IL-15 in the Combination Immunotherapy of Cancer.

Thomas A Waldmann,Kevin C Conlon,Sigrid Dubois,Milos D Miljkovic

doi:10.3389/fimmu.2020.00868

Thomas A Waldmann, Kevin C Conlon + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2020.00868

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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 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.

Highlights

The goal of immunotherapy is to direct the host immune system to attack patients’ cancer [1, 2]
When the maximum fold increases in the number of circulating natural killer (NK) cells with different agents and dosing schedules were compared, rhIL15 administered by bolus infusion at the MTD (0.3 mcg/kg/day) yielded a 2–3 fold increase in NK cells [43] (Table 1). rhIL15 administered subcutaneously at the expansion dose of 2 mcg/kg/day on days 1–5, and 8–12 was associated with a 10.8-fold increase in total circulating NK cells and a 39.7-fold increase in CD56bright NK cells [44]
RhIL-15 by continuous intravenous infusions (CIV) yielded dramatic augmentation in the number of circulating NK cells, it will have to be used in combination with other anticancer agents due to the inhibitory actions of immunological checkpoints and the lack of tumor specific targeting by NK cells (Tables 2, 3)

Summary

Introduction

The goal of immunotherapy is to direct the host immune system to attack patients’ cancer [1, 2]. When the maximum fold increases in the number of circulating NK cells with different agents and dosing schedules were compared, rhIL15 administered by bolus infusion at the MTD (0.3 mcg/kg/day) yielded a 2–3 fold increase in NK cells [43] (Table 1). RhIL15 administered subcutaneously at the expansion dose of 2 mcg/kg/day on days 1–5, and 8–12 was associated with a 10.8-fold increase in total circulating NK cells and a 39.7-fold increase in CD56bright NK cells [44].

Results

Conclusion