Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Abstract

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications

“…Of note, adoptive transfer of IL-12/15/18-preactivated NK cells is usually followed by the administration of IL-15 or IL-2 to support their survival and expansion, although cytokine support requires further characterization. Recent findings suggested that the infusion of IL-15 superagonist N-803 following adoptive CIML NK cell transfer may limit their clinical activity in comparison with IL-2 infusions ( 76 ). Remarkably, CAR-NK cells can be further modified to express and secrete cytokines such as IL-15 ( 77 – 82 ), so it would be interesting to explore if a therapy based on CAR-engineered CIML NK cells expressing IL-15 or IL-2 could further improve their efficacy.…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…Exogenous cytokine support has been proposed to lengthen NK therapy persistence. Nevertheless, the IL-15 superagonist complex N-803 reduces clinical responses in AML patients treated with haploidentical ML-NK cells because of CD8 + T lymphocytes stimulation (NCT03050216 and NCT01898793) ( 136 ). Alternatively, autocrine secretion from bicistronic CAR constructs containing cytokines may provide a better approach.…”

From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement

“…N-803 has been used instead of IL-2 to support cytokine-primed allogeneic NK cells transfer to AML patients in a relapse in two separate clinical trials (NCT03050216 and NCT01898793). Unexpectedly, the report stated that the use of N-803 instead of IL-2 led to reduced clinical activity (93). The authors showed that N-803 promotes recipient CD8+ T-cell activation, inducing a decrease in allogeneic NK cell persistence through rejection.…”