On April 1, 2026 Senti Biosciences, Inc. (Nasdaq: SNTI) ("Senti Bio"), a clinical-stage biotechnology company developing next-generation cell and gene therapies using its proprietary Gene Circuit platform, reported the publication of new peer-reviewed research in Cell Systems demonstrating its systematic framework for engineering NOT-gated chimeric antigen receptor (CAR) circuits in both T cells and natural killer (NK) cells. The study demonstrates how Logic-Gated receptor designs can significantly improve the efficacy, precision, and safety of cell therapies by enabling immune cells to selectively eliminate tumor cells while sparing healthy tissue. This foundational paper complements Senti’s 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 for Hematology Annual Meeting.

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The paper, titled "NOT-gated Chimeric Antigen Receptor Circuits in T and NK Cells," presents a comprehensive evaluation of dual-receptor CAR circuits that integrate an activating CAR (for cancer killing) with an inhibitory CAR (for healthy cell protection). By quantitatively analyzing more than 60 CAR circuit designs, the study defines core design principles that govern activation strength, inhibition dynamics, antigen dose response and functional durability across immune cell types.

"This study highlights the power of synthetic biology to introduce decision-making into living medicines," said Tim Lu, M.D., Ph.D., Chief Executive Officer and Co-Founder of Senti Biosciences. "By systematically dissecting the interaction between activating and inhibitory CARs, we provide a roadmap for building immune cells that are both effective and precise."

The study identifies inhibitory CARs based on the LIR1 receptor as particularly potent regulators of immune cell activity, outperforming several canonical immune checkpoint receptors. In T cells, optimized NOT-gated CAR circuits not only improved discrimination between tumor and healthy cells but also reduced markers of cellular exhaustion and preserved cytotoxic killing of cancer cells following repeated antigen exposure. These findings suggest that inhibitory CAR signaling can provide benefits beyond target specificity, potentially improving the durability of therapeutic responses.

"These results show that inhibitory CARs have very interesting and underappreciated properties that can improve the performance of immune cell therapies," said Wilson Wong, Ph.D., Professor of Biomedical Engineering at Boston University, and Scientific Co-Founder of Senti.

Importantly, the authors demonstrate that many NOT-gated CAR designs exhibited high performance in both T cells and NK cells. In an in vivo mixed-cell xenograft model, NOT-gated CAR T cells and CAR NK cells selectively eliminated tumor cells while sparing off-tumor cells expressing protective antigens. These results highlight the portability of logic-gated CAR circuits across ex vivo and in vivo CAR modalities, and their potential to treat cancers where clean tumor-specific targets are unavailable.

The findings further support the applicability of Senti Biosciences’ Gene Circuit platform to cell and gene therapy, which is designed to program cells with logic-based control over therapeutic activities. 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. A patent application has been filed covering aspects of the technology described in the study.

The full article is now available online in Cell Systems.

(Press release, Senti Biosciences, APR 1, 2026, View Source [SID1234664143])