Adoptive Immunotherapy with CD25/71 allodepleted donor T-cells to improve immunity after unrelated donor stem cell transplant

Many patients with leukaemia and genetic diseases are curable by stem cell transplantation (SCT) but do not have a matched sibling donor and are therefore transplanted from a matched unrelated (MUD) donor. When such transplants are done, we have to remove the majority of the immune T-cells from the graft to prevent a complication called graft-versus-host disease (GVHD), which occurs when 'alloreactive' T-cells from the donor attack the patient. However, this means patients have very little immunity for many months after SCT, resulting in a high rate of virus infections affecting the lungs, liver and other organs. These viral complications are a leading cause of death after this kind of transplant.

Our group and others have investigated an approach to improving immunity post-SCT by giving back T-cells from the donor, having specifically removed the cells that cause GVHD, whilst leaving the ones that fight viruses. We have already performed a clinical study in children which showed that giving such "allodepleted" T-cells does improve immunity after transplants from half-matched parents. We now wish to extend this approach to the unrelated donor setting in adults to maximise its clinical applicability. We have refined our method by studying the biology of the T-cells that cause GVHD and this has enabled us to design better ways of removing them, so that we believe we can give back more T-cells safely. We have developed a simple, robust and broadly applicable methodology for production of allodepleted T-cells and shown in clinical-scale dry runs that it works effectively in the unrelated donor setting. We now propose a randomised clinical study to determine if giving back allodepleted T-cells can safely improve T-cell immunity and anti-viral responses after unrelated donor SCT in adults with acute leukaemia. If successful, this study will lay the groundwork for a larger study in collaboration with an industrial partner, to determine if this strategy reduces virus infections and mortality after MUD SCT in a cost-effective manner. This approach may be of major clinical benefit to patients undergoing stem cell transplant by reducing the complications and mortality associated with viral infections.

The use of matched unrelated donors (MUD) has considerably broadened the applicability of stem cell transplantation (SCT), but the T-cell depletion used to prevent graft-versus-host disease (GVHD) in this setting results in a high rate of viral complications, which are a leading cause of death after MUD SCT.
We have investigated a strategy to improve immunity after SCT by giving back T-cells from the donor, having specifically removed the cells that cause GVHD by targeting activated cells expressing CD25, whilst preserving anti-viral responses. The principal advantage of this approach is that it augments immunity to multiple pathogens simultaneously with a low risk of GVHD. We have shown in a previous clinical study in children that immunotherapy with such "allodepleted" T-cells does improve immunity after transplants from half-matched parents. We now wish to extend this approach to the MUD setting in adults to maximise its clinical applicability. We have refined our method by studying the biology of the alloreactive T-cells, enabling us to design better ways of removing these cells, so that we believe we can give back more T-cells safely. We have developed a simple, robust, cost-effective and broadly applicable methodology for production of allodepleted T-cells based on immunomagnetic CD25/71 depletion and shown in clinical-scale dry runs under GMP conditions that it works effectively in the unrelated donor setting.
We now propose a Phase II randomised clinical study to determine if giving allodepleted T-cells can safely improve T-cell immunity and anti-viral responses after MUD SCT in adults with acute leukaemia. If successful, this study will lay the groundwork for a larger Phase III study in collaboration with an industrial partner, to determine if this strategy reduces transplant-related mortality after MUD SCT. This approach may be of major clinical benefit to patients undergoing SCT by reducing the morbidity/mortality associated with viral infections.

If successful, our strategy may be of major clinical benefit to adults and children with haematological malignancies (leukaemia, myelodysplasia, myeloma and lymphoma) and non-malignant disorders (aplastic anaemia and othe bone marrow failure syndromes, primary immunodeficiency and metabolic diseases) undergoing unrelated donor SCT by reducing the morbidity and mortality associated with viral infections. 800 patients undergo unrelated donor SCT yearly in the UK and 12,000 worldwide. Since viral infections are the leading cause of non-relapse mortality after SCT, the cost in terms of suffering to patients and their carers is high and preventing these would represent a major step towards improving outcomes after transplant. Further, since most patients undergoing MUD SCT are relatively young, a reduction in premature mortality will have a wider societal impact in terms of additional working years.

Given the cost of unrelated donor SCT (approximately £150,000) and the increased admission/drug costs associated with viral infections (> £22,500/patient), these impose a major economic burden on the health service. If effective, this strategy will confer significant economic benefit to transplant providers by reducing the costs associated with anti-viral drugs, increased hospital stay and premature death.

If the study proposed is successful, we will collaborate with a UK-based biotechnology industrial partner to perform a larger randomised Phase III efficacy study. The development of such studies will help put the UK at the forefront of development of novel cellular therapies.
More broadly, our study will be of significant benefit to other investigators working on other novel cellular therapies, including in regenerative medicine, by:
(a) demonstrating the feasibility of translating cellular therapies from bench to bedside
(b) providing experience and templates for putting cell therapy studies through the regulatory pathways which are currently tailored for drug products and
(c) developing a commercially viable model for a cellular therapeutic agent.