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. 2019 Jun 11;8(6):380–395. doi: 10.1002/psp4.12426

Figure 5.

Figure 5

Case study 3. (a) Population quantitative systems pharmacology model of immuno‐oncology. Multiple molecular targets modulating immuno‐suppression and immuno‐activation in the tumor microenvironment are represented as well as direct tumor cell kill mechanisms. Green lines = stimulation; red lines = inhibition, regulation; black lines: variable turnover. (b) Simulations using the quantitative systems pharmacology model. A sample of model simulations is shown, for the following treatment scenarios: (i) control isotype mAb, (ii) anti‐PD‐(L)1 (10 mg/kg 3 q.w., blue arrows) monotherapy treatment, (iii) radiation therapy (RT; 5 Gy, red triangles) + anti‐PD‐(L)1 (10 mg/kg 3 q.w., blue arrows) given concurrently, (iv) RT3 (5 Gy, red triangles) + anti‐PD‐(L)1 (10 mg/kg 3 q.w., blue arrows) given sequentially. Thin gray lines represent individual responses, and dashed red lines represent population median. Per treatment scenario, a total of 2,000 virtual experiments were simulated; each virtual experiment included 100 individual animals. To evaluate an efficacy metric with respect to treatment response, a responder was defined as an individual animal with a tumor volume of ≤10 mm3 at day 50 of treatment; median efficacy for each treatment scenario was estimated with a 90% confidence interval (shown in brackets). Cell colors on the heatmap map to median efficacies: red = no response; orange = 50% responders in the corresponding treatment scenario; green = 100% responders. T eff, effector T cells; IAR, immune activation rate function; ISC, immune suppressive cells function; APC, antigen‐presenting cells; TV, tumor volume; Agsys, systemic antigen level. mAB, monoclonal antibody; anti‐PD‐(L1), anti‐programmed cell death protein 1 or anti‐programmed death ligand 1 antibody; aCTLA4, anti‐cytotoxic T‐lymphocyte‐associated protein 4 antibody; q.w., once weekly; aCD73, Ecto‐5'‐nucleotidase (CD73) inhibitor; A2ARi, Adenosine A2A receptor inhibitor; OX40L, OX40 ligand; CXCR2i, CXCR2 inhibitor; aCSF1‐R, Colony stimulating factor 1 receptor (CSF1‐R) inhibitor; STAT3ASO, Signal transducer and activator of transcription 3 (STAT3) antisense oligonucleotide (ASO); PI3Kgi, phosphoinositide 3‐kinase gamma (PI3Kg) inhibitor