A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)

Grünwald, Viktor; Desar, Ingrid M.E.; Haanen, John B.A.G.; Fiedler, Walter; Mouritzen, Ulrik; Olsen, Minna W.B.; Herpen, Carla M.L. van

doi:10.3109/0284186x.2010.509104

Cited by 37 publications

(20 citation statements)

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Section: T Cells and Nk T Cells (1-4) Its Receptor (Il-21r)mentioning

confidence: 99%

“…It also regulates the proliferation, survival, differentiation and effector functions of NK cells (1,5,16). As a promising cytokine for cancer immunotherapy, IL-21 has been undergoing Phase I and II testing in clinical trials for the treatment of early phase renal cell carcinoma and melanoma (17)(18)(19).Accumulated data have shown that tumors may exploit certain inhibitory checkpoints and pathways to escape immune attack, even in the face of a strongly induced antitumor immune response. In these tumor-escaping mechanisms, the expression of programmed death ligand 1 (PD-L1) by the tumor may play an important role in its resistance to immune destruction (20).…”

mentioning

confidence: 99%

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Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

Pan

Mao

et al. 2012

Oncology Letters

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Abstract. Cancer immunotherapies are designed to elicit T-cell responses that inhibit tumor growth. Previous studies have demonstrated that interleukin 21 (IL-21) is a promising cytokine for cancer immunotherapy due to its ability to induce the immunity of T cells and natural killer cells, whereas blockade of the interaction of programmed death receptor-1 (PD-1) with its ligand (PD-L1) reduces peripheral tolerance. In the current study, we investigated IL-21 alone and in combination with soluble PD-1 (sPD-1) for the treatment of experimental H22 murine hepatocarcinoma. The naked plasmids pmIL-21 and/or psPD-1 were used for local gene transfer by injection. In these assays, sPD-1 combined with IL-21 was found to significantly inhibit the growth of the tumors in mice. Combined treatment with IL-21 and sPD-1 enhanced the antitumor immune response compared with that induced by IL-21 alone. Combined treatment was found to increase CTL cytotoxicity, increase the number of CTLs and NK cells in splenocytes, upregulate the cytokines IFN-γ and IL-2 and downregulate IL-10. Thus, immunotherapy with IL-21 in combination with sPD-1 was found to induce a more efficacious antitumor immune response, which may have potential clinical implications. IntroductionInterleukin 21 (IL-21), a member of the common γ-chain (γc) receptor cytokine family, has been shown to have structural homology to IL-2 and IL-15. IL-21 is mainly secreted by activated CD4+ T cells and NK T cells (1-4). Its receptor (IL-21R)is widely expressed on various cell types within the immune system, including NK cells, B cells, T cells, macrophages and dendritic cells (DCs) (5-9). The widespread lymphoid distribution of the IL-21R leads to pleiotropic action of IL-21 in the innate and adaptive immune responses. A number of preclinical studies have shown that IL-21 has important antitumor effects (10-12). The antitumor activity of IL-21 has been shown to mainly depend on CD8 + T cells and NK cells. IL-21 promotes the activation and antigen-dependent proliferation of CD8 + T cells and enhances their cytolytic activity (13-15). It also regulates the proliferation, survival, differentiation and effector functions of NK cells (1,5,16). As a promising cytokine for cancer immunotherapy, IL-21 has been undergoing Phase I and II testing in clinical trials for the treatment of early phase renal cell carcinoma and melanoma (17)(18)(19).Accumulated data have shown that tumors may exploit certain inhibitory checkpoints and pathways to escape immune attack, even in the face of a strongly induced antitumor immune response. In these tumor-escaping mechanisms, the expression of programmed death ligand 1 (PD-L1) by the tumor may play an important role in its resistance to immune destruction (20). PD-L1 is normally expressed in a broad spectrum of cell types and plays a crucial role in the maintenance of peripheral tolerance. Upregulated expression of PD-L1 has been found in certain solid tumors, including hepatocellular carcinoma. Its overexpression is significantly associated with t...

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Section: T Cells and Nk T Cells (1-4) Its Receptor (Il-21r)mentioning

confidence: 99%

mentioning

confidence: 99%

Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

Pan

Mao

et al. 2012

Oncology Letters

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“…Additionally, IL-21 and IL-21R were increased in all transplanted organs to a similar extent and might promote graft-versus-host disease (GVHD) by enhancing the production of effector CD4 + T cells [102,103]. Recent studies revealed the potent pleiotropic effects of IL-21 in pulmonary disorders [104,105], renal diseases [106,107] and diabetes [108,109] …”

Section: Discussionmentioning

confidence: 99%

IL-21 and Related Diseases

Niu¹,

Chen²

2011

J Clin Cell Immunol

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IL-21, which is produced by activated NKT cells and CD4 + T cells, exhibits pleiotropic effects not only on a variety of immune cells but also on non-immune cells. It has been demonstrated that IL-21 plays significant roles in the process of autoimmune diseases, inflammatory diseases and cancers. This review intends to give the reader an overview of this cytokine and the relationships between IL-21 and the related diseases of different body systems.

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“…82). It is also noteworthy that dose-limiting toxicities have been observed in patients with RCC treated with the targeted agent sunitinib and either rhIL21 (hematologic toxicity) or the anti-CTLA-4 agent tremelimumab (renal failure), further emphasizing the need for caution when evaluating combinations (83,84).…”

Section: Clinical Experience and Considerations In Combining Novel Immentioning

confidence: 99%

Immuno-oncology Combinations: A Review of Clinical Experience and Future Prospects

Antonia

Larkin

Ascierto

2014

Clinical Cancer Research

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Immuno-oncology is an evolving treatment modality that includes immunotherapies designed to harness the patient's own immune system. This approach is being studied for its potential to improve long-term survival across multiple tumor types. It is now important to determine how immunotherapies may be most effectively used to achieve the best possible patient outcomes. Combining or sequencing immunotherapies that target distinct immune pathways is a logical approach, with the potential to further enhance the magnitude of the antitumor immune response over single agents. Early clinical data in patients with melanoma treated with two immune checkpoint inhibitors, ipilimumab and nivolumab, suggest support for this combination approach. Numerous other combination approaches are being evaluated in early-phase clinical trials; however, their clinical activity remains unknown. Clinical experience to date has shown that when combining an immuno-oncology agent with an existing therapeutic modality, it is important to determine the optimal dose, schedule, and sequence. Clin Cancer Res; 20(24); 6258-68. Ó2014 AACR.

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A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC)

Abstract: (2011) A Phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC), Acta Oncologica, 50:1, 121-126,

Cited by 37 publications

References 28 publications

Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

IL-21 and Related Diseases

Immuno-oncology Combinations: A Review of Clinical Experience and Future Prospects

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