Newest Modalities in Bone Marrow Transplantation

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Richard Champlin, M.D., Chair, Dept. of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center - Newest Modalities in Bone Marrow Transplantation

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Newest Modalities in Bone Marrow Transplantation

  1. 1. New Modalities in Stem Cell Transplantation Richard Champlin, M.D.
  2. 2. Major Innovations SCT-CT• Nonmyeloablative Conditioning• Alternative Donors – Cord Blood – Haploidentical Transplants• Cell Therapy – T-cells – Chimeric Antigen Receptors – NK Cells
  3. 3. Hematopoietic Stem Cell Transplantation Preparative D D Regimen D D HSCT D RR D R D RL DRL D Allogeneic hematopoietic is an effective, but toxic treatment for hematologic malignancies, associated with a high risk of morbidity and mortality (10->50%), restricting its use to young patients without comorbidities
  4. 4. Goal of Conditioning Regimen• Provide immune suppression to prevent rejection and create “space” for engraftment• Eradicate the malignancy – Most effective drugs/radiation treatments for hematologic malignancies also kill normal myeloid and lymphoid cells – Kill malignant stem cells
  5. 5. Allogeneic BMT for CML Importance of GVL High Dose Chemoradiotherapy Donor Lymphocyte InfusionRemission T-cell depletion Identical twin Unmodified Limit of Detection BMT Time
  6. 6. Graft-vs-Malignancy Allogeneic SCT• High dose therapy and allogeneic SCT is an effective treatment for hematologic malignancies• Much of the benefit of alloSCT is due to immune GVL effect; therefore maximally ablative therapy may not be needed.• Lower dose nonmyeloablative preparative regimens are sufficient to prevent rejection.• We hypothesized that a reduced intensity, nonmyeloablative allogeneic transplant could reduce toxicity and allow successful treatment of older patients and those with major comorbidities.
  7. 7. Nonablative and Reduced Intensity RegimensNonablative Reduced Intensity Ablative TBI/CyT F-TBI 2Gy BuF BuCy MF FCR Myelosuppression Champlin et al 2000
  8. 8. Nonmyeloablative Transplant PreparativeDsc DT DT Regimen D DT DT DT HSCT +DLI Dsc DT DB RR DNK Dsc R DT DNK RL R DRL RL D Recipient Donor Mixed Chimera Complete Chimera
  9. 9. Busulfan AUC Relative to Toxicity and aGVHD 0.8 Probability of Mucositis ≥ 3 Probability of GI Toxicity ≥ 3 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 0.0 0.0 800 1000 1200 1400 1600 1800 800 1000 1200 1400 1600 1800 AUC AUC Probability of Hepatic Toxicity ≥ 2 Probability of GVHD ≥ 2 1.0 0.8 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 0.0 0.0 800 1000 1200 1400 1600 1800 800 1000 1200 1400 1600 1800 AUC AUC Andersson et al 2002
  10. 10. Pathophysiology of Acute GVHDAPC=antigen-presenting cell; CTL=cytotoxic T lymphocyte; IFN=interferon;IL=interleukin; LPS=lipopolysaccharide; Mac=macrophage; NK=natural killer cell;TH=T-helper cell; TNF-α=tumor necrosis factor-alpha.
  11. 11. Grade 2-4 Acute GVHD 1.00AC 0.75U HR 3.1 (CI= 1.3-7.2)TE 0.50G BUCY/FMVHD 0.25 0.00 NMA 0 50 100 Days
  12. 12. Nonablative BMT• Reduced toxicity• Reduced GVHD• Similar infections occur, but generally respond to therapy• Lower treatment related mortality• Can extend the use of HSCT to patients up to 75 years of age
  13. 13. Comparisons Albative vs. RIC SCT • Lack of randomized controlled trials • Non-randomized comparisons always confounded by different patient populations – Ablative- young, fit patients – RIC- Older patients with comorbidities • Conclusions – RIC higher relapse, lower NRM, survival not significantly different. • Can one develop effective anti-tumor preparative regimens, with acceptable (less) toxicity?
  14. 14. IV Bu-Flu Overall Survival and Event Free Survival 1.0 1.0 0.8 0.8 Event-free probabilitySurvival Probability 0.6 0.6 0.4 0.4 In remission, PB.blast=0 Active Disease, PB.blast=0 Active Disease, PB.blast>0 0.2 In remission, PB.blast=0 0.2 Active Disease, PB.blast=0 p<0.0001 Active Disease, PB.blast>0 p<0.0001 0.0 0.0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time(weeks) Time(weeks)
  15. 15. Nonablative AlloSCT vs Chemo for Elderly AML
  16. 16. Opportunities for Cure in CML Preparative RegimenCML Cell Mass Donor Lymphocyte Imatinib Infusion Time
  17. 17. Survival
  18. 18. Ablative Allo-BMT in Indolent Lymphoma 100 Survival DFS Probability, % 80 Treatment-related mortality Relapse 60 40 20 0 0 1 2 3 4 5 6van Besien et al. Blood. 1998;92:1832-1836. Years
  19. 19. NON-MYELOABLATIVE ALLOGENEIC SCT Conditioning Regimen Rituximab Fludarabine 30 mg/m2 Rituximab 375 mg/m2 Cyclophosphamide 750 mg/m2 1000mg/m2 ASCTDays -13 -6 -5 -4 -3 0 +1 +8•ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated SCT•Tacrolimus and methotrexate were used for GVHD prophylaxis
  20. 20. FCR allo SCT for Low Grade Lymphoma Khouri et al Blood 2008
  21. 21. Rituximab: Mechanism of Action Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Macrophage, Monocyte, or Natural Killer Cell CD20 FcγRI, FcγRII, or FcγRIII CELL LYSISAnderson DR, et al. Biochem Soc Trans. 1997;25:705-708,Clynes RA, et al. Nat Med. 2000;6:443-446.
  22. 22. RituximabAntigen Presentation and Cross-Priming Tumor Cell T Cells FcR Tumor Antigen Dendritic Cell
  23. 23. Efficacy of Nonablative HSCTHighly Effective Dose Intensity(better than ablative) ImportantLGL, CLL CMLMantle cell lymphoma AML /MDSMyeloma (tandem)? LCL, Hodgkin’s diseaseRenal Cell, Ovarian ALLBreast CA-Promising
  24. 24. ATG with RIC SCT CIBMTR-Soiffer Blood 2011• Compare T-replete transplants with no ATG, ATG, Alemtuzumab• ATG- assoc with decreased cGVHD, increased relapse, worse PFS and survival• Alemtuzumab- assoc with decreased acute and cGVHD, increased relapse, no change in survival
  25. 25. Best Available Donor
  26. 26. MD Anderson Cord Blood Bank Elizabeth J. Shpall MD
  27. 27. Cord Blood Transplantation• Rich source of stem cells• ~50,000 units banked, immediately available for transplantation• Immunologically immature- less prone to produce GVHD• Less risk of transmitting infection• Can successfully transplant across HLA mismatch• Major concern- low stem cell dose, longer time to engraftment- may be overcome by ex vivo expansion• Results comparable to MUD BMTs
  28. 28. Mesenchymal Stem Cells (MSC) • MSC are a stromal component of the hematopoietic microenvironment. • They provide cellular and extracellular components of the stem cell “niche”. • When isolated and used in vitro in combination with cytokines, MSC markedly increase the expansion of CB hematopoietic progenitors.
  29. 29. Co-culture with MSC significantly enhances ex vivo expansion of CB cellsFold increase x13 x25 x7 x14 x200 x44 Day 14 hematopoietic output from liquid culture of CD133+ (solid bar) vs. co-culture of non-selected CB cells with MSC (striped bar) Robinson et al. Bone Marrow Transplantati
  30. 30. MSC-CB Expansion Trial Engraftment Data Median time to engraftment (range) Neutrophil (>500/µl) 15 days (range 9-42) Platelet (>20,000/µl) 40 days (range 13-62) Cumulative Incidence of Engraftment Neutrophil (>500/µl) 97% (n=31) Platelet (>20,000/µl) 81% (n=26) - One patient died before engraftment de Lima et al. Blood (ASH Annual Meeting Abstracts), 2010; 116: 362
  31. 31. Post Transplant Cyclophosphamide for Haploidentical Transplantation
  32. 32. NST for Haploidentical Transplantation Luznick et al 2008
  33. 33. Cell Therapy +/- HSCT
  34. 34. T-cell Immune ResponseT-Cell Activationand Proliferation 36
  35. 35. Chimeric antigen receptors (CARs)TCR-complex Antibody α βγε εδ ζ ζ vL Fab vH CL CH1 vH vL Chimeric antigen receptor (Eshhar et al; PNAS 1993)
  36. 36. Chimeric Antigen Receptors Cooper et al
  37. 37. Allo NK-based conditioning:Ablation of recipient targets Kill recipient APCs = protection from GvHD Donor DC alloreactive DC NK cells DC NK Lysis NK NK Lysis leukemia Lysis Kill leukemia = T TT T GvL effect Kill recipient T cells = improved engraftment Ruggeri et al. Science 2002
  38. 38. Addition of NK cells to HSCTPhase I/II study to determine toxicity and efficacy of addition ofalloreactive NK cells to high dose chemotherapy and allogeneicstem cell transplantation for myeloid leukemias Haploidentical Allo reactive Allo match Busulfan NK Cells PBPC ATG Fludarabine Champlin et al
  39. 39. Hematopoiesis T-lymphocytesStem Cells B-lymphocytes Granulocytes Monocytes Eosinophils Basophils Erythrocytes Megakaryocytes Platelets
  40. 40. GlandsGI tract, islet cells Immune System Blood Heart Stem CellMesenchymal Blood vessels Fibrous tissue Nervous System Liver and other organs
  41. 41. Approach to Abrogate GVHD
  42. 42. Suicide Switch- Prevention of GVHD 45
  43. 43. Modified Caspace 9- Self Destruct Switch 46
  44. 44. If We Can Prevent GVHD• Dramatically expand use of allogeneic SCT • Bone marrow failure/immune deficiency/metabolic diseases of hematopoietic cells • Non malignant hematologic/metabolic/immune mediated diseases – Thalassemia, Hemoglobinapathies – Autoimmune diseases » Arthritis, Diabetes, Rheumatologic diseases, …… • Tolerance for Organ Transplants • Malignant Diseases – Eliminates major toxicity of highly effective treatment
  45. 45. Ideal Nonablative Hematopoietic Transplant Preparative D D D D D Regimen D D Vaccine or Immune HSCT Effector cells R R R D D DR D D R D D RL R DRL RL D Recipient Donor Tolerant Complete Chimera Mixed Chimera No GVHD, Immune Reconstitution, GVL for malignancy

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