IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion

Conlon, Kevin C.; Potter, E. Lake; Pittaluga, Stefania; Lee, Chyi‐Chia Richard; Miljković, Miloš D.; Fleisher, Thomas A.; Dubois, Sigrid; Bryant, Bonita R.; Petrus, Michael; Perera, Liyanage P.; Hsu, Jennifer L.; Figg, William D.; Peer, Cody J.; Shih, Joanna H.; Yovandich, Jason L.; Creekmore, Stephen P.; Roederer, Mario; Waldmann, Thomas A.

doi:10.1158/1078-0432.ccr-18-3468

Cited by 91 publications

(103 citation statements)

References 51 publications

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“…Consequently, IL-15 increased the maturation of DCs in the presence of NK cells activated by Cetuximab. Recently, phase I clinical trials have tested human recombinant IL-15 (rhIL-15) as intravenous bolus monotherapy [ 52 ], subcutaneous injection [ 53 ] and continuous intravenous infusion [ 54 ]. The latter induced a massive 38-fold increase in total circulating NK cells and 358-fold increase in CD56 bright NK cells.…”

Section: Discussionmentioning

confidence: 99%

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

Juliá¹,

Mordoh

Levy³

2020

Cells

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Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.

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Section: Discussionmentioning

confidence: 99%

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

Juliá¹,

Mordoh

Levy³

2020

Cells

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“…Several NK-based immunotherapies have been explored, including adoptive transfer of autologous NK cells, which refers to the transfusion of ex vivo activated and expanded NK cells into patients; 141 CAR-NK cell therapies, which involve the transfusion of engineered NK cells expressing CARs against a specific tumor antigen; 142 cytokine therapies, which involve the infusion of specific cytokines to augment NK cell activity; 143 and mAb-based therapies, referring to the delivery of antibodies to block inhibitory receptors on NK cells. 144 Analogous to ICIs, which block inhibitory pathways in T cells, the blockade of inhibitory receptors on NK cells also demonstrates promise, and several NK cell inhibitory receptors have been explored for their therapeutic potential and clinical utilization.…”

Section: Tumor-infiltrating Immune Cells and Their Associations With mentioning

confidence: 99%

The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications

2020

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Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), have obtained durable clinical responses, but their efficacies vary, and only subsets of cancer patients can benefit from them. Immune infiltrates in the tumor microenvironment (TME) have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients. Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. However, the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells. With recent advances in single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry, systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells. In this review, we outline the recent progress in cancer immunotherapy, particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells, and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy. We believe such a review could strengthen our understanding of the progress in cancer immunotherapy, facilitate the elucidation of immune cell modulation in tumor progression, and thus guide the development of novel immunotherapies for cancer treatment.

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“…NCT01875601) in which the cytokine is administered employing different dosing regimens, including intravenous bolus and subcutaneous and continuous infusion of monomeric sIL-15 both in adult and pediatric solid tumors. [90][91][92][93][94] There is also a number of clinical trials (NCT01727076, NCT01885897, NCT02523469), based on the utilization of an IL-15N72D/IL-15Rα-Fc super-agonist complex, termed N-803 (formerly Alt-803, from NantKwest, Culver City, California, USA) supposed to maximize expansion and priming of immune cells (NK and CD8 + T-cells). 95 96 However, in the latter setting a drawback rises from the rapid consumption of the injected IL-15 agonists due to the rapid and huge expansion of the target immune cells.…”

Section: Clinical Trials Rhil-15 Is Currently Under Investigation In mentioning

confidence: 99%

Interleukin-15 and cancer: some solved and many unsolved questions

Fiore

Matteo

Tumino

et al. 2020

J Immunother Cancer

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Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8+/CD44+ T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications.

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IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion

Cited by 91 publications

References 51 publications

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

Cetuximab and IL-15 Promote NK and Dendritic Cell Activation In Vitro in Triple Negative Breast Cancer

The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications

Interleukin-15 and cancer: some solved and many unsolved questions

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