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Senti Biosciences, Inc. (Nasdaq: SNTI) announced the publication of new peer-reviewed research in Cell Systems describing a systematic framework for engineering NOT-gated chimeric antigen receptor (CAR) circuits in both T cells and natural killer (NK) cells. The study reports that logic-gated receptor designs can improve the efficacy, precision, and safety of cell therapies by enabling immune cells to selectively eliminate tumor cells while sparing healthy tissue.
The paper, titled NOT-gated Chimeric Antigen Receptor Circuits in T and NK Cells, evaluates dual-receptor CAR circuits that combine:
Across more than 60 CAR circuit designs, the authors quantitatively analyze design principles affecting activation strength, inhibition dynamics, antigen dose response, and functional durability across immune cell types.
The study identifies inhibitory CARs based on the LIR1 receptor as particularly potent regulators of immune cell activity, reporting that they outperform several canonical immune checkpoint receptors.
In T cells, the optimized NOT-gated CAR circuits are described as improving discrimination between tumor and healthy cells, reducing markers of cellular exhaustion, and preserving cytotoxic killing after repeated antigen exposure. The authors state these results suggest inhibitory CAR signaling may provide benefits beyond target specificity, potentially improving durability of therapeutic responses.
The paper also reports that many NOT-gated CAR designs show high performance in both T cells and NK cells. In an in vivo mixed-cell xenograft model, the study states that NOT-gated CAR T cells and CAR NK cells selectively eliminated tumor cells while sparing off-tumor cells expressing protective antigens.
The authors conclude that the logic-gated CAR circuits are portable across ex vivo and in vivo CAR modalities. They also describe the approach as potentially enabling treatment of cancers where clean tumor-specific targets are unavailable.
The findings are presented as supporting the applicability of Senti Biosciences’ Gene Circuit platform, which is designed to program cells with logic-based control over therapeutic activities. The company states that NOT-gated CAR circuits represent a foundational approach for enhancing safety and expanding the therapeutic window of engineered immune cells in cancer and other diseases. The company also reports that a patent application has been filed covering aspects of the technology described in the study.
Tim Lu, M.D., Ph.D., Chief Executive Officer and Co-Founder of Senti Biosciences, said the study demonstrates how synthetic biology can introduce decision-making into living medicines by systematically dissecting the interaction between activating and inhibitory CARs to provide a roadmap for building immune cells that are both effective and precise.
Wilson Wong, Ph.D., Professor of Biomedical Engineering at Boston University, and Scientific Co-Founder of Senti, said the results highlight properties of inhibitory CARs that he described as interesting and underappreciated for improving the performance of immune cell therapies.
The company noted that the publication complements its recent announcements on positive clinical data with its Logic-Gated SENTI-202 product in the treatment of relapsed/refractory Acute Myeloid Leukemia presented at the 2025 American Society of Hematology Annual Meeting. The full article is available online in Cell Systems.
Senti Bio is a clinical stage biotechnology company developing cell and gene therapies for patients living with incurable diseases. The company states it leverages a synthetic biology platform to engineer Gene Circuits into medicines with enhanced precision and control, designed to precisely kill cancer cells, spare healthy cells, increase specificity to target tissues, and/or be controllable even after administration.
Senti Bio’s wholly-owned pipeline comprises cell therapies engineered with Gene Circuits targeting challenging liquid and solid tumor indications. The company states its Gene Circuits have been shown preclinically to work in both NK and T cells, and that it has demonstrated preclinical potential in other modalities and diseases outside oncology through partnerships.
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