Current therapies for myeloid diseases have only modest success and the vast majority of patients will ultimately die. Clearly, novel therapies are warranted and adoptive immunotherapies represent an exciting and promising cancer therapy. The success of antibody-mediated therapy targeting immune checkpoint underscores the therapeutic potential of counteracting immune inhibition and T cell exhaustion. Other alternative immunotherapies consist of bispecific T cell engagers (BiTEs), which have had some success for leukemia. A major advance for adoptive T cell therapy is the chimeric antigen receptor (CAR), which is a single chain variable fragment (scFv) fused to the signal domains of a T cell receptor. CAR-T cell therapy has significant potential as a cancer therapy because T cells can expand in numbers to eradicate large volume disease, traffic throughout the body, and provide patients with long-lived tumor immunity. In particular, clinical success with CART19 has generated high complete response rates in patients with B-cell acute lymphoblastic leukemia (B-ALL).
Currently, CAR T cells are being developed against CD33, CD123, CD44v6, as well as other antigens. Early pre-clinical work suggests that CAR-T cell directed towards CD33 and CD123 are effective, but unfortunately also kill normal myeloid and/or hematopoietic stem cells. Considering the extensive B cell aplasia reported with CD19-targeted CAR T cells, a similar off-tumor, on-target toxicity for myeloid malignancies could result in bone marrow failure and/or death. Therefore, we have decided to compare the co-expression of various tumor markers on AML to identify candidates for multi-antigen targeting. CAR-T cells with a combination of either of these markers would prove effective targeting against leukemic stem cells leaving normal stem cells unharmed.
Director of Hematology Department
Moffitt Cancer Center