Figure 6. The in vivo model predicted clinical pharmacodynamics and tumor evolution across anatomical sites.

(a) Scheme of organ compartment and cell trafficking. Remainder, all the rest of the non-lymphoid organs; k_{B cell}, the turnover rate of B cell; k_{traff, in} and k_{traff out,} B cell trafficking rate. For parameters and trial information, see Materials and methods, and Supplementary file 1b and c; (b–e) Observed and simulated patient B cell profiles in blood; (f) Simulated CD19 evolution in non-responder patients of trial MT103-211; (g) Simulated cell lysis potency for each organ in trial MT103-104; (h) Simulated baseline (day 0), and post-treatment (day 7 and 14) B cell organ distribution in patients with OS >30 months of trial MT103-206. Bar plot, simulated baseline and post-treatment tumor burden; (i–l) Sensitivity analyses for the impact of drug concentration (i), T cell density (j), B cell density (k), and CD19 expression (l) on B cell depletion. T cell density change is allowed in the simulations (b–e), details see Supplementary file 1b. BM, bone marrow; LN, lymph nodes; OS, overall survival; Rmd, remainder.

Figure 6—figure supplement 1. The effect of blood flow on the production and stability of immunological synapses (IS).

(a) Cell co-culture was conducted at different flow velocities, producing different shear stresses to mimic the effect of blood flow. Initial setup: 2 X, 2 × 10⁶ total cells/mL; E:T(1), E:T ratio = 1; CD3(L), CD3 expression (Low); CD3(M), CD3 expression (medium); CD19(M), CD19 expression (medium); 100 ng/mL, blinatumomab concentration; 60 min, incubation duration. (b) Cell incubation was conducted at static condition (initial setup: 2 X, E:T(1), CD19(M), CD3(L), 100 ng/mL, 60 min, shear stress = 0) and followed by adding different shear stresses (5 min) to test the stability of pre-existing IS. The reference line (100%) indicated the frequency of the effector cells engaged at static condition.

Figure 6—figure supplement 2. Simulated baseline (day 0), and post-treatment (day 7 and 14) B cell organ distribution in patients of trial MT103-206.

The in vivo model was applied to perform the simulations. Bar plot showed the simulated tumor burden at baseline and post-treatment. BM, bone marrow; LN, lymph nodes; OS, overall survival; Rmd, remainder, all the rest of the non-lymphoid organs.