CLL1/CD33 CAR T cell therapy for refractory AML

Anti CD19 CAR T cells have shown impressive efficacy in B-ALL and lymphoma and have obtained FDA approval. A barrier for CAR targeting AML is that AML cells share antigens with normal hematopoietic precursor cells. In AML, common antigens are CD33, CD123 and C-type lectin-like molecule-1 (CLL1). CD33 and CD123 are expressed on myeloid lineage cells and myeloid leukemic blasts as well as normal hematopoietic stem cells (HSC), but CLL1 expression is restricted to more mature hematopoietic stem cells and therefore seems an ideal target.

Dr. Fang Liu (Chengdu Military Hospital, Chengdu, China) hypothesized that simultaneously targeting multiple antigens (addressing both the bulky blast population and leukemic stem cells) could be an effective strategy. Liu demonstrated that mice bearing U937 human lymphoma cells treated with CLL1-CD33b c(compound)CAR T cells showed significantly improved survival compared to control T cells. She also presented data from the first patient of a CLL1b-CD33b cCAR phase I trial: a 44-year-old female with AML-M4 with normal karyotype. During the month after treatment, a transient cytokine release syndrome (CRS, grade 1) was observed, as well as transient pancytopenia (a resulting lung infection was controlled by antibiotics). “CLL-CD33 cCAR T cell therapy can be developed as a ‘bridge to transplant’, a supplement to chemotherapy, or as a standalone therapy for patients with aggressive, relapsing/refractory AML.”

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