Engineered cell therapy has completely changed the treatment of blood cancer, but precise selection of the correct target to kill cancer cells while retaining healthy cells has always been a challenge for certain types of diseases. Now, Senti Bio has promising early data showing that CAR-NK (natural killer) cell therapy developed from the biotechnology gene circuit platform can solve this problem and provide a ready-made option for acute myeloid leukemia (AML).

Senti uses a technology called "logic gated gene circuit" to design CAR-NK cells to target AML cells that express FLT3 or CD33. In the mouse model, the cells increase the lethality of AML, and the CAR construct that recognizes the internal mucin (EMCN) protein keeps immunotherapy away from healthy cells. Senti will present this discovery at the annual meeting of the American Society of Hematology (ASH).

Drawing on knowledge from the fields of computing and electronics, Senti uses logic-gated gene circuits to build CAR-NK cells that can recognize multiple targets to activate therapy or remain silent. Senti scientists believe that this technology can come in handy for designing CAR cell therapies for AML. This is because the disease lacks a single target antigen, which is fully expressed in both AML leukemia stem cells and immature leukemia blasts. In addition, according to Senti, none of the known targets of AML are unique to blood cancers.

Senti, the winner of Fierce Biotech Fierce 15 in 2018, is combining the FLT3 OR CD33 gate gene circuit with the EMCN NOT gate in an off-the-shelf CAR-NK cell therapy called SENTI-202. Senti research director Dr. Brian Garrison told Fierce Biotech Research via email that the company is now optimizing the design and is targeting the first human clinical trial application with the FDA in 2023. 

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For the OR gate, Senti designed an activated CAR construct to connect antibody fragments that can recognize FLT3 and CD33 expressed in AML cells. Garrison explained that the CD33 component will be able to target primordial cells, while the FLT3 part will enable CAR-NK cells to fight against leukemia stem cells, which is essential for potential curative treatments. By targeting two tumor-associated antigens, the OR gate limits the possibility that engineered CAR-NK cells cannot recognize different cancer cells.

In a laboratory dish, FLT3 OR CD33 CAR-NK cells are superior to the single-target CAR-NK for FLT3 or CD33 in killing cancers in several leukemia cell lines. Senti researchers stated in an abstract that the new CAR-NK cells in AML mouse models carrying cancer xenografts “showed significant cytotoxicity to primary AML patient samples and significantly reduced tumor burden. And improved the survival rate of mice." 

Garrison said that in a patient xenograft model, all control mice died of the disease on day 64, while all rodents that obtained CAR-NK cells were still alive.

The Senti team wrote: "We believe that our strategy of targeting FLT3 and CD33 at the same time will produce a stronger synergistic anti-tumor effect, resulting in a longer-lasting remission and reducing the risk of recurrence due to the escape of a single antigen."

For the non-gated component designed to reduce off-target toxicity, the team chose EMCN, a surface antigen that is expressed on up to 76% of healthy hematopoietic stem cells but not on AML cells. The team created an inhibitory CAR with the ability to suppress immune activity.

One of the EMCN-specific inhibitory CAR configurations can protect up to 67% of cells expressing FLT3 and EMCN from the FLT3 targeted activation CAR in laboratory dishes.

The researchers also mixed FLT3 cells with or without EMCN expression to simulate healthy cells and AML cells. They found that non-logic gated CAR-NK cells preferentially kill FLT3 cells without EMCN.

Related: Bayer's VC division led a $105 million financing for "gene circuit" startup Senti Bio

Garrison explained that in the end, the researchers combined the OR gate and the NOT gate and added a proprietary IL-15 platform that can improve the persistence of CAR-NK cells and produce a longer-lasting anti-tumor response.

In the laboratory dish, the complete SENTI-202 circuit protects about half of healthy blood cells from CAR-NK toxicity, while showing the same killing activity as CAR-NK cells without a NOT gate. Garrison suggests that based on decades of experience in bone marrow transplantation in this field, experts believe that protecting about 10% to 20% of hematopoietic stem cells may be sufficient to provide clinical benefits.

Senti Bio is the idea of ​​a team of famous scientists in the field of biomedical engineering, including MIT researchers Tim Lu, MD, Ph.D. and Jim Collins, Ph.D.

Gene circuit technology has aroused the interest of large pharmaceutical companies. In January of this year, the company raised US$105 million in a Series B financing led by Bayer's venture capital arm.

The SENTI-202 CAR-NK readings at the ASH conference marked the first complete proof-of-concept data set of Senti Bio’s OR gate and NOT gate gene circuit. Targets, while limiting extra-tumor toxicity," Garrison said in a statement.

SENTI-202 is one of the first programs that appeared on the Senti platform. The company is also developing SENTI-301, which aims to treat liver cancer against GPC3, and SENTI-401, a CAR-NK cell therapy under development for colorectal cancer.

Editor's note: This story was updated on December 13th and contains additional information provided by Senti.

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