drug_type
RELEVANT_DRUG
intervention_type
Cellular therapy
drug_description
Off-the-shelf allogeneic CAR NK cell therapy with a logic-gated NOT design targeting CD33 and/or FLT3 and an inhibitory CAR to spare healthy cells; includes IL-15 support to enhance NK persistence/function for AML/MDS.
nci_thesaurus_concept_id
C206380
nci_thesaurus_preferred_term
Allogeneic Calibrated Release IL-15-expressing Logic-Gated Gene Circuit Anti-CD33/FLT3 CAR-NK Cells SENTI-202
nci_thesaurus_definition
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.
drug_category
CAR NK
drug_class
Cellular Therapy
drug_delivery_route
Intravenous
drug_mechanism_of_action
Off-the-shelf allogeneic NK cells engineered with an OR-gated activating CAR targeting CD33 and/or FLT3 and a NOT-gated inhibitory CAR recognizing EMCN to spare healthy hematopoietic stem cells; includes calibrated-release IL-15 to enhance NK persistence and function. Antigen engagement triggers NK activation and cytolytic killing of CD33/FLT3-positive AML/MDS cells while minimizing on-target/off-tumor toxicity.
drug_name
SENTI-202
nct_id_drug_ref
NCT06325748