Tumor Cells Expressing Anti-CD137 scFv Induce a Tumor-Destructive Environment

Yang, Yi; Yang, Shilin; Ye, Zhengmao; Jaffar, Jade; Zhou, Yifeng; Cutter, Erin; Lieber, André; Hellström, Ingegerd; Hellström, Karl Erik

doi:10.1158/0008-5472.can-06-3593

Cited by 41 publications

(35 citation statements)

References 29 publications

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“…Triggering of CD137 by agonistic antibodies and aptamers as well as tumor-expressed CD137 ligand (CD137L) potently stimulates T-cell antitumor immunity. [16][17][18][19][20][21][22][23][24][25] In addition, CD137 has been shown to stimulate the reactivity of mouse NK cells. 26,27 However, although CD137L is expressed on human carcinoma and lymphoma cells, 28,29 the consequences of CD137-CD137L interaction for antitumor reactivity of NK cells in humans are yet unclear.…”

Section: Introductionmentioning

confidence: 99%

CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells

Baessler¹,

Charton²,

Schmiedel³

et al. 2010

Blood

106

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Section: Introductionmentioning

confidence: 99%

CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells

Baessler¹,

Charton²,

Schmiedel³

et al. 2010

Blood

106

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“…Our results are not easily reconciled with the general notion of 4-1BB and its ligand as costimulatory molecule system. In fact, triggering of 4-1BB by agonistic antibodies and aptamers as well as tumor-expressed 4-1BBL potently stimulates T-cell anti-tumor immunity [12,29,30]. In addition, 4-1BB also stimulates the reactivity of mouse NK cells [15][16][17].…”

Section: Discussionmentioning

confidence: 99%

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

et al. 2011

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NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.

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“…Antitumor effects were reported in several mouse models with agonistic 4-1BB-specific antibodies (21,22). Also, vaccination with tumor cells transfected to express a 4-1BB-specific antibody fragment (scFv) on the cell surface or admixture of them to wild-type tumor cells induced strong antitumor responses (23,24). Furthermore, antibody fusion proteins with the extracellular domain of 4-1BBL showed targetmediated costimulation in vitro (25,26) and antitumor activity in vivo (27).…”

Section: Introductionmentioning

confidence: 99%

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

Kermer

Hornig

Harder

et al. 2014

Molecular Cancer Therapeutics

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Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common g-chain (gc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Ra chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-g release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.

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Tumor Cells Expressing Anti-CD137 scFv Induce a Tumor-Destructive Environment

Cited by 41 publications

References 29 publications

CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells

CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

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