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. 2023 Apr 13;9:125. doi: 10.1038/s41420-023-01426-w

Fig. 3. Ex vivo drug sensitivity correlates with in vivo sensitivity in a CLL patient case and guides precision medicine.

Fig. 3

a Time-line illustrating the treatment history of the CLL patient case. T0 and T1 indicate time-points when blood samples were collected from the patient. AE, adverse event; CR, complete response; FC(R), fludarabine + cyclophosphamide (+ rituximab); NR, no response; PD, progressive disease. The figure was created with BioRender.com. b Peripheral blood mononuclear cells (PBMCs) from sample T0 were treated with the indicated drug (ibrutinib, idelalisib or venetoclax) at five different concentrations (1–10,000 nM) for 30 min, followed by stimulation with anti-IgM (10 μg/ml) for 5 min. The cells were then fixed, permeabilized and stained with antibodies against CD19 and intracellular proteins as indicated. The cells were analyzed with a BD LSR Fortessa flow cytometer, and the data were analyzed with Cytobank (https://cellmass.cytobank.org/cytobank/). The graphs show the median signals as Arcsinh Ratio relative to DMSO (0.1%) control treated cells for the indicated proteins in CD19+ B cells. The vertical lines indicate the reported peak plasma concentration for each drug. c PBMCs from samples T0 and T1 were co-cultured with CD40L/APRIL/BAFF fibroblasts for 24 h to prevent spontaneous apoptosis of the CLL cells. The CLL cells were then separated from the fibroblast layer and treated with a drug library consisting of 94 single agents (left) and 87 drug combinations (right) at 5 different concentrations (1–10,000 nM; 0.1–1000 nM for copanlisib and dasatinib) for 72 h. Cell viability was then assessed with the CellTiter-Glo luminescent cell viability assay. The graphs show the drug sensitivity scores to the different treatments, which were calculated based on the area under the concentration-response curve. High score indicates high sensitivity to the treatment. Select treatments are annotated, and the responses to idelalisib, venetoclax, and idelalisib + venetoclax are indicated in pink. d Blood counts of the CLL patient in response to treatment with idelalisib + venetoclax combination. Note the non-linear time scale. Graphs were made with GraphPad Prism 9 (San Diego, CA, USA).