Enhanced AML Therapy with SENTI-202: Targeting Leukemia with Precision Using Logic Gated CAR-NK Cells

The abstract details the development of a novel CAR-NK cell therapy, designated as SENTI-202, aimed at treating acute myeloid leukemia (AML). The therapy addresses two main challenges: the absence of a single target antigen that is uniquely expressed in AML cells and the potential for off-tumor toxicity due to the presence of current target antigens in healthy tissues.

The researchers utilized a bioinformatics platform to identify a combination of AML-associated and healthy tissue antigens for targeting. The SENTI-202 therapy is an allogeneic CAR-NK cell that employs a FLT3 OR CD33 NOT Endomucin (EMCN) gene circuit. This design allows the therapy to target AML tumor cells while sparing healthy hematopoietic stem cells (HSCs).

In vitro studies showed that the engineered NK cells with activating CARs (aCARs) recognizing both FLT3 and CD33 were more effective than single target CARs. The cells demonstrated high cytotoxicity and cytokine secretion against various leukemia cell lines. Two CAR configurations were tested: bicistronic and bivalent CARs, with the latter showing greater efficacy.

The therapy also showed significant cytotoxicity against primary AML patient samples and reduced tumor burden in mouse models, suggesting a synergistic anti-tumor effect and a potential for durable remission.

To protect healthy HSCs, the team developed inhibitory CARs (iCARs) that recognize a healthy cell antigen, EMCN. The iCARs were shown to protect FLT3+ EMCN+ cells from cytotoxicity mediated by the FLT3 aCAR.

Finally, the NOT GATE portion of the gene circuit was demonstrated to selectively target FLT3+ EMCN- cells, mimicking a clinical scenario and showing cell-specific control of NK responses.

In conclusion, the SENTI-202 CAR-NK cell therapy, with its OR and NOT logic gated CAR gene circuits, is a promising candidate for treating AML. The OR gate enhances tumor clearance, while the NOT gate safeguards healthy HSCs, potentially reducing the need for bone marrow transplants. The approach could also be extended to other cancer types with similar challenges.