Children with leukemia or lymphoma that has unfortunately re-occurred after conventional treatment can be cured using biological therapy. One such approach uses hematopoietic progenitor-cell transplant (HPCT), previously referred to as bone marrow transplant, in which the patient undergoes conditioning therapy to remove residual leukemia and lymphoma and then recovers with the aid of infused hematopoietic progenitor cells, which restores the marrow's functions. Importantly, the infused graft contains precursor cells, which give rise to T cells, a class of white blood cells or immune cells. When these engrafted T cells grow back they can recognize the recipient's remaining cancer cells and the patient can achieve a long-term remission. However, if these T cells recognize normal recipient cells, then the patient can suffer from a type of immune disease referred to as graft-versus-host-disease (GVHD). Thus, HPCT can be considered as a form of T-cell therapy that can be used to treat leukemia and lymphoma that are resistant to conventional approaches, but, at the same time, serious complications can occur as a result of T cells attacking normal body cells.

My laboratory is working on modifying T cells so that we can perform "T-cell transplants" rather than HPCTs on patients with high-risk leukemia and lymphoma. We have used genetic techniques to equip T cells with the tools necessary to specifically destroy leukemia/lymphoma cells while leaving normal healthy cells undisturbed. This is accomplished by removing a small amount of blood containing the T cells, and then reprogramming these cells in the laboratory by introducing a gene to make a new receptor on the surface of the cells. This receptor guides the T cells to a molecule called CD19, which is commonly found on many leukemia and lymphoma cells. Thus, genetically modified T cells expressing this receptor for CD19 can be used to target a wide variety of blood-borne cancers. A "first-in-humans" clinical trial using "first generation" CD19-specific T cells is currently under way.

This grant application proposes to build upon these lines of investigation to develop the data for a new T-cell trial focusing on children with leukemia and lymphoma who have undergone a HPCT. Unfortunately, the majority of patients (children and adults) who seek a HPCT do not have a suitable genetically matched family donor. To improve the accessibility of HPCT for these patients, we now have the capability of using a child¿s parents as a source of hematopoietic progenitor cells. This type of transplant is referred to as a haploidentical HPCT. This is accomplished by stripping away the donor's T cells prior to infusion of the graft. This greatly reduces the possibility of GVHD occurring, but when these T cells are removed the patient is at risk for relapse. To help prevent cancer relapse in these patients we will infuse the genetically retooled T cells so that they can specifically attack residual leukemia and lymphoma cells.

In particular, this grant proposes three lines of experimentation to improve the therapeutic potential of CD19-specific T cells. These investigations are designed to improve the persistence of the T cells after infusion, which is predicted to lead to improved cancer-fighting potential. It is expected that the principles learned from this investigation will be broadly applied to both children and adults using T cells with specificity for cancers other than leukemia/lymphoma and in clinical settings other than HPCT. Since HPCT can be used to help individuals suffering from radiation toxicity, this grant also has implications for treatment of casualties from radiation accidents or terrorist attacks. By combining T-cell therapy with gene therapy, it is expected that the next clinical trial will infuse T cells with the potential to improve the survival of children with leukemia and lymphoma undergoing haploidentical HPCT. In aggregate, this grant has broad application for the Department of Defense and the care of military personnel and their families.