Hematopoietic Stem Cell Transplantation as Immunotherapy

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Hematopoietic Stem Cell Transplantation as
Immunotherapy
Dr. Donna Hogge Leukemia/BMT Program of B.C.
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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 gt80
  unrelated donor transplants in spite of
  prophylactic immunosuppression

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Graft vs Leukemia Reactions After Bone Marrow
Transplantation(Horowitz et al. Blood 75555,
1990)
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Can the graft vs tumor reaction operate
independently of cytoreductive therapy to effect
disease control?
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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)

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Graft-vs-Leukemia Effect of Donor Lymphocyte
Transfusions in Marrow Grafted Patients(Kolb et
al Blood 862041, 1995)
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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
• plt0.00001

Collins et al. JCO, 1997
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Donor Leukocyte Infusions - Vancouver Experience
(1991 - 2002)
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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

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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

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(No Transcript)
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NST Autologous SCT for Multiple Myeloma
(Maloney et al ASH, 2001)

• n41 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)

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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

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NST Initial Results

• Engraftment - donor chimerism can be achieved in
  gt90 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

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HSV-TK Gene Transfer into Donor Lymphocytes for
Control of Allogeneic GVL(Bonini et al. Science
2761719. 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

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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

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ganciclovir
Bonini et al. Science 2761719, 1997
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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

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From Mutis and Goulmy. Sem in Hematol 3923, 2002
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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

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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 (lt 2 X 104 CD3 c/kg)
  ? ?? GVHD
• ?? CD34 c dose (gt5 X 106 c/kg) ? rejection
• Pt conditioned with TBI fludarabine, thiotepa,
  ATG
• no GVHD prophylaxis

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Alloreactive NK cell killing
Tumor Cell
NK cell
MHC recognized- NK function inhibited
MHC NOT recognized - NK cell activated, tumor
cell lysed
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Donor NK Cell Alloreactivity in Mismatched
SCT(Ruggeri et al Science 2952097)
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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