A first-in-class ex vivo combination between cytokine-induced memory like (CIML) NK cells and a CD38 targeting antibody recruiting molecule (ARM) as a novel approach to target NK cells without cellular engineering for the treatment of multiple myeloma.

Abstract

8523 Background: Cytokine-induced memory-like (CIML) NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for several weeks to months. Antibody Recruiting Molecules (ARM) are bifunctional molecules that simultaneously bind a given tumor marker and engage endogenous IgG antibodies, therefore binding and activating NK cells via their FcR and targeting them to kill tumors cells. A first in class therapy that has the potential to improve the activity of CIML NK cells by combining them with KP1237, a CD38-ARM is presented for the treatment of newly diagnosed multiple myeloma (MM) patients who are minimal residual disease positive (MRD+) and eligible for autologous stem cell transplant (ASCT). Methods: Specific killing of CD38 expressing MOLP-8 cells by CIML NK cells alone or in combination with KP1237 was measured. Additionally, NK and CIML NK cells from healthy volunteers and MM patients at various stages of the disease were tested for activity against autologous and allogeneic tumor cell targets. In these experiments, surface phenotype and activation status of NK cells were determined. Results: A statistically significant increase in specific killing was observed when KP1237 was used in combination with CIML NK cells in an ADCC assay against CD38 expressing MOLP-8 (p = 0.0105, mean 61.8 ± SD 9.1 and mean 83.7 ± SD 13.58 for CIML NK alone and CIML NK+KP1237, respectively). This effect was accompanied by an increase in plasma membrane retention of CD107a. Surface phenotype of NK and CIML NK cells from healthy volunteers and MM patients was compared since the functional activity of NK cells from such patients is debated. We report surface expression of CD56, CD16, CD57, NKG2D, Nkp44, Nkp46, CD107a, KIR2DL2/3/DS2, and CD69 as well as frequencies of CD57hi CD56+ mature versus CD57lo CD56+ immature NK cell subsets. Further, autologous CIML NK cells + KP1237 exhibit cytotoxicity towards patient plasma cells. Conclusions: The activity of CIML NK cells towards CD38 expressing MM target cells is improved by the addition of KP1237 avoiding the need for cellular engineering with chimeric antigen receptors. This led to the development of the combination drug product consisting of patient autologous CIML NK cells, KP1237 and IVIG. Clinical development is under way for (MRD+) MM patients eligible for ASCT.