allogeneic calibrated release IL-15-expressing logic-gated gene circuit anti-CD33/FLT3 CAR-NK cells SENTI-202

A preparation of off-the-shelf (OTS) natural killer (NK) cells engineered to express three chimeric proteins: 1) a bivalent activating chimeric antigen receptor (aCAR), controlled by OR logic gated gene circuit, specific for the tumor-associated antigens (TAAs) cluster of differentiation 33 (CD33) and FLT3 tyrosine kinase receptor (Fms-like tyrosine kinase 3; FLT3; FLT-3; CD135; fetal liver kinase-2; FLK2) (CD33 OR FLT3 (OR GATE) aCAR), 2) an inhibitory CAR (iCAR) recognizing endomucin (EMCN) and controlled by NOT logic gate (NOT EMCN (NOT GATE) iCAR), and 3) a calibrated release interleukin 15 (IL-15) (crIL15), with potential immunostimulating and antineoplastic activities. Upon administration, the allogeneic crIL-15-expressing logic-gated gene circuit anti-CD33/FLT3 CAR-NK cells SENTI-202 targets and binds to CD33 and/or FLT3 expressed on the surface of tumor cells, such as primary acute myeloid leukemia (AML) blasts and leukemic stem cells (LSCs). This induces selective toxicity in tumor cells expressing CD33 and/or FLT3. To protect CD33/FLT3-expressing healthy hematopoietic stem cells (HSCs) from potential aCAR-mediated on-target/off-tumor toxicity, the iCAR recognizes and binds to the healthy cell surface protein EMCN, which is selectively expressed on healthy HSCs but absent on tumor cells. The crIL-15 allows for activation of the IL-15 receptor pathway, which increases the persistence, activation and killing activity of SENTI-202 and other immune cells. CD33 and FLT3 are expressed on healthy HSCs and on a variety of cancer cells.