Acute leukemia is the most common type of cancer in childhood and is the primary cause of cancer-related deaths in children. An option for patients with high-risk hematological malignancies is immune therapy, which utilizes or boosts the body’s immune system to fight cancer. Two main types of immune therapy are allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T (CAR-T) cell therapy. These two types of therapies are the focus of my PhD project and will be explained in further detail below.
Allo-HCT has evolved into the primary and potentially curative treatment procedure for patients with high-risk hematologic malignancies. Hematopoietic cells can be derived from bone marrow (BM), cord blood (CB) or peripheral blood (PB), from either matched unrelated or related donors. Survival rates are still around 50–65% due to relapsed disease and adverse effects associated with the procedure. Risk factors involve graft rejection, acute and chronic graft-versus-host-disease (GvHD) and viral reactivations (VR). These complications have been reported to be a consequence of the chemotherapy or transplant preparative regimens, leading to immune dysregulation and to protracted lymphopenia. In addition, the use of GvHD prophylaxis and treatment may have a major impact on immune reconstitution (IR) and therefore affects the risk of VR and relapse. In this project, we aim to gain more insight in the effect of immunosuppressive therapies on the dynamics of the immune system and clinical outcome after allo-HCT.
CAR-T cell therapy has grown as the most encouraged therapeutic approach for treatment of chemotherapy-refractory or relapsed malignancies. CAR T cells are a patient’s own T cells that are genetically modified to stably express a CAR with specificity for a tumor antigen, being able to trigger T cell activation similarly to endogenous T cell receptors (TCRs). In B cell leukemia, CD19 is an attractive tumor antigen due to the high and stable expression of CD19 on tumor cells. Furthermore, CD19 expression is restricted to normal and malignant B cells, limiting therapy toxicities to B cell aplasia, which can be managed with immunoglobulin replacement. CAR19 T cell therapy has been associated with long-lasting complete remission, however, approximately 50-60% still relapses due to tumor antigen escape (CD19 negative relapse) or CAR-T cell dysfunction (CD19 positive relapse). With this PhD project, we would like to gain more insights in the mechanisms behind CAR-T cell therapy failure, to eventually reduce relapse rates and improve survival outcome.