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New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)
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New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD)

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  • 1. New Strategies for the Prevention and Treatment of Graft vs. Host Disease (GVHD) Simrit Parmar, MD Stem Cell Transplant & Cellular Therapy BTG2013, Hong Kong
  • 2. Risk Factors for Acute GVHD • HLA disparity • Increasing age • Donor and recipient gender disparity • Type and status of underlying disease • Amount of radiation and intensity of the transplant conditioning regimen • Doses of methotrexate and cyclosporine or tacrolimus
  • 3. Acute GVHD: Pathophysiology 1. Recipient conditioning 2. Donor T cell activation 3. Cellular and Inflammatory Effectors
  • 4. Acute GVHD • Acute GVHD – Typically occurs around the time of engraftment. – Previously mis-defined as GVHD which occurs prior to day 100 post-transplant. – Three main organs involved: • Skin: macularpapular rash • GI system: Nausea / Vomiting and Diarrhea • Liver Abnormalities: typically cholestatic (jaundice). – Incidence of 9-50% of sib transplants. Vigorito et al. Blood 2009
  • 5. Acute GVHD: Survival and Relapse • Grade 0 acute GVHD — hazard ratio (HR) for TRM: 1.0 • Grade I — HR 1.5 (95% CI 1.2-2.0) • Grade II — HR 2.5 (95% CI 2.0-3.1) • Grade III — HR 5.8 (95% CI 4.4-7.5) • Grade IV — HR 14.7 (95% CI 11-20) • Grade 0 acute GVHD — hazard ratio (HR) for relapse 1.0 • Grade I — HR 0.94 (95% CI 0.8-1.2) • Grade II — HR 0.60 (95% CI 0.5-0.8) • Grade III — HR 0.48 (95% CI 0.3-0.8) • Grade IV — HR 0.14 (95% CI 0.02-0.99) D E A T H R E L A P S E
  • 6. “Be good or I’ll send you to transplant” “”I am telling you, by the time they get done with you, you’ll be wearing diapers” “Do you want a little vidaza or total body skin sloughing?”
  • 7. GVHD Prophylaxis
  • 8. “No Free Lunch” Principle GVHD • Relapse • Rejection • Delayed Immune Reconstitution GVHD
  • 9. Immune Function in HCT • Dysfunctional immune responses are common in clinical medicine • Major mechanism of disease control due to GVT reactions, yet major limitation of allogeneic HCT is GVHD • Controlling GVHD could lead to use of allogeneic HCT in other clinical settings such as treatment of autoimmune diseases and tolerance induction for organ transplantation
  • 10. Risk of GVHD in Two Eras Gooley et al. N. Engl. J Med 363:2091, 2010
  • 11. In vivo tracking of light emitting donor cells Allogeneic HCT B T M BM BM BM B T Bone Marrow Splenocytes FVB/N WT luc+ Balb/c H-2q/Thy1.1H-2d/Thy1.2 CD4+ CD8+ B220+ NK1.1+ Gr-1/Mac-1+ 2x105 cells/well Absolute light emission 0.00 0.05 0.10 0.15 Luciferase 2A eGFPAct luc+ reporter mouse
  • 12. Acute Graft-vs-Host Disease Development Beilhack, A. et al. Blood. 2005. 106:1113
  • 13. The Evolution of acute GVHD
  • 14. Approaches to the Prevention of GVHD • Pharmacologic – CNI/MTX – CNI/MTX vs Rapa/MTX • Graft source – BM vs PBPC – MRD vs URD vs UCB • T Cell depletion – CD34 Selection – ATG, Campath • Immune regulation
  • 15. Regulation of Immune Function • Critically important in health and disease • Compartmentalization of immune responses • Cytokines • Regulatory T cells (Treg, NK-T, iTreg, others) RegulationReactivity T regulatory cellT effector cell CD4+ T Cell Subsets
  • 16. CD4+CD25+ Regulatory T Cells • Major population of cells which regulate immune reactions • Express transcription factor FoxP3 • Deficiency or mutation of FoxP3 has autoimmune consequences in animal models and humans • Cell contact-dependent suppression of alloreactive responses in mixed lymphocyte reactions (MLR) • Prevent organ specific autoimmune diseases in animal models (e.g. IBD, diabetes) • IL-10 and TGF- implicated in mediating suppressive effect in vivo
  • 17. Regulatory T-cells • Allogeneic HCT recipients with aGVHD had Treg frequencies 40% less than those without aGVHD. • Treg frequencies decreased linearly with acute GVHD severity. • The frequency of Tregs at acute GVHD onset predicted response to therapy. Magenau et al. BBMT. 2010.
  • 18. Magenau et al. BBMT. 2010. 38% 63% Circulating Tregs predict OS
  • 19. d15 Death from GVHD 100 5000 1000 20000 1 10 100 1000 10000 0 20 40 60 0 20 40 600 20 40 60 Time [d] post BMT RelativeSignalIntensity 0 25 50 75 100 0 20 40 60 Time [d] post BMT Survival[%] TCD BM only, n = 14 TCD BM + Tcon, n = 15 TCD BM + Tcon + Treg n = 9 Control of GVHD with Retention of GVL TconBM only Tcon + Treg 500 5000 d5 Edinger et al. Nature Medicine 9:1144, 2003
  • 20. Challenges for Clinical Translation of Treg • Treg are rare cell populations • Paucity of unique markers for isolation and availability of clinical grade reagents • Marginal functional assays in humans • Regulatory requirements
  • 21. Expanded CB Tregs show FOXP3 demethylation and suppress alloMLR
  • 22. 3rd Party CB Tregs Prevent GVHD
  • 23. In vivo tracking of Treg transduced with GFP and Firefly Luciferase
  • 24. Treg Treg+PBPC Day -1 Day 0 Day 3 dorsal
  • 25. Treg Treg+PBPC Day -1 Day 0 Day 3 dorsal
  • 26. Treg Treg+PBPC Day -1 Day 0 Day 3 dorsal
  • 27. Treg Treg+PBPC Day -1 Day 0 Day 3 dorsal
  • 28. Treg Treg+PBPC Day 3 Day 10 ventral
  • 29. Proposed phase I Clinical Trial Treg Doses to be Studied Dose Cohort Treg Dose Dose Level 1 1 × 105 Tregs/kg Dose Level 2 5 × 105 Tregs/kg Dose Level 3 1 × 106 Tregs/kg Dose Level 4 5 × 106 Tregs/kg Dose Level 5 1 × 107 Tregs/kg
  • 30. Next Step: Adoptive Therapy with Treg Day -8 Day -7 Day -6 Day -5 Day -4 Day -3 Day -2 Day- 1 0 +1 +2 Day +3 Day +4 Day +6 BU Test Dose 32mg/m2 Rest BU BU BU BU BMT Infusion of Ex-vivo Expanded Tregs FLU 40 mg/m 2 FLU 40 mg/ m2 FLU 40 mg/ m2 FLU 40 mg/ m2 CY** 50 mg/k g CY** 50 mg/k g Day -6 Day -5 Day -4 Day -3 Day -2 Day-1 0 MEL BU BU BU Infusion of Ex-vivo Expanded Tregs BMT FLU 40 mg/m2 FLU 40 mg/m2 FLU 40 mg/m2 FLU 40 mg/m2 MMF+Sirolimus
  • 31. Individual clinical outcome of patients who received a Treg dose > 30x105/kg
  • 32. Haploidentical Transplant Schema (Stanford) Mel, TT, Flu + Thymoglobulin@ 0 +14 +16Day -10 CD34+ cell selected graft CD4+CD25+ Treg CD4+/CD8+ Tcon Cell Dose 5-10 x 106/kg 105/kg 3x105/kg 106/kg Endpoints: Chimerism Immune reconstitution Acute and chronic GVHD EFS, OS BB IND13923
  • 33. Selection of CD4+CD25+ Tregs (U. Perugia) Cells (x109) 1060 (540-1370) 280 (202- 390) %CD4CD25 3.0 (1.5-7.45) 92.4 (90-97.1) N° cells (x 106) 330 (221-1020) 256 (185.6-365.4) %CD4CD25high 0.3 (0.12- 0.89) 33.6 (14.4-39.6) N° cells (x 106) 36.12 (19.98 - 84) 68.6 (20.9-143) Starting fraction Final fraction CD25 CD127 CD4 FoxP3 Gate on CD4CD25+high Gate on CD4CD25+ Fox P3+ cells 71.9 ± 15 % Immunomagnetic Selection of CD4+CD25+Cells 1st step: Depletion of CD8+/CD19+cells 2ndstep: Enrichment of CD25+ cells
  • 34. >50 >100 >200 0 50 100 150 200 CD4/ l DayspostBMT >50 >100 >200 0 20 40 60 80 100 CD8/ l DayspostBMT Recovery of CD4+ and CD8+ T cell subpopulations 0 50 100 150 200 250 1 2 3 4 5 6 7 8 9 10 11 12 SpectratypecompexityScore Donors Months after transplant Complexityscore Spectratyping Pattern of immunoreconstitution
  • 35. Evaluable Patients Patients with CMV reactivation 0 10 20 30 40 50 60 70 80 90 100 0-30 31-60 61-90 91-120 121-150 151-180 181-365 >365 100 96 82 75 67 56 48 2928 50 34 22 9 9 1 1 0 5 10 15 20 25 30 0-30 31-60 61-90 91-120 121-150 151-180 181-365 >365 27 21 16 10 9 5 2 12 5 1 0 0 0 0 0 Days after transplant Days after transplant CMV reactivation episodes Tregs Group Control Group p<0.05
  • 36. Outcomes – U. of Perugia Event-Free Survival 12/26 (46%) • Regimen Related Toxicities: – Veno-occlusive disease (3) – Multi-organ failure (1) • Acute GVHD grade III-IV (2) • Serious infections (7) • Relapse (AML 1) Median follow-up 18.5 months (range 16.1-27.6) D’Ianni et al. Blood 2011
  • 37. Conclusions • GVHD remains the most significant complication following allogeneic HCT • Murine studies have demonstrated that immune regulatory mechanisms play a significant role in controlling dysfunctional immune responses including GVHD • Clinical translation is ongoing with promising early results

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