New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity

Bailey, Cavan P.; Budak‐Alpdoğan, Tülin; Sauter, C; Panis, M.; Buyukgoz, Cihangir; Jeng, Emily K.; Wong, Hing C.; Flomenberg, Neal; Alpdoğan, Önder

doi:10.18632/oncotarget.17875

Cited by 17 publications

(12 citation statements)

References 47 publications

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“…While marked elevations of the cytokines IFN-γ, TNF-α, and IL-10 were observed with ALT-803 treatment in mice, no toxicities were seen [61]. ALT-803 significantly reduced tumor burden and prolonged survival in an impressive number of animal models of cancer, namely, murine multiple myeloma [60], glioblastoma [62], 4T1 breast cancer [61], B16 melanoma [61], CT26 colon carcinoma [63] rat bladder cancer [64], ovarian cancer [65], murine mastocytoma, and B cell lymphoma[66]. In side-by-side comparison with rhIL-15, ALT-803 induced superior anti-tumor responses in the B16F10 melanoma and CT26 colon carcinoma models [61,63].…”

Section: Il-15 Super-agonistsmentioning

confidence: 99%

The potential and promise of IL-15 in immuno-oncogenic therapies

Robinson

Schluns²

2017

Immunology Letters

154

136

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This review provides an in-depth description of the preclinical and clinical studies demonstrating the effectiveness and limitations of IL-15 and IL-15 analogs given as an exogenous immuno-oncology agent. IL-15 is a cytokine that primarily stimulates the proliferation and cytotoxic functions of CD8 T cells and NK cells leading to enhanced anti-tumor responses. While initially showing promise as a cancer therapeutic, the efficacy of IL-15 was limited by its short in vivo half-life. More recently, various approaches have been developed to improve the in vivo half-life and efficacy of IL-15, largely by generating IL-15/IL-15Rα conjugates. These new IL-15 based agents renew the prospect of IL-15 as a cancer immunotherapeutic agent. While having some efficacy in inducing tumor regression as a monotherapy, IL-15 agents also show great potential in being used in combination with other immuno-oncological therapies. Indeed, IL-15 used in combination therapy yields even better anti-tumor responses and prolongs survival than IL-15 treatment alone in numerous murine cancer models. The promising results from these preclinical studies have led to the implementation of several clinical trials to test the safety and efficacy of IL-15-based agents as a stand-alone treatment or in conjunction with other therapies to treat both advanced solid tumors and hematological malignancies.

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Section: Il-15 Super-agonistsmentioning

confidence: 99%

The potential and promise of IL-15 in immuno-oncogenic therapies

Robinson

Schluns²

2017

Immunology Letters

154

136

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“…We hypothesize that the introduction of T cell-stimulating cues in the PIC hydrogels may contribute to promoting T cell viability and functionality in order to outperform T cell delivery through bolus injection. This can be exploited by introducing IL-2 or IL-15 agonists into the PIC gels that may locally enhance T cell viability and persistence ( 18 , 53 ), while circumventing the toxicity associated with high dose bolus IL-2 ( 24 ). Alternatively, scaffolds bearing T cell-activating cues such as agonistic CD3 and CD28 antibodies ( 54 ) alone or together with αCD137 and IL-15 agonists ( 55 ) can be used to promote vigorous in situ T cell expansion and improve functionality.…”

Section: Discussionmentioning

confidence: 99%

Injectable Biomimetic Hydrogels as Tools for Efficient T Cell Expansion and Delivery

et al. 2018

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Biomaterial-based scaffolds are promising tools for controlled immunomodulation. They can be applied as three dimensional (3D) culture systems in vitro, whereas in vivo they may be used to dictate cellular localization and exert spatiotemporal control over cues presented to the immune system. As such, scaffolds can be exploited to enhance the efficacy of cancer immunotherapies such as adoptive T cell transfer, in which localization and persistence of tumor-specific T cells dictates treatment outcome. Biomimetic polyisocyanopeptide (PIC) hydrogels are polymeric scaffolds with beneficial characteristics as they display reversible thermally-induced gelation at temperatures above 16°C, which allows for their minimally invasive delivery via injection. Moreover, incorporation of azide-terminated monomers introduces functional handles that can be exploited to include immune cell-modulating cues. Here, we explore the potential of synthetic PIC hydrogels to promote the in vitro expansion and in vivo local delivery of pre-activated T cells. We found that PIC hydrogels support the survival and vigorous expansion of pre-stimulated T cells in vitro even at high cell densities, highlighting their potential as 3D culture systems for efficient expansion of T cells for their adoptive transfer. In particular, the reversible thermo-sensitive behavior of the PIC scaffolds favors straightforward recovery of cells. PIC hydrogels that were injected subcutaneously gelated instantly in vivo, after which a confined 3D structure was formed that remained localized for at least 4 weeks. Importantly, we noticed no signs of inflammation, indicating that PIC hydrogels are non-immunogenic. Cells co-delivered with PIC polymers were encapsulated within the scaffold in vivo. Cells egressed gradually from the PIC gel and migrated into distant organs. This confirms that PIC hydrogels can be used to locally deliver cells within a supportive environment. These results demonstrate that PIC hydrogels are highly promising for both the in vitro expansion and in vivo delivery of pre-activated T cells. Covalent attachment of biomolecules onto azide-functionalized PIC polymers provides the opportunity to steer the phenotype, survival or functional response of the adoptively transferred cells. As such, PIC hydrogels can be used as valuable tools to improve current adoptive T cell therapy strategies.

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“…Dendritic cells are thus unlikely to be a confounding driver of N-803exacerbated disease that can be reversed with CD8-depleting antibody. However, as N-803 can promote secretion of IFN- from CD8 T cells 31,39,59,60 , and IFN- can cause pathologic accumulation of TFH cells and GCs [61][62][63] , we speculate that excess IFN- production after N-803 or IL-2C therapy may provoke worse disease outcomes, a possibility that we will continue to explore. Regardless of the mechanism by which CD8 T cells may aggravate disease measures in this model, it is interesting to note that our results contrast with those obtained following therapeutic application of IL-2C to the B6 × DBA/2 F1 cGvHD mouse model of lupus-like disease 29 , in which IL-2C-stimulated CD8 T cells ameliorated disease.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

Reighard

Krishnamurthy

Cevik

et al. 2019

Preprint

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Certain therapies (i.e. daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple sclerosis and associated mouse models. The clinical benefits are putatively attributable to an enhanced capacity of NK cells to kill activated pathogenic T cells. Whether a parallel approach will also be effective in systemic lupus erythematosus (lupus), a multi-organ autoimmune disease driven by aberrant responses of self-reactive T and B cells, is unclear. In the present study we assess the therapeutic impact of IL-2 and IL-15-based strategies for expanding NK cells on measures of lupus-like disease in a mouse model. Unexpectedly, cytokine-mediated expansion of cytotoxic lymphocytes aggravated immunological measures of lupus-like disease. Depletion studies reveal that the negative effects of these cytokine-based regimens are largely mediated by expansion of CD8 T cells rather than NK cells. These results provoke caution in the use of cytokine-based therapeutics to treat co-morbid cancers in patients with lupus and highlight the need for new methods to selectively expand NK cells in order to further assess their clinical value in autoimmune disease.Lupus | SLE | CD8 T | NK cell | IL-15 | IL-2 | Immunotherapy | TFH

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New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity

Cited by 17 publications

References 47 publications

The potential and promise of IL-15 in immuno-oncogenic therapies

The potential and promise of IL-15 in immuno-oncogenic therapies

Injectable Biomimetic Hydrogels as Tools for Efficient T Cell Expansion and Delivery

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

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