PI-053 - DEVELOPING A MECHANISTIC MODEL OF IL-15 MEDIATED NK CELL PROLIFERATION WITH IMPLICATIONS IN IMPROVING CAR NK CELL THERAPY EFFICACY.

N. Chicoine¹, H. Wang², K. Piatkov², G. Mugundu³, L. Chu²; ¹Northeastern University, Boston, MA, USA, ²Takeda Development Center Americas, Inc., Cambridge, MA, USA, ³Takeda Development Center Americas, Inc., Lexington, MA, USA.

Background: IL-15 has an important role in natural killer (NK) cell regulation, making it a topic of interest for augmenting CAR NK cell therapies. In order to aid the preclinical and clinical development of CAR NK products and to understand IL-15’s role in NK proliferation, we developed a mechanistic model of in-vivo IL-15-mediated NK cell proliferation based on published clinical trial data.

Methods: The model consists of two sub-models: (1) a two-compartment IL-15 pharmacokinetics (PK) model with target-mediated drug disposition (TMDD), and (2) a two-compartment model of IL-15 mediated NK cell redistribution and proliferation. Using Monolix 2021R1 (Lixoft), we fitted both sub-models using IL-15 PK and cellular kinetic data from clinical trial studies of recombinant human IL-15 (Conlon et al. 2015, J Clin Oncol; Conlon et al. 2019, Clin Cancer Res). Lastly, we explored simulations of continuous intravenous (CIV) infusion rhIL-15 dosing needed to achieve varying levels of NK cell expansion and persistence.

Results: The model fittings suggest that the model structure accurately captures both the IL-15 clearance and NK proliferation behavior. Differences in proliferation rates were exhibited between bolus infusion and CIV dosing and were captured using covariates during the fitting. Simulations of 4-week CIV dosing regimens suggest 0.5 ug/kg/day is needed to achieve 10-fold NK cell expansion and 3.5 ug/kg/day dosing is needed for >100-fold expansion.

Conclusion: Our model provides a tool for understanding the role of IL15 in NK cell regulation and assessing IL-15 levels required to achieve varying levels of NK cell expansion. Our model structure can be expanded to include IL-15 secretion dynamics from armored CAR NK cells and effects of lymphodepletion on NK cell count and basal IL-15 levels.