STOCKHOLM – A novel compound chimeric antigen receptor (cCAR) T-cell construct directed against two different targets may one day serve as a standalone therapy, as a supplement to chemotherapy, or as a bridge to transplant for patients with refractory acute myeloid leukemia (AML), investigators asserted.
To date, however, only one patient – a man with treatment-refractory AML – has been treated with the cCAR T, which contains two independent complete units, one directed against CD33 to target bulky disease and the other targeted against CLL1 on leukemic stem cells.
The patient was a 44-year-old man with AML who remained refractory after four cycles of chemotherapy and had 20% bone marrow blasts. He achieved a complete response after infusion with the cCAR T cells and went on to bone marrow transplant with no evidence of minimal residual disease (MRD) at 3 months of follow-up, Dr. Liu said.
Although anti-CD19 CAR T cells have been demonstrated to have significant efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia, AML is a tougher problem to solve because the heterogeneity of myeloid leukemia cells allows some cells to escape targeting by enhanced T cells, which leads to eventual relapse.
To get around this problem, the investigators created a CAR T with a one-two punch, with one component targeting the antigen CLL1, which is expressed on leukemic stem cells, and a second, separate component targeting CD33, a myeloid marker expressed on bulk AML disease cells in a majority of patients.
They first tested the cCAR T cells against several AML cell lines and primary human AML samples, then in mouse models of human AML.
In vitro assays showed that the construct had specific antitumor activity against cell lines engineered to express either of the target antigens and also against samples from AML patients. In mouse models created with engineered CLL1 or CD33 expressing cell lines and an AML cell line, the cCAR T cells caused significant reductions in tumor burden and led to prolonged survival, Dr. Liu said.
Since CAR T-cell therapy is associated with serious or life-threatening side effects, such as the cytokine-release syndrome, the investigators built an “off switch” into the cCAR T construct that could be activated by CAMPATH, a monoclonal antibody directed against CD52. Introducing this agent into the mice quickly neutralized the cCAR T therapy, Dr. Liu said.
Finally, the investigators tested the construct in the human patient. He received the cCAR T construct after conditioning with fludarabine and cyclophosphamide; he had a complete remission by day 19 after receiving the cells and was MRD negative. He went on to an allogeneic stem cell transplant on day 44, and he remained MRD negative 3 months after transplant.
Side effects associated with the treatment were a grade 1 cytokine release syndrome event, manifesting in fever and chills, lung infection, and red blood cell transfusion dependence but also platelet transfusion independence.
The investigators have initiated a phase 1 trial and plan to enroll 20 patients to further evaluate the efficacy and safety of the cCAR T construct.
The study was supported by iCell Gene Therapeutics. Dr. Liu reported having no conflicts of interest.
SOURCE: Liu F et al. EHA Congress, Abstract S149.