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Hematopoietic Stem Cell Transplantation as Immunotherapy

Hematopoietic Stem Cell Transplantation as Immunotherapy. Dr. Donna Hogge Leukemia/BMT Program of B.C. Graft Versus Host Disease Post Allogeneic Hematopoietic Stem Cell Transplant. Immunological reaction mediated by donor T lymphocytes against recipient tissues (skin, liver, gut)

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Hematopoietic Stem Cell Transplantation as Immunotherapy

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  1. Hematopoietic Stem Cell Transplantation as Immunotherapy Dr. Donna Hogge Leukemia/BMT Program of B.C.

  2. Graft Versus Host Disease Post Allogeneic Hematopoietic Stem Cell Transplant • Immunological reaction mediated by donor T lymphocytes against recipient tissues (skin, liver, gut) • may occur as an ‘acute’ form within 100d of BMT or a chronic form thereafter which may persist for years • some degree of GVHD seen in ~50% sibling and >80% unrelated donor transplants in spite of prophylactic immunosuppression

  3. Graft vs Leukemia Reactions After Bone Marrow Transplantation(Horowitz et al. Blood 75:555, 1990)

  4. Can the graft vs tumor reaction operate independently of cytoreductive therapy to effect disease control?

  5. Donor Leukocyte Infusions (DLI) for Relapse post BMT • Peripheral blood mononuclear cells collected from marrow donors using a blood cell separator • In initial studies the dose was highly variable (0.1 - 15 x 108c/kg recipient weight)

  6. Graft-vs-Leukemia Effect of Donor Lymphocyte Transfusions in Marrow Grafted Patients(Kolb et al Blood 86:2041, 1995)

  7. Relationship of DLI Response to GVHD • 93% CR patients developed acute GVHD • 88% CR patients developed chronic GVHD • 13% patients who had neither acute nor chronic GVHD obtained CR • p<0.00001 Collins et al. JCO, 1997

  8. Donor Leukocyte Infusions - Vancouver Experience (1991 - 2002)

  9. Sensitivity to Graft vs Malignancy Effects • Sensitive • CML • Low grade NHL • CLL • Intermediate • AML • Intermediate grade NHL • Multiple Myeloma • Insensitive • ALL • High grade NHL • Promising (more data required) • breast cancer • renal cell carcinoma

  10. Nonmyeloablative Stem Cell Transplants (NST) • aka ‘reduced intensity conditioning transplants’ or ‘mini-transplants.’ • Rationale -  intensity of chemo/radiotherapy conditioning to  morbidity and mortality • Conditioning is sufficiently ‘immunosuppressive’ to allow engraftment of donor cells • Engrafted donor cells mediate the therapeutic ‘graft vs tumor’ effect

  11. NST + Autologous SCT for Multiple Myeloma(Maloney et al ASH, 2001) • n=41 median age 52 y (29 - 71) • Stage II (27%) or III (73%), 90% previous VAD chemo • Cy + G-CSF BPC mobilization and collection ~30d • autologous SCT with melphalan 200 mg/m2 40 - 120d • sibling NST with 200 cGY TBI (MMF + CSA GVH prophylaxistaper 80 - 180 d)

  12. NST + Auto SCT for Myeloma (cont) • Full chimerism by 1 - 2 mos without DLI • GVHD - 46% grade II - IV acute - 45% chronic • TRM at 1 yr - 12% (6 pts, 3 with GVHD) Disease Status Study Entry Post NST • CR - 6 6 - CR • PR - 15 9 - CR 5 - PR 1 - SD • Relapsed/refractory - 20 10 - CR 6 - PR 1 - SD 2 - PD

  13. NST Initial Results • Engraftment - donor chimerism can be achieved in >90% of patients with various conditioning regimens • Toxicity- TRM of ~ 20% in most series • acute and chronic GVHD and opportunistic infections seen with myeloablative conditioning still occur • Efficacy -longer follow-up, larger patient numbers, randomized trials required

  14. HSV-TK Gene Transfer into Donor Lymphocytes for Control of Allogeneic GVL(Bonini et al. Science 276:1719. 1997) • HSV-TK (herpes simplex virus-thymidine kinase) gene expression renders cells susceptible to killing by ganciclovir • retroviral transduction of HSV-TK into DLI • DLI to treat relapse of CML (3), AML (3) or CmML (1), or EBV-LPD (2) post allo SCT

  15. HSV-TK Gene Transfer (cont) • 5/8 patients show tumor regression (3 CR) • 3 pts developing GVHD are treated with ganciclovir - 2 CR of acute GVH - 1 PR of chronic GVH • HSV-TK-transduced cells disappear as GVH regresses

  16. ganciclovir Bonini et al. Science 276:1719, 1997

  17. Hematopoietic Specific Minor Histocompatibility Ag (mHags) as Targets for Immunotherapy • mHags - peptides from polymorphic proteins, expressed on the plasma membrane and recognized by allo-MHC-restricted T cells • certain mHags have restricted expression on hematopoietic cells • effective lysis of leukemia cells and progenitors by mHag-specific CTLs

  18. From Mutis and Goulmy. Sem in Hematol 39:23, 2002

  19. Cellular Immunotherapy Strategies Using mHags HA-1/HA-2 • Immunotherapy of leukemic relapse with self-restricted mHag-specific CTLS after allo-SCT • vaccination of SCT donors with autologous dendritic cells pulsed with mHag peptides or transduced with mHag cDNA • use CTLs as a ‘booster’ in recipient after SCT

  20. Haploidentical SCT(Second European Workshop 12 - 14 Oct., 2000, Perugia, Italy) • ‘All’ patients will have a family donor • barriers include - graft rejection and GVHD • aggressive T-cell depletion (< 2 X 104 CD3+ c/kg)   GVHD •  CD34+ c dose (>5 X 106 c/kg) rejection • Pt conditioned with TBI + fludarabine, thiotepa, ATG • no GVHD prophylaxis

  21. Alloreactive NK cell killing Tumor Cell NK cell MHC recognized- NK function inhibited MHC NOT recognized - NK cell activated, tumor cell lysed

  22. Donor NK Cell Alloreactivity in Mismatched SCT(Ruggeri et al Science 295:2097)

  23. Conclusions • Donor alloreactivity can be harnessed for anti-tumor efficacy • Separating GVL from GVH for clinical SCT protocols remains challenging • Current progress in identifying and isolating effector cells and target antigens should soon allow the GVL effect to benefit more patients

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