Phase I study of transfer of effector memory T cells (Tem) following allogeneic stem cell transplantation. Short title- Transfer of Tem (ToTem)

Healthy bone marrow produces blood cells, including those of the immune system that fight infections. All these blood cells originate from stem cells. When cancer affects a patient's bone marrow, it can no longer carry out its normal function. In order to restore healthy blood cell production and to fight the cancer, some patients are given healthy stem cells from a donor's bone marrow. Although bone marrow transplants can cure many patients, they can have serious side effects. One of these serious side effects, that affects about half of patients, is 'graft versus host disease' (GVHD). This happens because the bone marrow contains donor immune cells (the 'graft') that see the patient's healthy cells (the 'host') as foreign and attacks them. It mainly affects the tissues of the skin, the liver and the gut and can be life threatening.

There are ways of preventing GVHD by using drugs that dampen down (suppress) the donor's immune cells in the patient's body, therefore stopping them from overreacting and attacking their body. However, the use of these immune supressing drugs has a major drawback because the immune system becomes weaker and cannot fight infections as well. These infections are sometimes very severe and can lead to patients dying.

We have been working on new ways to prevent the donor's immune system causing GVHD in the patient's body without weakening it so much that it cannot fight infections as well. We have developed a new, simple way to take additional infection-fighting immune cells from the same donor's blood. When these are given to patients, they may help fight infections but not overreact and cause GVHD. If this works, it could be widely used at many hospitals across the country. This is because it uses equipment that is already used routinely by most bone marrow transplant centres.

Therefore, this clinical trial aims to find out if giving patients these additional infection-fighting immune cells from the donor will reduce their chance of getting an infection without causing GVHD. Patients undergoing a bone marrow transplant will be asked if they want to give their consent to be part of the study. For these patients, we will give additional donor immune cells about one month after the transplant. They will also receive the standard GVHD prevention treatment. Different doses of the donor immune cells will be given to individual patients to work out which dose is best. All patients will be closely monitored for signs of GVHD or infection. They will also have blood tests to determine how well and quickly their immune systems recover. If the trial shows a possible benefit to patients, we will plan to extend the study to a larger number of patients. This will provide the necessary proof whether the treatment works in patients needing a bone marrow transplant.

Following allogeneic stem cell transplantation (allo-SCT), a major risk is graft-versus-host disease (GVHD) that leads to mortality in 10% of patients. Prevention of GVHD relies upon depletion of donor T cells or drugs that block T cell function. However, these methods also increase the risk of life threatening infection and lead to mortality in a further 10-15% of patients. There is an important unmet need for better means of accelerating immune recovery following allo-SCT while avoiding GVHD.

Pre-clinical studies have shown that CD62L- effector memory T cells (Tem) improve immune recovery after allo-SCT but do not cause GVHD. We have validated a clinical-scale strategy for selection of donor Tem using a CliniMACs-based depletion of CD62L+ cells and have demonstrated favourable product characteristics compared to methods using CD45RA-based depletion (1).

We hypothesise that the early transfer of CD62L- donor Tem will accelerate GVHD-free immune recovery post allo-SCT. Our strategy therefore represents an affordable technology adoptable by any transplant centre. Our aim is to perform a phase I clinical study to determine the safety and maximum tolerated dose (MTD) of Tem following allo-SCT, where grade II-IV acute GVHD is the dose-limiting toxicity (DLT). The results will be used to define a safe Tem dose that can be taken forward into a future phase II efficacy trial. Donor Tem will be given at day 28 following allo-SCT incorporating standard immune prophylaxis against GVHD. We will use a Bayesian continual reassessment model with up to four CD62L- Tem dose levels to determine the MTD. The primary endpoint will be the occurrence of the DLT. Secondary endpoints will include measures of clinical outcome and biological endpoints that measure immune recovery. We are collaborating with other clinical investigators using a CD45RA-based selection method to determine the same biological endpoints, which will inform testing of each strategy in the future.

Evidence that transfer of CD62L- Tem is safe and early indication that it accelerates immune reconstitution would provide a stimulus for further clinical testing of this strategy in a randomised phase II study. Confirmation of safety and clinical efficacy in this setting could lead to further evaluation of this strategy in comparison to alternate approaches, including those using competing technologies. If the CD62L depletion approach demonstrates superiority over alternatives, it could be readily applied at low cost by individual allogeneic transplant centres without the need for a hub-and-spoke distribution model.

By sharing clinical and biological endpoints with our US collaborators (who are evaluating a competing technology involving memory T cell selection through CD45RA depletion), we envisage that decisions regarding further trial design or prioritisation of one technology over another can be made at an early stage. If our proposed phase I study of CD62L- Tem or subsequent randomised studies indicate lack of safety or efficacy, then this will allow prioritization of alternate or competing strategies while providing useful clinical and biological information regarding the limitations of the CD62L- Tem approach.


Evidence of CD62L- Tem clinical efficacy in phase I-II trials would stimulate further investigation in other allogeneic haematopoietic stem cell transplant settings, including haplo-identical and unrelated donor transplantations. The incidence of acute and chronic GVHD is significantly greater following unrelated donor haematopoietic stem cell transplantation than HLA-identical related transplantation. Current strategies for GVHD prevention also in this setting also rely upon extensive T cell depletion and immune recovery is even slower than observed following HLA-identical related transplants. Thus, trials testing similar GVHD prevention strategies as ToTem would be applicable in this group.

Information regarding the fate of CD62L- versus CD45RA- memory T cells following adoptive transfer to human patients will be relevant to other groups working in the field of T cell therapies for cancer or infection where efficacy may depend upon the differentiation state of transferred T cells.