ASH: Senti Bio's gene circuit CAR-NK cell therapy enhances cancer killing and safety in leukemia models

Engineered cell therapy has revolutionized the treatment of blood cancers, but precisely selecting the right target to kill off cancer cells while sparing healthy cells has been challenging for some disease types. Now, Senti Bio has promising early data that a CAR-NK (natural killer) cell therapy developed from the biotech’s gene circuit platform could solve that problem—and provide an off-the-shelf option—in acute myeloid leukemia (AML).

Senti uses a technology dubbed “logic-gated gene circuits” to design CAR-NK cells to target AML cells expressing FLT3 OR CD33. In mouse models, the cells improved killing of AML, while a CAR construct that recognizes the endomucin (EMCN) protein steered the immune therapy away from healthy cells. Senti will report the findings at the American Society of Hematology (ASH) annual meeting.

Taking a page from the computation and electronic areas, Senti uses logic-gated gene circuits to build CAR-NK cells that can identify more than one target to either activate the therapy or go silent. The technology could come in handy for designing CAR cell therapies for AML, Senti's scientists figured. That's because the disease lacks a single target antigen that’s adequately expressed across both AML leukemic stem cells and immature leukemic blast cells. In addition, none of the known targets for AML are unique to the blood cancer, according to Senti.

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

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For the OR gate part, Senti engineered an activating CAR construct to connect snippets of antibodies that could recognize FLT3 and CD33, which are expressed in AML cells. The CD33 component would enable targeting of primarily blast cells, while the FLT3 part would turn CAR-NK cells against leukemic stem cells, which are critical to a potentially curative treatment, Garrison explained. By targeting two tumor-associated antigens, the OR gate limits the probability that the engineered CAR-NK cells will fail to recognize different cancer cells.

In lab dishes, the FLT3 OR CD33 CAR-NK cells outperformed single-target CAR-NKs against FLT3 or CD33 at killing off cancer in several leukemia cell lines. The novel CAR-NK cells “demonstrated significant cytotoxicity against primary AML patient samples and significantly reduced tumor burden and improved mouse survival” in AML mouse models carrying cancer xenografts, Senti researchers said in an abstract. 

In one patient xenograft model, all control mice had died from disease by day 64, while all rodents that got the CAR-NK cells were still alive, Garrison said.

“We believe that our strategy of concurrently targeting FLT3 and CD33 will result in a more robust synergistic anti-tumor effect, leading to a more durable remission with decreased risk of relapse due to single antigen escape,” the Senti team wrote.

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

One of the EMCN-specific inhibitory CAR configurations protected up to 67% of cells that expressed both FLT3 and EMCN from FLT3-targeted activating CAR in lab dishes.

The researchers also mixed FLT3 cells with or without EMCN expression to mimic healthy cells and AML cells. The NOT logic-gated CAR-NK cells preferentially killed the FLT3 cells without EMCN, they found.

RELATED: Bayer's VC arm leads $105M round for 'gene circuit' startup Senti Bio

Lastly, the researchers combined the OR gate and the NOT gate and added a proprietary IL-15 platform that could improve CAR-NK cell persistence and create a more durable antitumor response, Garrison explained.

In lab dishes, the full SENTI-202 circuit protected about half of healthy blood cells from CAR-NK toxicity while showing the same killing activity as CAR-NK cells without the NOT gate did. Based on decades of bone marrow transplant experiences in the field, Garrison suggested, experts believe that protecting about 10% to 20% of hematopoietic stem cells is likely sufficient to provide clinical benefits.

Senti Bio is the brainchild of a team of prominent scientists in biomedical engineering, including Massachusetts Institute of Technology researchers Tim Lu, M.D., Ph.D., and Jim Collins, Ph.D.

The gene circuit technology has attracted the interest of Big Pharma companies. In January, the company raised $105 million in a series B round led by Bayer’s venture capital arm.

 In April, Roche’s gene therapy unit Spark Therapeutics inked a $645 million-plus biobucks pack with the biotech to work on gene therapies directed toward the central nervous system, eye or liver.

The SENTI-202 CAR-NK readout at the ASH meeting marks the first complete proof-of-concept data set for Senti Bio’s OR gate and NOT gate gene circuits, and the data support the idea that the technology may enable “enhanced broader-spectrum cancer targeting while limiting off-tumor toxicity,” Garrison said in a statement.

SENTI-202 is one of the first programs to emerge from Senti’s platform. The company is also developing SENTI-301, which is designed to target GPC3 for treating liver cancer, along with SENTI-401, a CAR-NK cell therapy being developed for colorectal cancer.

Editor's Note: The story has been updated on Dec. 13 with additional information provided by Senti.