IL-15 in the Combination Immunotherapy of Cancer

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 CD56 bright 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.

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

“…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.…”

IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models

“…IL-15 as a monotherapy for solid tumors is not as effective as expected ( 42 ). Two major strategies including IL-15 superagonist and combination therapy have been pursued to improve its therapeutic efficacy.…”

“…Combination immunotherapy has been proposed to enhance the efficacy of IL-15 ( 42 ). MDSCs are predominant in 4T1 breast tumor and have been reported to associate with tumor burden or late stage breast tumor ( 38 ).…”

Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma

“…In clinical trials evaluating IL-15, a low level of response was observed. To potentially overcome these poor responses, studies are being conducted to determine the potential of combining IL-15 or IL-15/IL-15Rα with other immune modifiers, including checkpoint inhibitors [ 40 , 41 , 42 ]. Interestingly, in the pIL-12 clinical trials, patients who had a poor response were observed to have elevated tumor levels of PD-1 and PD-L1 [ 34 , 43 ].…”