Graft versus Tumour EffectSSC Presentation

January 2011

Charlotte Patterson

Summary of Presentation

• Purpose of this iSSC• What is Stem cell Transplantation & GvHD?• What is GVT?

Lab evidenceClinical evidenceEvidence Based Medicine

• Separating GvHD and GVT Use of regulatory T cells

• References

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.

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

ConditioningTherapy

Aplastic

BMT

Engraftment andDonor Haematopoiesis

(neutrophils >0.5-1 x 109 andPlatelets 20-50x109)

Complications• Myelosuppression

Sepsis, bleeding, anaemia• Mucositis• Fatigue• Immunosuppression

peri-transplant infections• GvHD• Organ failure• Graft rejection• Transplant related mortality

<3% autologous transplants10-50% allogenic transplants

Graft versus Tumour effect?

• Lab-based evidence• First observed in studies involving mice in the

1950s.

TBI

Allogenic BMT

Syngeneic BMTInjection with Murine LeukaemiaVirus

Graft versus Tumour effect?

• How does it work?

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-HSCT4. T cell depletion of allo-HSCT increases the risk of

relapse.5. Donor Lymphocyte Infusions (DLI)

3. Incidence of GvHD inversely correlates with Relapse

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.

PICO

P 40 year old man, relapsed CML, post- SIB allo-BMT

I DLI administrationC No DLIO Disease free survival

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.

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...

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.

Blood, Vol. 115, Issue 9, 1666-1667, March 4, 2010

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)

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>