IL-15 in the Combination Immunotherapy of Cancer.

Frontiers in Immunology
Thomas A WaldmannKevin C Conlon

Abstract

We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10- day number of circulating NK cells, a 358-fold increase in CD56bright NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 μg/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of γc cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 ...Continue Reading

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Citations

Sep 10, 2020·Frontiers in Immunology·John A HangaskyDaniel V Santi
Nov 19, 2020·Journal for Immunotherapy of Cancer·Piera Filomena FioreBruno Azzarone
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Methods Mentioned

BETA
flow cytometry
xenograft
xenografts

Clinical Trials Mentioned

NCT01385423
NCT02395822
NCT03388632
NCT02689453
NCT03759184
NCT03905135
NCT04150562
NCT04185220

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