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Graft versus Tumour effect
- 1. Graft versus Tumour Effect SSC Presentation January 2011 Charlotte Patterson
- 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)
- 5. Complications • Myelosuppression Sepsis, bleeding, anaemia • Mucositis • Fatigue • Immunosuppression peri-transplant infections • GvHD • Organ failure • Graft rejection • Transplant related mortality <3% autologous transplants 10-50% allogenic transplants
- 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
- 7. Graft versus Tumour effect? • How does it work?
- 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)
- 9. 3. Incidence of GvHD inversely correlates with Relapse
- 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.
- 15. Blood, Vol. 115, Issue 9, 1666-1667, March 4, 2010
- 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>
Editor's Notes
- 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.