addition of nivolumab alone enhanced ex vivo TIL responses to a similar extent as GITRL (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, in addition to activating intra‐tumoral T‐cell responses, targeting co‐stimulatory receptors can stimulate systemic anti‐tumor immunity which may protect against tumor recurrence . Currently, antibodies targeting different co‐stimulatory receptors are being evaluated in clinical trials for several types of solid cancer …”

Section: Introductionmentioning

confidence: 99%

“…15 Currently, antibodies targeting different co-stimulatory receptors are being evaluated in clinical trials for several types of solid cancer. 16,17 One of the co-stimulatory receptors under active clinical investigation in solid malignancies is CD357, TNF receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR). We have previously revealed that tumor-infiltrating T cells in HCC are functionally compromised.…”

Section: Introductionmentioning

confidence: 99%

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GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

Beek

Zhou

Doukas

et al. 2019

Intl Journal of Cancer

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No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti‐PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co‐inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co‐stimulatory receptors might be able to stimulate anti‐tumor immunity in HCC is as yet unknown. We investigated whether agonistic targeting of the co‐stimulatory receptor GITR could reinvigorate ex vivo functional responses of tumor‐infiltrating lymphocytes (TIL) freshly isolated from resected tumors of HCC patients. In addition, we compared GITR expression between TIL and paired samples of leukocytes isolated from blood and tumor‐free liver tissues, and studied the effects of combined GITR and PD1 targeting on ex vivo TIL responses. In all three tissue compartments, CD4 + FoxP3 + regulatory T cells (Treg) showed higher GITR − expression than effector T‐cell subsets. The highest expression of GITR was found on CD4 + FoxP3 hi CD45RA − activated Treg in tumors. Recombinant GITR‐ligand as well as a humanized agonistic anti‐GITR antibody enhanced ex vivo proliferative responses of CD4 + and CD8 + TIL to tumor antigens presented by mRNA‐transfected autologous B‐cell blasts, and also reinforced proliferation, IFN‐γ secretion and granzyme B production in stimulations of TIL with CD3/CD28 antibodies. Combining GITR ligation with anti‐PD1 antibody nivolumab further enhanced tumor antigen‐specific responses of TIL in some, but not all, HCC patients, compared to either single treatment. In conclusion, agonistic targeting of GITR can enhance functionality of HCC TIL, and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC.

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Harnessing co-stimulatory TNF receptors for cancer immunotherapy: Current approaches and future opportunities

Cited by 21 publications

References 216 publications

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

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