Allogeneic Universal Chimeric Antigen Receptor (CAR) - Invariant Natural Killer T (iNKT) cells Against Acute Myeloid Leukemia

Acute Myeloid leukemia (AML) is the most prevalent form of acute leukemia and is still associated with high mortality rates. Despite intensive chemotherapy, residual disease can still persist and eventually results in relapse in most patients. Allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to cure the disease, through a Graft-versus-Leukemia (GVL) effect eradicating tumor cells. Unfortunately, an insufficient GVL effect leads in some patients to disease relapse. Moreover, some patients suffer from the main side effect of allogeneic HSCT, namely Graft-versus-Host-Disease (GvHD). Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of B-cell malignancies but their use in AML is still experimental and limited by several barriers. First, autologous T cells are frequently functionally impaired after chemotherapy. Second, AML cells display heterogeneous surface antigen expression which limits the efficacy of CAR T therapy and single antigen targeting can lead to antigen negative relapse. Finally, targeting myeloid markers expressed as well on normal myeloid cells may cause long-term myeloablation. Invariant natural killer T (iNKT) cells are a rare subset of T lymphocytes, which cannot induce GvHD in an allogenic context. iNKT cells are a promising platform for CAR-based immunotherapy because of their anti-tumor potency and immunomodulatory effect. The main goal of my project is to generate CAR iNKT cells directed against several antigens expressed on AML cells. Our hypothesis is that multiple antigen-targeting CAR iNKT cells generated from different donors will show potent anti-tumor efficacy against AML without the induction of GvHD and myelosuppression. To achieve this aim, we will generate second generation CAR iNKT cells specific for CD33, CD123 and CD38 from healthy donors and we will test their antitumor activity, separately or combined, against AML cells both in vitro and in vivo. Moreover, we will assess CAR iNKT cells safety in terms of GvHD induction and myelotoxicity. Through this work, we will be able to engineer iNKT cells as a cell therapy platform to be employed against AML.