The IL-15 receptor agonist N-803 combined with the anti-CD20 monoclonal antibody rituximab expands NK and CD8 T cells and alters single cell immune transcriptomes in a phase 1 clinical trial in lymphoma

Abstract

Abstract IL-15 is a cytokine that is crucial for the development, survival, and activation of NK cells, and pre-clinical studies demonstrated that IL-15 augments antibody-dependent cellular cytotoxicity. We hypothesized that IL-15 would augment anti-CD20 mAb (rituximab)-directed responses in patients with indolent non-Hodgkin’s lymphoma. To address this, we performed a first-in-human combination clinical trial of the IL-15 super agonist N-803 with rituximab, and investigated the impact of this novel immune combination on NK, CD8 T cells, and monocytes. The combination was safe and demonstrated clinical activity, including in patients refractory to rituximab. To understand the in vivo impact on the patients’ immune systems, we performed mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which measures single-cell RNA-seq and cell surface proteins simultaneously. N-803 induced expansion of NK (12.5-fold) and CD8 T cells (2-fold) in serial blood samples and upregulated CD38, chemokines, and MHC class II family member expression while maintaining CD16 expression on NK. On CD56dim NK, N-803 increased activating receptors, decreased CD57, and modulated transcription factor expression (AP-1, Eomes, CEBPB/D). CD56bright NK cells were primed, with increases in granzyme A, B, and K. Therapy also markedly altered the monocyte compartment, significantly upregulating type 1 interferon and interferon gamma pathways in CD14+ monocytes, and decreased the percent of CD16+ monocytes, suggestive of potential trafficking to the tumor. Collectively, our data demonstrates that N-803 plus rituximab induces complex immune activation, and supports N-803 combination with other mAbs and immunotherapies.