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. 2024 Feb 13;30(3):716–729. doi: 10.1038/s41591-024-02808-y

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — a, Schema depicting treatment schedule for modules 1 (durvalumab–olaparib), 2 (durvalumab–danvatirsen) and 3 (durvalumab–ceralasertib), showing durvalumab administration (blue arrows), combination agent dosing (continuous colored bars), and pretreatment/on-treatment blood sample collection time points (stars). BID, twice daily. b–g, Effects of ceralasertib and durvalumab treatment on longitudinal blood-derived transcriptomes are depicted in the box plots showing differentially expressed monocyte-associated signatures (b), CD8 T-cell-associated signatures (c), dysfunctional/exhausted CD8 T-cell-associated signatures (d), TNF-α-associated signatures (e), interferon-γ-associated signatures (f) and interferon-α-associated signatures (g). P values are for comparisons with respective cycle 0, day (D) 1 time points. P values for visit dates represent linear mixed model effects, illustrating changes in on-treatment samples. h–q, Effects of ceralasertib, olaparib and danvatirsen with durvalumab on longitudinal blood-derived T cell repertoire: box plots showing productive Simpson T cell clonality with durvalumab–ceralasertib (h); waterfall plots showing changes in clonality on treatment by patient with durvalumab–ceralasertib on cycle 0, day 1 versus cycle 1, day 1 (i) and cycle 1, day 1 versus cycle 1, day 22 (j); box plots showing distributions of T cell clonality with durvalumab–olaparib (k), and waterfall plots showing changes in clonality on treatment by patient with durvalumab–olaparib on cycle 1, day 1 versus cycle 1, day 15 (l); box plots showing distributions of T cell clonality with durvalumab–danvatirsen (m), and waterfall plots showing changes in clonality on treatment per patient with durvalumab–danvatirsen on cycle 1, day 1 versus cycle 1, day 15 (n); box plots of expanded T cell clones (o), newly detected expanded T cell clones (p) and Morisita index for durvalumab plus olaparib, danvatirsen or ceralasertib at indicated visit dates (q). P values for visit dates represent two-sided Wilcoxon paired signed-rank tests between time points or two-sided Wilcoxon signed-rank tests between study modules, with correction for multiplicity of testing (Benjamini–Hochberg procedure), illustrating changes in on-treatment samples. r, Proposed immunomodulatory mechanism of action effects of ceralasertib with durvalumab in the periphery and tumor. For all box plots (b–h, k, m and o–q), box centerlines show medians, box limits show upper and lower quartiles, and whiskers show range.

Fig. 5 — a, Schema depicting treatment schedule for modules 1 (durvalumab–olaparib), 2 (durvalumab–danvatirsen) and 3 (durvalumab–ceralasertib), showing durvalumab administration (blue arrows), combination agent dosing (continuous colored bars), and pretreatment/on-treatment blood sample collection time points (stars). BID, twice daily. b–g, Effects of ceralasertib and durvalumab treatment on longitudinal blood-derived transcriptomes are depicted in the box plots showing differentially expressed monocyte-associated signatures (b), CD8 T-cell-associated signatures (c), dysfunctional/exhausted CD8 T-cell-associated signatures (d), TNF-α-associated signatures (e), interferon-γ-associated signatures (f) and interferon-α-associated signatures (g). P values are for comparisons with respective cycle 0, day (D) 1 time points. P values for visit dates represent linear mixed model effects, illustrating changes in on-treatment samples. h–q, Effects of ceralasertib, olaparib and danvatirsen with durvalumab on longitudinal blood-derived T cell repertoire: box plots showing productive Simpson T cell clonality with durvalumab–ceralasertib (h); waterfall plots showing changes in clonality on treatment by patient with durvalumab–ceralasertib on cycle 0, day 1 versus cycle 1, day 1 (i) and cycle 1, day 1 versus cycle 1, day 22 (j); box plots showing distributions of T cell clonality with durvalumab–olaparib (k), and waterfall plots showing changes in clonality on treatment by patient with durvalumab–olaparib on cycle 1, day 1 versus cycle 1, day 15 (l); box plots showing distributions of T cell clonality with durvalumab–danvatirsen (m), and waterfall plots showing changes in clonality on treatment per patient with durvalumab–danvatirsen on cycle 1, day 1 versus cycle 1, day 15 (n); box plots of expanded T cell clones (o), newly detected expanded T cell clones (p) and Morisita index for durvalumab plus olaparib, danvatirsen or ceralasertib at indicated visit dates (q). P values for visit dates represent two-sided Wilcoxon paired signed-rank tests between time points or two-sided Wilcoxon signed-rank tests between study modules, with correction for multiplicity of testing (Benjamini–Hochberg procedure), illustrating changes in on-treatment samples. r, Proposed immunomodulatory mechanism of action effects of ceralasertib with durvalumab in the periphery and tumor. For all box plots (b–h, k, m and o–q), box centerlines show medians, box limits show upper and lower quartiles, and whiskers show range.