Interleukin-15 receptor and Cluster of Differentiation 38 (CD38) functional interaction (IL-15R/CD38)

The functional interaction between the Interleukin-15 receptor (IL-15R) and Cluster of Differentiation 38 (CD38) is a therapeutic axis leveraged to enhance the efficacy of immunotherapy in hematologic malignancies, particularly multiple myeloma [1]. IL-15R is a heterotrimeric complex comprising IL-15RA, CD122, and CD132 that mediates the survival, activation, and proliferation of natural killer (NK) cells and CD8+ T cells [2][3]. CD38 is a multifunctional ectoenzyme and cell surface marker highly expressed on malignant plasma cells, making it a primary target for monoclonal antibodies like daratumumab [4]. The synergy between these two pathways arises because IL-15 signaling expands the pool of effector NK cells required for CD38-targeted antibody-dependent cellular cytotoxicity (ADCC) [5]. This interaction is critical for overcoming NK cell exhaustion or depletion, which are common resistance mechanisms in patients receiving long-term anti-CD38 therapy [1][5]. Clinical strategies targeting this interaction include the combination of IL-15 superagonists, such as nogapendekin alfa inbakicept (N-803), with anti-CD38 antibodies to provide a prime and pull effect that increases the density and cytotoxic activity of immune effectors at the tumor site [6][7]. Emerging research also explores bispecific molecules or immunocytokines that physically link IL-15 to a CD38-targeting domain to localize cytokine activity and minimize systemic toxicity [8]. Overall, the IL-15R/CD38 functional interaction represents a promising frontier for achieving deeper and more durable clinical responses in refractory cancers [9].

Other names

IL-15/CD38 axisCD38-IL15 synergyIL-15R-CD38 interactionIL-15 and CD38 combination therapy

Synergistic enhancement of NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) through IL-15-induced effector cell expansion and activation.