Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment modality for patients with relapsed/refractory (r/r) CD19+ B-cell hematological malignancies, such as acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). The prognosis of patients in whom the disease is not under control or has relapsed after HSCT, is particularly grim. For these patients, the therapeutic options are limited. One of the few available salvage strategies involves the use of donor lymphocyte infusions (DLI). The mechanism of action of DLI relies on the administration of immune effector cells, predominantly T cells, from the stem cell donor, with the ultimate goal to elicit a "graft-versus-leukemia" or "graft-versus-tumor" effect. Unfortunately, DLI have only modest clinical activity and can evoke or exacerbate serious transplant-related side effects such as "graft-versus-host" disease. CD19-targeted chimeric antigen receptor (CAR)-T cell therapy offers new hope for patients with r/r B-cell hematological malignancies. Here, T-cells derived from the patient (autologous) are genetically modified to express a CD19 CAR, a synthetic receptor enabling binding of the cells to the CD19-expressing target cells. Upon engagement, the CAR will trigger activation of the T cells which will then become cytotoxic towards the target cells.
In this project, DLI products will be loaded with an in-house developed and optimized CD19 CAR. By using allogeneic cells derived from healthy donors as source for CAR-T cell manufacturing, which are usually "fitter" than autologous, patient-derived T cells, we aim to enhance the anti-tumoral activity of the CAR-T cells.
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