Senti Bio Prioritizes Logic Gated Cell Therapies

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Positive preclinical data related to SENTI-202 and SENTI-401 were presented at conferences last year.

Senti Bio will be prioritizing the development of its logic gated cell therapy candidates which are based on the company’s Gene Circuit technology, in particular SENTI-202 and SENTI-401, according to a corporate update.1

SENTI-202 is an investigational allogeneic chimeric antigen receptor (CAR) natural killer (NK) cell therapy candidate intended to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It targets both CD33 and FLT3 with the company’s “OR” logic gate, while incorporating the “NOT” logic gate to spare cells expressing EMCN. The company is currently planning investigational new drug (IND)-enabling studies for the therapy. A recently initiated technology transfer to Senti Bio’s cGMP manufacturing facility is expected to help support clinical-scale manufacturing for SENTI-202 and the company’s other allogeneic NK cell product candidates.

“The team's accomplishments with SENTI-202 have generated very promising data over the past year that was presented at the American Society of Hematology Annual Meeting last month,” Timothy Lu, MD, PhD, chief executive officer and co-founder, Senti Bio, said in a statement.1 “The data included human cell models and in vivo models that showcase the ability of our OR gate to broadly kill CD33 and/or FLT3 expressing leukemic blasts and leukemic stem cells, and our NOT gate to protect healthy cells expressing the EMCN protective antigen, including human hematopoietic stem cells. The team has completed pre-IND interactions with the FDA and believes that our planned IND-enabling studies and manufacturing and analytical processes will support a phase 1 trial for SENTI-202, with the ultimate goal of targeting patients with CD33 and/or FLT3 expressing hematologic malignancies including AML and MDS. Initiating process and analytical technology transfer to our Alameda cGMP facility is another milestone that puts us one step closer to providing clinical-scale manufacturing for our CAR-NK cell development candidates.”

SENTI-401, another investigational NK cell therapy, is intended to treat colorectal cancer and other CEA tumor antigen-expressing solid tumors. In preclinical research, CAR-NK cells expressing a CAR that targets CEA in conjunction with calibrated-release IL-15 and IL-21 demonstrated significant killing activity against CEA-expressing tumors in vitro in the presence of inhibitory TGF-beta, and in a mouse model. Furthermore, the NOT gate was able to protect up to 98% of model healthy cells expressing CEA and VSIG2, the protective antigen.

Senti Bio also announced intention to deprioritize development of SENTI-301A, a preclinical GPC3-targeted CAR-NK therapy intended to treat hepatocellular carcinoma (HCC) which does not incorporate the OR and NOT logic gates, until it is able to establish a strategic geographic partnership for its continued development for regions in Asia where HCC is more common than it is in the United States.1,2 Furthermore, the company indicated it is exploring the application of its gene circuit technology to additional therapeutic areas. In particular, it was noted that the company is engaged in research collaborations for non-oncology indications with Spark Therapeutics and BlueRock Therapeutics for the development of adeno-associated viral vector-based gene therapies and induced pluripotent stem cell-derived cell therapies, respectively, which will incorporate gene circuit technology.

CGTLive previously spoke with Alba Gonzalez-Junca, associate director of Research, Senti Biosciences, at the Onco Cell Therapy Summit (OCTS) USA 2022, about the company’s development of logic gated CAR-NK cell therapies. Gonzalez-Junca explained how the mechanisms behind SENTI-202 and SENTI-401 function.

"By targeting multiple tumor antigens we can target (in the case of AML) the bulk leukemic cells, but also the leukemic stem cells,” Gonzalez-Junca said during the interview. “That will cause better responses and longer remissions. But on the other hand, this can also raise the levels of toxicity on the healthy cells, and that's why the NOT gate is necessary. So the more you expand the tumor-targeting, the more risks you have of healthy tissue toxicity, so that's why both things go hand in hand."

REFERENCES
1. Senti Bio announces pipeline prioritization to focus on logic gated cell therapies; updates cash runway guidance. News release. Senti Biosciences, Inc. January 27, 2023. Accessed January 30, 2023. https://investors.sentibio.com/news-releases/news-release-details/senti-bio-announces-pipeline-prioritization-focus-logic-gated 
2. Pipeline. Senti Biosciences, Inc. Website. Accessed January 30, 2023. https://www.sentibio.com/pipeline 
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