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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). Simrit Parmar, MD Stem Cell Transplant & Cellular Therapy BTG2013, Hong Kong. Risk Factors for Acute GVHD. HLA disparity Increasing age Donor and recipient gender disparity

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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 3. Cellular and Inflammatory Effectors 2. Donor T cell activation

  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 TH R E L AP SE

  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 GVHD • Relapse • Rejection • Delayed Immune • Reconstitution

  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. 2x105 cells/well Absolute light emission CD4+ CD8+ luc+ reporter mouse H-2q/Thy1.1H-2d/Thy1.2 B220+ NK1.1+ FVB/N Bone Marrow Gr-1/Mac-1+ BM 0.00 0.05 0.10 0.15 BM BM T Balb/c WT B B M T Splenocytes bAct Luciferase 2A eGFP luc+ Allogeneic HCT In vivo tracking of light emitting donor cells

  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 Reactivity Regulation of Immune Function • Critically important in health and disease • Compartmentalization of immune responses • Cytokines • Regulatory T cells (Treg, NK-T, iTreg, others) T regulatory cell T 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. Circulating Tregs predict OS 63% 38% Magenau et al. BBMT. 2010.

  19. Control of GVHD with Retention of GVL Survival [%] Time [d] post BMT BM only Tcon Tcon + Treg 5000 5000 Death from GVHD TCD BM only, n = 14 d5 TCD BM + Tcon, n = 15 TCD BM + Tcon + Treg n = 9 100 500 20000 d15 1000 Relative Signal Intensity 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 Tregtransduced with GFP and Firefly Luciferase

  24. dorsal TregTreg+PBPC Day -1 Day 0 Day 3 Day 10

  25. dorsal TregTreg+PBPC Day -1 Day 0 Day 3 Day 10

  26. dorsal TregTreg+PBPC Day -1 Day 0 Day 3 Day 10

  27. dorsal TregTreg+PBPC Day -1 Day 0 Day 3 Day 10

  28. ventral TregTreg+PBPC Day 3 Day 10

  29. Proposed phase I Clinical Trial

  30. Next Step: Adoptive Therapy with Treg MMF+Sirolimus

  31. Individual clinical outcome of patients who received a Treg dose > 30x105/kg

  32. Haploidentical Transplant Schema (Stanford) Endpoints: Chimerism Immune reconstitution Acute and chronic GVHD EFS, OS CD34+ cell selected graft CD4+CD25+ Treg CD4+/CD8+ Tcon Mel, TT, Flu + Thymoglobulin@ Day -10 0 +14 +16 5-10 x 106/kg 105/kg 3x105/kg 106/kg Cell Dose BB IND13923

  33. Gate on CD4CD25+high Starting fraction Final fraction 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) Gate on CD4CD25+ CD25 CD4 FoxP3 CD127 Selection of CD4+CD25+Tregs (U. Perugia) 1st step: Depletion of CD8+/CD19+cells Immunomagnetic Selection of CD4+CD25+Cells 2ndstep: Enrichment of CD25+ cells Fox P3+ cells 71.9 ± 15 %

  34. Pattern of immunoreconstitution Recovery of CD4+ and CD8+ T cell subpopulations Spectratyping Donors Complexity score Months after transplant

  35. CMV reactivation episodes Tregs Group EvaluablePatients Days after transplant Patients with CMV reactivation p<0.05 Control Group Days after transplant

  36. Outcomes – U. of Perugia Median follow-up 18.5 months (range 16.1-27.6) 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) 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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