2. Summary of Presentation
• Purpose of this iSSC
• What is Stem cell Transplantation & GvHD?
• What is GVT?
Lab evidence
Clinical evidence
Evidence Based Medicine
• Separating GvHD and GVT
Use of regulatory T cells
• References
3. Purpose of this iSSC
• Is there evidence for the graft versus tumour effect,
and does is reduce transplant related mortality for
haematological malignancies?
• Improve my knowledge of HSCT and GvHD.
• GVT is still not completely understood.
4. What is Stem Cell Transplantation?
• Haematopoietic Stem Cell Transplantation (HSCT) allows high
doses of chemotherapy to be administered to patients with
malignant and non-malignant disease, which would otherwise
destroy their haematopoietic ability.
Leukaemia
Conditioning
Therapy
Aplastic
BMT
Engraftment and
Donor Haematopoiesis
(neutrophils >0.5-1 x 109 and
Platelets 20-50x109)
6. Graft versus Tumour
effect?
• Lab-based evidence
• First observed in studies involving mice in the
1950s.
TBI
Allogenic BMT
Syngeneic BMT
Injection with Murine Leukaemia
Virus
8. Clinical Evidence
1. Anecdotal Reports that abrupt withdrawal of
immunosuppression in patients with tumour
relapse post-allo-HSCT can re-establish complete
remission.
2. Higher relapse rates post syn-HSCT VS allo-HSCT.
3. Incidence of GvHD inversely correlates with
incidence of relapse post allo-HSCT
4. T cell depletion of allo-HSCT increases the risk of
relapse.
5. Donor Lymphocyte Infusions (DLI)
10. 5. Donor Lymphocyte Infusions
• These are given to patients who:
– Receive non-myeloablative/reduced intensity
conditioning regimens.
– Patients with mixed or falling donor chimerism
post-HSCT
• Less myeloablative regimes lead to a mixed
chimerism post-HSCT
• DLIs are used to convert to a full donor chimerism
• These enhance engraftment, reduce graft
rejection (ie. reduce host VS graft), and help
induce GVT.
11. PICO
P 40 year old man, relapsed CML,
post- SIB allo-BMT
I DLI administration
C No DLI
O Disease free survival
12. 5. Donor Lymphocyte Infusions
• In 1987 was demonstrated that relapse following BMT in
patients with leukaemia or MM could be treated with DLIs.
• Treatment of these patients was previously thought
impossible.
• Successful treatment with DLIs was confirmed in different
centres worldwide.
• EBMT data showed:
– 77/100 (72%) patients relapsing after allo-BMT for CML
were successfully treated with DLIs
– 22/58 (44.8%) patients relapsing after allo-BMT for other
haematological malignancies eg. Lymphomas, ALL, AML,
Myelodysplastic syndromes.
13. Separating GvHD and GVT
- Despite the beneficial effects of GVT, the allo-
reactive T cells also cause GvHD.
- The beneficial effects of GVT don’t always
outweigh the adverse effects of GvHD.
- Researchers are now developing methods of
inducing GVT without the adverse effects of
GvHD...
14. Use of T regulatory Cells?
- Addition of T-regulatory cells
in mice suppresses GvHD
whilst permitting GVT to still
take place.
- This promotes tumour
rejection, and significantly
improves survival in mice.
16. Conclusions
- There is both clinical and lab based evidence for
GVT.
- The beneficial effects of GVT need to outweigh
the negative effects of GvHD.
- Is it possible to separate GvHD and GVL
- lab based evidence suggests that there are
different mechanisms behind GVT and GvHD.
- In the future this might be possible in a clinical
setting (no evidence base for use of T-regs in
clinical medicine at present)
17. References
• BARNES, DWH. et al. (1956) Treatment of Murine Leukaemia with X-rays and homologous
Bone Marrow, BMJ Sept 1956, 626-627
<http://www.ncbi.nlm.nih.gov/pubmed/13356034>
• MATHE, G. et al. (1965) Adoptive Immunotherapy of Acute Leukaemia: Experimental and
Clinical results. Cancer Research, 25: 1525-1531
<http://www.ncbi.nlm.nih.gov/pubmed/5323965>
• SLAVIN, S. et al. (2001) Immunotherapy of cancer with alloreactive lymphoctes, Lancet
Oncology 2: 491-9
< http://www.ncbi.nlm.nih.gov/pubmed/11905725>
• EDINGER, M. Et al (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumour
activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nature
Medicine 9, 1144-1150.
< http://www.ncbi.nlm.nih.gov/pubmed/12949524>
•Kolb, HJ. et al. (1995) Graft versus-leukaemia effect of donor lymphocyte transfusions in
marrow grafted patients Blood, 86: 2041-2050.
<http://www.ncbi.nlm.nih.gov/pubmed/7655033>
•WEIDEN, PL. Et al (1979) Antileukaemic effect of Graft-versus-host disase in human
recipients of allogenic marrow grafts. N Engl J Med 300:1068-1073
< http://www.ncbi.nlm.nih.gov/pubmed/34792>
•HESS, AD (2010) Separating GvHD and GVL Blood 115, 9: 1666-1667
<http://www.ncbi.nlm.nih.gov/pubmed/20203273>
Notas do Editor
Indications: malignancies eg AML, ALL, CML, CLL, MM and lymphomas
Conditioning: myeloablative and non-myeloablative may be used eg. Cyclophosphamide, fludarabine, busuphan.
Bone Marrow Transplant: Autograft (may be used for solid tumours), allograft (HLA matched, preferable sibling- 10/10 antigens MUD), syngeneic (from twins). Choice of BM, Peripheral blood (stimulated by G-CSF) and Umbilical cord blood.
Engraftment- sustained reutrn of neutrophils and platelets recorded as 1st 3 consecutive days of neutrophils >0.5-1 x 109 and platelets 20-50 x 109. Generally to be successful, >1.5 x 105/kg CD34 +ve cells.
Complications are either related to drugs used, result of immunosuppression or transplant related toxicity.
GvHD- acute- skin- rash and blistering
Gut- diarrhoea, n&v
Liver- jaundice, liver failure
Chronic GvHD- more of an autoimmune disease
Organ failure- direct result of very immunosuppressive regimens
GvHD is the primary cause of death post-BMT
Immune response mediated by donor T cells recognising recipient antigens presented by APCs in the context of the MHC as ‘foreign’.
Results in host tissue damage.
May be acute or chronic:
Acute GvHD:
within 100 days post-BMT
40% patients
Graded I-IV based on severity
Risk factors: HLA compatability, Stem cell source, Infective episode, T cell dosage.
Skin, gut and liver targeted.
Chronic GvHD:
> 100 days post-BMT
25-35% patients
Risk factors: Previous aGvHD (only 25-35% cases occur without previous GvHD)
More of an autoimmune disase
Skin (80%), Oral (70%), Occular (50%)
Mice were injected with leukaemia cells, inducing leukaemia in the mice. Then treated with TBI (myeloablatvie regime). Then given BMT
Those given allo-HSCT survived with no evidence of leukaemia, but developed GvHD.
Antitumour effect mediated by the allogenic cells in the BMT- thought to be mediated by T cells and NK cells
“adoptive immunotherapy” 1965 coined by Mathe et al in France.
A- pateint with leukaimia, a= leukaemic cells, alpha= virus that may have induced the leukaemia.
Zig zag line- TBI given- as much as can be tolerated. Considerably reduces leukaemic cells, but can’t completely irradicate them.
However, sufficiently myeloablative to recieve BMT from subject B
The immunologically competent cells of subject B react with antigenic elements they encounter
Leukaemic cells a
Viral cells alpha- viral irradication reduces the chance of replabse (b)
Howeer, also react with the hosts own antigens GvHD.
The main problem is the immunotherapeutic modality- the immune response post-allo HSCT is not tumour specific, alloreactive lymphocytes that produce GVT also target the host causing GvHD.
Problem is separating beneficial anti tumour effects and GvHD.
1979 New England Journal of Medicine- patients receiving allogenic SCT were less likely to relapse if they developed GvHD
Non myeloablative regimes were developed 10 years ago for older patients (55yrs +) or those with comorbitidies, as these regimes are less toxic to the BM, other tissues and organs therefore reduces transplant related mortality.
The myeloablation is sufficient to treat the underlying maligancy and preserve the GVT effect, without the toxic effects of high dose chemo.
Very effective due to introduction of fludarabine, a less cytotoxic drug which may be used as part of the conditioning regimen.
Treat overt relapse
Prevent relapse in high risk patients
EBMT= European and North American Bone Marrow registry
Best clinical evidence in by DLIs*
After initial demonstration of GVT, was hypothesised that GVT may be beneficial in treating patients transplanted for malignancy who have subsequently relapsed.
Treatment for these patients was previously thought impossible.