Total Lymphoid Irradiation Conditioning For HSCT: From Mice to Humans

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Total Lymphoid Irradiation Conditioning For HSCT
From Mice to Humans

• Meagan Jacoby
• November 2, 2007

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Trends in Allogeneic TransplantsRecipient
Age1987-2004
20 yrs 21-40 yrs 41-50 yrs 51-60 yrs gt60 yrs
Modified from IBMTR
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Conditioning Regimens

• Myeloablative
• Anti tumor effect of conditioning regimen
• Rely on SCT for hematopoiesis
• Complete chimera
• Nonmyeloablative
• Conditioning regimens less toxic
• Host hematopoieisis returns lt28 days
• Mixed chimera after SCT
• Rely on graft vs tumor

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Conditioning Regimens

• Reduced intensity
• Used in 40 HSCT currently
• Requires successful SCT for hematopoiesis
• Graft vs Tumor effect
• Transient mixed chimerism?mutual tolerance?less
  acute GVHD?

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Acute GVHD

• Alloreactive T cells play key role
• Conditioning regimen?tissue damage?inflammatory
  cytokines?Th1 donor T cells?proinflammatory?tissue
  damage
• Nonmyeloablative/reduced intensity regimens
  extend to older pt/comorbids

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Acute GVHD Grading
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Acute GVHD in Reduced Intensity Regimens
Reduced Intensity Regimen
RI
MA
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Total Lymphoid Irradiation

• Initially for Hodgkins
• Dose for conditioning less ( 80 cGy X 10 doses)
• Bone marrow relatively protected

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TLI ATG Protects Mice From Acute Lethal GVHD
SKIN
GUT
TBI/ATS BMPB
TLI/ATS BM
TLI/ATS BMPB
Lan et. al, 2001.
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Stable Mixed Chimerism After TLI ATG Conditioning
Day 100
Donor
Lan et. al, 2001.
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Mouse NK T Cells

• NK T cells subset of a/B T cells express NK
  markers
• Ability to rapidly secrete cytokines and
  influence Th1 vs Th2 response
• Express restricted T cell repertoire
• Invariant a chain binds CD1
• CD1 nonpolymorphic MHC class I like molecule

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The Role of NKT Cells

• Donor NKT cells inhibit GVHD in lethally
  irradiated mice
• NKT cells increase from 1 to 60 of T cell
  subset after TLI (90 ATS)

NKT Cells Required for GVHD Protection
Host wt or NKT deficient BALB/c Donor cells
C57/Bl6 BM PBMC
Lan et al, 2003
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The Role of IL-4

• IL-4 secretion by splenic NKT cells increases 30
  fold after TLI
• IL-4 secretion by entire splenic T cell subset
  increases 10 fold after TLI

Protection from GVHD Dependent on Host IL-4
Secretion
Lan et. al, 2001.
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The Role of IL-4

• Cytokine Profile of Mixed Chimeras Daygt100

Lan et al, 2003
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Conclusions From Animal Studies

• TLI ATS protects mice from acute lethal GVHD
  and can be used as a conditioning regimen
• NK T cells become more predominant in spleen
  after TLI
• Host NKT cells are necessary for full protection
• IL-4 production by the host necessary for full
  protection

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What About Humans?
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What About Humans?

• Can TLI ATG conditioning reduce acute GVHD
  while allowing Graft versus Tumor effect?

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Patient Eligibility

• 37 consecutive pt
• gt50
• lt50 too high risk myeloablative Tx
• Lymphoid any dz status
• Leukemia lt5 blasts

• Pregnant
• Decompensated Liver Dz
• DLCO lt35
• EFlt30
• Karnofskylt50
• HIV

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Patient Characteristics
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TLI/ATG Conditioning for Hematolymphoid
Malignancies Using MRD/URD
GVHD prophylaxis
ATG 1.5 mg/kg/day
CSA
Day 0
Days -11 to -7
MMF
Day 180
Days -4 to -1
Days -11 to -7
Infection Prophylaxis HSV if acyclovir 400 mg
BID CMV blood PCR weekly EBV blood PCR every 2
weeks PCP Septra DS BID weekends D42 Fungus if
prior infection or URD
TLI 800 cGy over 10 fractions
Courtesy of Dr. Stockerl-Goldstein
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Chimerism after TLI-ATG Conditioning
6 patients lost chimerism 4/6 loss occurred
during progression
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Outcomes in Lymphoid Malignancies

• 24 patients
• 13 sib 11 MUD
• Acute GVHD
• Grade 0 22
• Grade 1 1
• Grade III 1
• 3/4 CR?CR
• 12/18 PR?CR
• 17/24 survived

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Outcomes in Acute Leukemias

• 13 patients
• 10 sib 3 MUD
• Acute GVHD
• Grade 0 13
• 4 Relapse
• 10/13 survived

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Overall Outcomes

• Incidence acute II-IV GVHD 1/37 3
• Well-tolerated
• Mild neutropenia
• 28/37 patients no significant infection
• Lymphoid malignancies
• Actuarial OS 62 PFS 55
• Acute leukemias
• Actuarial OS 73 PFS 69

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What About NKT Cells?

• PB obtained post TLI-ATG contained too few host T
  cells for analysis in these pt
• Examined PB 5 subsequently enrolled pt
• Median percentage NKT of all T cells increased by
  10 fold

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Cytokine Production 1-7 mo Post-Transplant
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Future Directions
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Patient Characteristics
Donor Source HLA MRD 38 (54)
HLA URD 32 (46) Disease status
pre TLI/ATG CR 30 (43)
PR 31 (44)
PD 9 (13) Posttransplant IS
CSA/MMF 70 (100)
No. of patients 70 Median age 55
(2167) Diagnosis no. () AML/ALL 24
(35) Lymphoid 46 (65) Advanced Disease No.
() AML/ALL 11 (46) Lymphoid 40 (87)
Advanced Stage Disease Beyond CR1 for leukemia
or beyond CR2 for lymphoma
Courtesy of Dr. Stockerl-Goldstein
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Stable and Complete Chimerism
Donor cells
(N40)
(N40)
(N40)
(N40)
(N40)
(N40)
Days after Transplantation
Courtesy of Dr. Stockerl-Goldstein
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Actuarial OS, EFS and Risk of Relapse in 70
Patients
Courtesy of Dr. Stockerl-Goldstein
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Low Incidence of Acute GVHD After TLI and
Thymoglobulin Conditioning
Courtesy of Dr. Stockerl-Goldstein
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References

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  nonmyeloablative versus conventional
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• Lan, et al. Predominance of NK1.1TCR or DX5TCR T
  Cells in Mice Conditioned with Fractionated
  Lymphoid Irradiation Protects Against
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• Marris, et al. Allogeneic hematopoietic cell
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• Bendelec et al. MOUSE CD1-SPECIFIC NK1 T CELLS
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  Rev. Immunol. 1997. 1553562.
• Niederweiser, et al. Low-dose total body
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  hematopoietic cell transplantation (HCT) from HLA
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