Fig. 2

Model calibration and extrapolation to humans. A-D) Numerical solution of the model exhibiting kinetics of key variables under treatment with NP-delivered anti-miR-155 in NSCLC-bearing mice. (A) Mass kinetics of NPs in plasma and tumor interstitium (inset) following twice-a-week injection of NPs loaded with a dose of 4,000 ng of anti-miR-155. %ID represents percent of injected dose. (B) Concentration kinetics of NP-delivered anti-miR-155 in tumor cells and TAMs. (C) Concentration kinetics of miR-155 in tumor cells and TAMs. (D) Concentration kinetics of unbound PD-L1 on tumor cells and TAMs, and unbound PD-1 on CD8 + T cells (inset). (E-G) Non-linear least squares fits of the model to published in vivo datasets of tumor volumetric growth kinetics in NSCLC under control conditions and treatment with (E) anti-miR-155, cisplatin, combination of anti-miR-155 and cisplatin, (F) atezolizumab, (G) and pembrolizumab. (H-K) Numerical solution of the allometrically scaled model showing key system variables following treatment with anti-miR-155 loaded NPs in an average adult patient. (H) Mass kinetics of NPs in plasma and tumor interstitium (inset) following once every three weeks (Q3W) injection of NPs loaded with the allometrically scaled dose of anti-miR-155 in humans (i.e., 0.026 mg/kg). (I) Concentration kinetics of NP-delivered anti-miR-155 in tumor cells and TAMs. (J) Concentration kinetics of miR-155 in tumor cells and TAMs. (K) Concentration kinetics of unbound PD-L1 on tumor cells and TAMs, and unbound PD-1 on CD8 + T cells (inset). (L) Corresponding tumor growth kinetics under control and treatment conditions involving anti-miR-155 at three different dosages (0.026 mg/kg, Q3W; 0.026 mg/kg, QW (once weekly); 0.26 mg/kg, Q3W). The yellow diamond on x-axis marks the initiation of treatment; the dotted dark red line defines the threshold to transition from stable disease to progressive disease, as per RECIST 1.1. Abbreviations: TGI- tumor growth inhibition, TTP- time to progression