Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency

Vincent, Marie; Bessard, Anne; Cochonneau, Denis; Teppaz, Géraldine; Solé, Véronique; Maillasson, Mike; Birklé, Stéphane; Garrigue‐Antar, Laure; Quéméner, Agnès; Jacques, Yannick

doi:10.1002/ijc.28059

Cited by 64 publications

(54 citation statements)

References 49 publications

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“…Furthermore, tumor-directed antibody fusion proteins with RD_IL-15 showed improved antitumor effects in comparison to untargeted RD_IL-15 in different mouse models (13,14). The strong potential of RD_IL-15 was also demonstrated and shown to be predominant in the trifunctional fusion protein of the present study.…”

Section: Discussionsupporting

confidence: 64%

“…Also, a fusion protein composed of IL-15, IL-15Ra's sushi domain, and apolipoprotein A-I (Apo A-I) has been reported, inducing therapeutic effects in lung and liver metastases mouse models (11). Furthermore, tumor targeting by antibody fusion proteins with IL-15 (12) or RD_IL-15 (13,14) resulted in enhanced antitumor effects in different mouse models. On the other hand, improved therapeutic effects could be achieved by the combination of IL-15 with other immunomodulatory approaches, for example, cytokines (IL-21, IL-7, IL-12; refs.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 64%

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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“…al. [87] where immunotherapy can be achieved along with cytotoxicty. The molecules of immunocytokines can be designed to have a bifunctional nature, both cytokine and antibody.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8 and Interleukin-17 for Cancer

Zarogoulidis¹,

Katsikogianni²,

Tsiouda³

et al. 2014

Cancer Investigation

103

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Interleukin 7 and 15 are considered powerful pro-inflammatory cytokines, they have the ability to destabilize chromosomes and induce tumorigenesis. Additionally, they can control malignancy proliferation by influencing the tumor microenvironment and immune system. Immunotherapy has been proposed as a treatment modality for malignancy for over a decade; the exact mechanisms of action and pathways are still under investigation. Interleukin 7 and 15 have been extensively investigated in hematological malignancies since their mode of action influences the stimulation of the immune system in a more direct way than other malignancies such as lung, melanoma, and breast, renal and colorectal cancer.

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“…injection of tumor cells and to synergize with anti-GD2 or anti-CD20 when targeted to the tumor in preclinical mouse models. Thus, RLI could be an interesting immune modulator for use in cancer therapy (10)(11)(12). However, to date, no report has challenged its antitumor activity as a stand-alone treatment in preclinical solid tumor models.…”

mentioning

confidence: 99%

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

Desbois

Coutzac

et al. 2016

The Journal of Immunology

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Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker–IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi+ domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)high T cell Ig mucin-3+ CD8+ T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8+ T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8+ T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti–PD-1/RLI compared with 43 and 6% with RLI or anti–PD-1, respectively. Altogether, this work provides evidence that the sushi–IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti–PD-1 treatment and is a promising approach to stimulate host immunity.

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Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency

Cited by 64 publications

References 49 publications

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

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

Interleukin-8 and Interleukin-17 for Cancer

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

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