Senti Bio Announces Promising Preclinical Data for SENTI-202, a Next-Generation Logic-Gated CAR-NK Therapy Targeting Acute Myeloid Leukemia

Although engineered cell therapies have revolutionized the treatment of blood cancers, precisely selecting the right targets to kill cancer cells while sparing healthy cells remains a challenge for certain types of cancers. For instance, CAR cell therapy for acute myeloid leukemia (AML) has been hindered by the lack of a single target antigen that is stably expressed across AML leukemic stem cells and immature blast subpopulations, as well as the absence of truly AML-specific target antigens (current target antigens are also expressed on healthy tissues, potentially leading to off-tumor toxicity).

Senti Bio’s off-the-shelf CAR-NK cell therapy SENTI-202, developed for AML, has yielded promising early data. The company employs a technology known as “logic-gated gene circuits” to engineer CAR-NK cells targeting AML cells expressing FLT3 or CD33. In mouse model experiments, these cells enhanced the killing ability against AML, while the CAR construct recognizing EMCN protein ensured the immunotherapy did not mistakenly harm healthy cells. Senti will present these results at the American Society of Hematology (ASH) Annual Meeting in December.

Senti Biosciences, Inc. is located in California, USA, and was founded in 2016 by Tim Lu (Guandong Lu), Philip Lee, Jim Collins, and Dr. Wilson Wong. The company is committed to developing next-generation cell and gene therapies using an advanced genetic circuit technology platform, with the mission of defeating complex diseases with smarter medicines to improve people's lives.

Source: Senti Bio Official Website

Specifically, to maximize the clearance of AML tumors and reduce off-tissue toxicity, Senti utilized a proprietary bioinformatics-paired antigen discovery platform to determine the optimal combination of targeting AML tumor-associated antigens and healthy tissue antigens using OR and NOT logic-gated CAR gene circuit approaches. SENTI-202 combines FLT3 OR CD33 with EMCN NOT-gated gene circuits, designed to broadly target FLT3 and/or CD33-expressing AML tumor cells (including leukemia stem cells and immature leukemia blast subsets) while sparing healthy hematopoietic stem cells (HSCs).

In vitro studies show that FLT3 OR CD33 CAR-NK cells outperform FLT3 or CD33 single-target CAR-NK cells in killing several leukemia cell lines. Researchers reported in the ASH abstract that the novel CAR-NK cells demonstrated significant cytotoxicity against primary AML patient samples and significantly reduced tumor burden in an AML mouse model bearing xenografts, improving survival rates. The strategy of simultaneously targeting FLT3 and CD33 will generate a stronger synergistic anti-tumor effect, leading to more durable remissions and reducing the risk of relapse due to single-antigen escape.

For the NOT logic gate component designed to reduce off-target toxicity, the research team selected EMCN, a surface antigen expressed on up to 76% of healthy HSCs but not on AML cells. They developed an inhibitory CAR with the ability to suppress immune activity.

In vitro studies showed that a CAR with EMCN-specific inhibition protected up to 67% of cells co-expressing FLT3 and EMCN from being mistakenly targeted by FLT3-activated CAR.

Researchers also mixed FLT3 cells with cells that either express or do not express EMCN to simulate healthy cells and AML cells. They found that NOT logic-gated CAR-NK cells preferentially killed FLT3 cells that do not express EMCN.

The SENTI-202 CAR-NK data presented at the ASH meeting is Senti’s first complete proof-of-concept dataset for its OR and NOT gate genetic circuits, supporting the idea that this technology may achieve "enhanced broader cancer targeting while limiting off-tumor toxicity."

SENTI-202 is one of the first projects to emerge on the SENTI platform. The company is also developing SENTI-301, designed to target GPC3 for the treatment of liver cancer, as well as the CAR-NK cell therapy SENTI-401 for colorectal cancer.

This gene circuit technology has already attracted the interest of large pharmaceutical companies. In January this year, Senti Bio raised $105 million in a Series B financing round led by Bayer’s venture capital division. In April, the company also entered into a collaboration with Spark Therapeutics, a subsidiary of Roche focused on gene therapy. Senti is eligible to receive upfront payments, option fees, and milestone payments totaling over $645 million. Senti will be responsible for the design, construction, and testing of synthetic promoters, while Spark will obtain exclusive licenses for a certain number of synthetic promoters.

References:

1# ASH: Senti Bio's gene circuit CAR-NK cell therapy enhances cancer killing and safety in leukemia models (Source: FIERCE Biotech)

#2 2799 FLT3 OR CD33 NOT EMCN Logic Gated CAR-NK Cell Therapy (SENTI-202) for Precise Targeting of AML (Source: ASH)