Prof Robert Wynn, Consultant Paediatric Haematologist and Director of Bone Marrow Transplant at Royal Manchester Children’s Hospital, leads the GRANS clinical trial. He tells us how this innovative treatment is showing promising results for children with hardto-treat leukaemia.
When leukaemia isn’t cured with chemotherapy, we use cell therapies including transplant. Many children with leukaemia are cured by having a transplant when it would have been incurable with drugs. During a transplant, we give a donor’s bone marrow, and the immune cells of the donor reject and kill the patient’s leukaemia cells. We call this graft-versusleukaemia (GVL) and understanding, refining and redirecting this GVL will make a transplant even more effective and safe, and extend its use beyond leukaemia to children with solid tumours, for whom there are no effective treatments once chemotherapy fails.
We noticed that when we use cord blood – surplus blood taken from the placenta of newborn babies – then the transplant works better than using bone marrow, and fewer children relapse afterwards. There’s also less graft versus host disease (GvHD), which is where the donor immune cells don’t just kill leukaemia cells but attack healthy tissues in the body, too.
For children with acute myeloid leukaemia (AML) and residual disease (MRD positive after standard treatment), only 10% were cured with a transplant using bone marrow, but 50% were cured, without GvHD, using cord blood. These are remarkable differences.
Why does using cord blood work better?
Firstly, when we do cord transplants the donor is less well matched to the recipient and the immune cells can see the leukaemia cells better, using this mismatch. Secondly, we infuse more immune cells during cord transplants so there are more immune cells to reject and kill leukaemia cells. We noticed that when we give granulocytes (a type of white blood cells) to children having cord blood transplants then we see a surge of donor immune cells (called T-cells) stimulated by the infusion.
We noticed this by accident at first, but it happened every time we gave such an infusion to children receiving cord blood and granulocytes. We reasoned that as GVL is mediated by T-cells and is better with cord anyway, then this massive surge of T-cells might further decrease the chances of relapse in those with the highest risk leukaemia.
We opened the GRANS clinical trial for children, referred by a national multidisciplinary team, who had a transplant but had relapsed or refractory disease. During this trial, we gave granulocytes to children receiving a mismatched cord blood transplant. We have already published the results from the first ten children, and we continue to recruit children at Royal Manchester Children’s Hospital (RMCH).
Some key findings:
- GvHD rates and risks of serious complications are very low – the transplant is safe, despite the mismatch and the immune expansion
- Some children reject the transplant, which is unusual in normal cord transplant
- Almost all children go into remission and in many, this remission is sustained, and some are cured
What’s next?
We’ll evolve our protocol and we’re looking to extend the protocol to adult patients. We’ll use an expanded cord (increasing the number of stem cells) to reduce the risk of rejection. We’ll add a top-up of cells from the donor to try and prevent later relapse.
In the labs at the University of Manchester, we’re looking to see if these cord blood T-cells can see and reject solid tumour cancer cells. We’ve learnt about a lot of immune responses against leukaemia, but solid tumours are also killed by donor T-cells. With oncology colleagues here at the RMCH, I want to see if we can cure children with brain tumours and other solid tumours whose lives are currently lost to disease, and for whom drugs don’t work.
The Little Princess Trust, in partnership with CCLG, funded the lab science of this work, which helped us greatly. I think this project has the ability to cure more young patients, since it’s a refinement of a technique – bone marrow transplant – that’s already saved so many lives.
From Contact magazine issue 102 - Spring 2024
