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In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial  Divya T. Koura, John T.

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Presentation on theme: "In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial  Divya T. Koura, John T."— Presentation transcript:

1 In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial  Divya T. Koura, John T. Horan, Amelia A. Langston, Muna Qayed, Aneesh Mehta, Hanna J. Khoury, R. Donald Harvey, Yvonne Suessmuth, Cynthia Couture, Jennifer Carr, Audrey Grizzle, Heather R. Johnson, Jennifer A. Cheeseman, Jason A. Conger, Jennifer Robertson, Linda Stempora, Brandi E. Johnson, Aneesah Garrett, Allan D. Kirk, Christian P. Larsen, Edmund K. Waller, Leslie S. Kean  Biology of Blood and Marrow Transplantation  Volume 19, Issue 11, Pages (November 2013) DOI: /j.bbmt Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

2 Figure 1 Neutrophil engraftment. The percent of patients demonstrating neutrophil engraftment (the first of 3 consecutive days with an absolute neutrophil count >500/μL) is depicted in red for ABA patients and black for the contemporaneous control cohort. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

3 Figure 2 Viral reactivation and immune response in ABA patients. (A) CMV viral load. (B) EBV viral load. (C) Representative flow cytometry analysis of intracellular cytokine expression after stimulation with CMV-specific peptides. Cells were gated as follows: Lymphocytes were identified, and singlets were then gated. Live CD20−/CD14−/CD3+ cells were identified, and CD8+/CD4− cells were then identified. CD8+/CD4−/CD3+/CD20−/CD14− T cells producing both IFN-γ and TNF were then enumerated. (D) Summary data showing the percent of CD8+ T cells producing both IFN-γ and TNF. A comparison of baseline versus day +180 in both the ABA (n = 7) and StdRx (n = 3) cohorts. Data are mean ± SEM. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

4 Figure 3 Pharmacokinetic and pharmacodynamic analysis of abatacept during HCT. (A) Pharmacokinetic analysis. Abatacept levels were measured by ELISA on serum samples drawn on days −1, +5, +14, +28, + 42, +60, +100, +180, +365 post-transplantation. Data are mean ± SEM (n = 10). The inset shows the average peak abatacept levels for doses 1 and 2 and for doses 3 and 4, the average trough abatacept levels and the terminal half-life. (B) Pharmacodynamic analysis showing decreased CD4+ proliferation in patients treated with abatacept. Representative flow cytomety analysis shows Ki-67+ staining of CD4+ T cells in StdRx cohort patients (left) and ABA patients (right). Flow cytometry plots were first gated on lymphocytes, and then on CD3+/CD14− T cells. CD4+/CD8−/CD3+/CD14− T cells were then evaluated for the amount of Ki-67 expression. (C) Enumeration of Ki-67+ CD4+ T cells was performed using BD TruCount Beads as described in Methods. Data are mean ± SEM of the Ki-67+ CD4+ T cells in ABA patients (n = 10, red) and StdRx patients (n = 7, black). *P < .05; **P < .01, Wilcoxon rank-sum test. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

5 Figure 4 Longitudinal analysis of immune reconstitution in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10; red traces) and StdRx patients (n = 6; black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of 10 healthy controls (green). (A) Longitudinal analysis of the absolute lymphocyte count post-transplantation. (B) Longitudinal analysis of the absolute NK cell count (CD3−/CD20−/CD16+/CD56+/− lymphocytes) post-transplantation. (C) Longitudinal analysis of the absolute T cell count (CD3+/CD20− lymphocytes) post-transplantation. (D) Relative proportion of T cells (circles with solid lines) and NK cells (squares with dotted lines) post-transplantation in ABA patients (red traces) and StdRx patients (black traces). Also shown is the mean ± SEM of 10 healthy controls (green). Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

6 Figure 5 Reconstitution of CD4+ and CD8+ T cells post-transplantation. (A and B) Longitudinal analysis of CD4+ and CD8+ T cell reconstitution in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of 10 healthy controls (green diamonds). *P < .05, Wilcoxon rank-sum test. (C) Comparison of day +100 CD4+ T cell counts between ABA patients (n = 10) and the contemporaneous control cohort (n = 22). Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

7 Figure 6 Transient inhibition of accumulation of proliferating and activated CD4+ T cell subsets in ABA patients. (A) Representative flow cytometry showing the following gating strategy. Lymphocytes were gated, and then CD3+/CD14− T cells were identified. CD4+/CD8− and CD4−/CD8+ populations were identified, and then Tn (CD45RA+/CCR7+), Tcm (CD45RA−/CCR7+), Tem (CD45RA−/CCR7−), and Temra (CD45RA+/CCR7−) subpopulations of both CD4+ and CD8+ T cells were identified. The amount of proliferation (Ki-67 expression) or activation (dual HLA-DR+/CD38+ expression) on each of these subpopulations was then determined. (B-F) Longitudinal analysis of the number of proliferating (Ki-67+) total CD4+ (B), CD4+ Tn (C), Tcm (D), Tem (E), and Temra (F) subpopulations in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (G-J) Longitudinal analysis of the total number of reconstituting CD4+ Tn (G), Tcm (H), Tem (I), and CD4+ Temra (J) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (K and L) Longitudinal analysis of the total number of activated (HLA-DR+/CD38+) CD4+ Tem (K) and CD4+ Tcm (L) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (M) Representative flow cytometry analysis of putative Tregs. Lymphocytes were identified, and then CD3+/CD4+ T cells were identified. These cells were gated for CD127, CD25, and FoxP3. Putative Tregs are identified as CD3+/CD4+/CD127low/CD25high/FoxP3+ cells. (N) Longitudinal analysis of the total number of CD3+/CD4+/CD127low/CD25high/FoxP3+ cells in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). *P < .05; **P < .01, Wilcoxon rank-sum test. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

8 Figure 6 Transient inhibition of accumulation of proliferating and activated CD4+ T cell subsets in ABA patients. (A) Representative flow cytometry showing the following gating strategy. Lymphocytes were gated, and then CD3+/CD14− T cells were identified. CD4+/CD8− and CD4−/CD8+ populations were identified, and then Tn (CD45RA+/CCR7+), Tcm (CD45RA−/CCR7+), Tem (CD45RA−/CCR7−), and Temra (CD45RA+/CCR7−) subpopulations of both CD4+ and CD8+ T cells were identified. The amount of proliferation (Ki-67 expression) or activation (dual HLA-DR+/CD38+ expression) on each of these subpopulations was then determined. (B-F) Longitudinal analysis of the number of proliferating (Ki-67+) total CD4+ (B), CD4+ Tn (C), Tcm (D), Tem (E), and Temra (F) subpopulations in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (G-J) Longitudinal analysis of the total number of reconstituting CD4+ Tn (G), Tcm (H), Tem (I), and CD4+ Temra (J) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (K and L) Longitudinal analysis of the total number of activated (HLA-DR+/CD38+) CD4+ Tem (K) and CD4+ Tcm (L) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (M) Representative flow cytometry analysis of putative Tregs. Lymphocytes were identified, and then CD3+/CD4+ T cells were identified. These cells were gated for CD127, CD25, and FoxP3. Putative Tregs are identified as CD3+/CD4+/CD127low/CD25high/FoxP3+ cells. (N) Longitudinal analysis of the total number of CD3+/CD4+/CD127low/CD25high/FoxP3+ cells in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). *P < .05; **P < .01, Wilcoxon rank-sum test. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

9 Figure 6 Transient inhibition of accumulation of proliferating and activated CD4+ T cell subsets in ABA patients. (A) Representative flow cytometry showing the following gating strategy. Lymphocytes were gated, and then CD3+/CD14− T cells were identified. CD4+/CD8− and CD4−/CD8+ populations were identified, and then Tn (CD45RA+/CCR7+), Tcm (CD45RA−/CCR7+), Tem (CD45RA−/CCR7−), and Temra (CD45RA+/CCR7−) subpopulations of both CD4+ and CD8+ T cells were identified. The amount of proliferation (Ki-67 expression) or activation (dual HLA-DR+/CD38+ expression) on each of these subpopulations was then determined. (B-F) Longitudinal analysis of the number of proliferating (Ki-67+) total CD4+ (B), CD4+ Tn (C), Tcm (D), Tem (E), and Temra (F) subpopulations in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (G-J) Longitudinal analysis of the total number of reconstituting CD4+ Tn (G), Tcm (H), Tem (I), and CD4+ Temra (J) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (K and L) Longitudinal analysis of the total number of activated (HLA-DR+/CD38+) CD4+ Tem (K) and CD4+ Tcm (L) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (M) Representative flow cytometry analysis of putative Tregs. Lymphocytes were identified, and then CD3+/CD4+ T cells were identified. These cells were gated for CD127, CD25, and FoxP3. Putative Tregs are identified as CD3+/CD4+/CD127low/CD25high/FoxP3+ cells. (N) Longitudinal analysis of the total number of CD3+/CD4+/CD127low/CD25high/FoxP3+ cells in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). *P < .05; **P < .01, Wilcoxon rank-sum test. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

10 Figure 6 Transient inhibition of accumulation of proliferating and activated CD4+ T cell subsets in ABA patients. (A) Representative flow cytometry showing the following gating strategy. Lymphocytes were gated, and then CD3+/CD14− T cells were identified. CD4+/CD8− and CD4−/CD8+ populations were identified, and then Tn (CD45RA+/CCR7+), Tcm (CD45RA−/CCR7+), Tem (CD45RA−/CCR7−), and Temra (CD45RA+/CCR7−) subpopulations of both CD4+ and CD8+ T cells were identified. The amount of proliferation (Ki-67 expression) or activation (dual HLA-DR+/CD38+ expression) on each of these subpopulations was then determined. (B-F) Longitudinal analysis of the number of proliferating (Ki-67+) total CD4+ (B), CD4+ Tn (C), Tcm (D), Tem (E), and Temra (F) subpopulations in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (G-J) Longitudinal analysis of the total number of reconstituting CD4+ Tn (G), Tcm (H), Tem (I), and CD4+ Temra (J) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (K and L) Longitudinal analysis of the total number of activated (HLA-DR+/CD38+) CD4+ Tem (K) and CD4+ Tcm (L) cells in the ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). (M) Representative flow cytometry analysis of putative Tregs. Lymphocytes were identified, and then CD3+/CD4+ T cells were identified. These cells were gated for CD127, CD25, and FoxP3. Putative Tregs are identified as CD3+/CD4+/CD127low/CD25high/FoxP3+ cells. (N) Longitudinal analysis of the total number of CD3+/CD4+/CD127low/CD25high/FoxP3+ cells in ABA and StdRx cohorts. Shown are absolute numbers ± SEM of cells from ABA patients (n = 10, red traces) and StdRx (n = 6, black traces) measured longitudinally post-transplantation. Also shown is the mean ± SEM of cells from 10 healthy controls (green diamonds). *P < .05; **P < .01, Wilcoxon rank-sum test. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

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