Research Projects

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a primary curative treatment for various types of leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and some chronic leukemias. This approach involves transplanting stem cells from a genetically compatible donor (usually a sibling or matched unrelated donor) to restore the bone marrow’s ability to produce healthy blood cells after high-dose chemotherapy or radiation has eradicated the patient's leukemic and bone marrow cells, but relapse remains a major cause of treatment failure. To this end it is highly desirable to develop the approaches to overcome the problem of relapse after HSCT. The T cells directed against third party antigens are known to not cause GvHD, can survive longer in allogeneic hosts and also can induce tolerance and engraftment of hematopoietic stem cells across MHC barriers. Therefore, the present study is designed to generate WT-1 specific donor derived T cells and test them whether they can induce engraftment of HSCT across MHC barriers without relapse and GvHD. By targeting specific leukemia-associated antigens, these engineered T cells aim to enhance immune surveillance and eliminate residual cancer cells, potentially improving patient outcomes and minimizing relapse. Patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplant (HSCT) have a dismal prognosis, with few effective therapeutic options (1-3). Donor lymphocyte infusions (DLIs) may promote a graft-versus leukemia (GVL) effect, but any potential benefit must be weighed against the risk of graft-versus-host disease (GvHD) caused by the alloreactive cells present in the infused product (4,5). If DLIs are to be used as an adjuvant that prevents rather than treats post-HSCT relapse, there is an urgent need to enhance their safety by minimizing alloreactive T cells and amplifying the tumor-specific T-cell content, thereby augmenting beneficial GVL activity. To achieve this goal, our plan is to generate donor derived T cells against leukemic antigens to overcome the problem of relapse and GvHD. To maximize the therapeutic potential, we will expand T cells with reactivity for a cohort of leukemia-specific antigens that are frequently expressed in ALL - WT1, PRAME, and surviving (6-11). We hypothesized that these donors derived multiple leukemia antigen–specific T cells (mLSTs) could be safely administered to all patients with higher risk B- or T-cell ALL after allogeneic HSCT, to prevent relapse and GvHD.