Fig. 2: Adaptive therapy prolongs TTP by leveraging inter- and intra-tumoral competition.

AT: adaptive therapy, CT: continuous therapy, TTP: time to progression, ABM: agent-based model. a Example simulations of the treatment dynamics under continuous and adaptive therapy in our ABM ((n₀, f_R) = (75%, 0.1%)). Shown are the mean and standard deviation (shading) of the tumour cell number (sensitive, resistant and total; n = 250 independent replicates). Black bars represent a typical treatment schedule (see also Supplementary Fig. 4). Horizontal dotted lines show the initial cell number and the cell number at progression, respectively. Vertical lines and associated shading mark the mean, and the 1st and 3rd quartile of the distribution of TTP. b Snapshots from one of the replicates in a illustrating how adaptive therapy delays competitive release of resistance. c Adaptive therapy (blue line) results in a higher proportion of blocked resistant cell divisions than continuous therapy (yellow line) in the initial stages of treatment in the simulations in a (left panel). However, the ability of adaptive therapy to induce blocking depends on the initial tumour cell density (centre panel; (n₀, f_R)=(25%, 0.1%)) and the initial resistance fraction (right panel; (n₀, f_R)=(75%, 1%)). Lines and shading indicate mean and standard deviation, respectively. d Average frequency of sensitive cells, resistant cells, or empty space in a resistant cell’s neighbourhood in the simulations in a. This shows that there is not only inter-, but also significant, intra-specific competition during adaptive therapy. Values are the mean in the von Neumann neighbourhood across all resistant cells from 250 independent simulations. e Gain in TTP achieved by adaptive therapy relative to continuous therapy as a function of n₀ and f_R (n = 1000 independent replicates per condition). Adaptive therapy yields the greatest benefit when tumours are close to their carrying capacity and resistance is rare. The box, centre line, small white squares, and whiskers denote the inter-quartile range, median, mean, and 1.5x inter-quartile range, respectively. Negative values denote cases in which continuous therapy achieves a longer TTP. Resistance costs and turnover are assumed to be 0 throughout this figure.