Rewriting the Rules of AML Therapy: How SENTI-202 Strikes a Critical Balance in CAR-NK Cell Treatment

At the 2025 AACR Annual Meeting, Senti Biosciences shared new clinical data from its first-in-human study of SENTI-202, a next-generation allogeneic CAR-NK cell therapy designed to tackle one of the most complex hematologic cancers—acute myeloid leukemia (AML). Despite decades of research, AML remains difficult to treat due to its heterogeneity, rapid progression, and resistance to standard therapies. In this interview, Dr. Tim Lu, Co-founder and CEO, and Dr. Kanya Rajangam, President, Head of R&D, and Chief Medical Officer, share insights into how SENTI-202 leverages logic-gated Gene Circuit technology to address key challenges in AML therapy—and how this approach may reshape thinking around cell-based treatments and targeted therapies.

SENTI-202’s Multi-Target Logic Gates Enhance Precision and Efficacy to Treat the Heterogeneous Nature of AML

Senti Bio’s SENTI-202 is built with a novel multi-target logic gate that aims to improve the specificity and efficacy of AML treatments. AML is a complex cancer marked by the uncontrolled growth of immature white blood cells in the bone marrow. Traditionally, AML therapies have faced challenges in selectively targeting cancer cells without also harming healthy tissues. 

Dr. Lu emphasized the complexity of AML and the need for more tailored treatments. “One difficulty in treating AML lies in its heterogeneity. It’s not a single disease but a collection of subtypes, making it hard to treat with only one individual target. In addition, known AML targets are also expressed on healthy cells, resulting in significant toxicity against healthy cells during treatment.”

To solve these problems, SENTI-202’s logic gates are built using an “accelerator” chimeric-antigen receptor (CAR) and a “brake” CAR. The “accelerator” CAR initiates cancer cell killing when CD33 or FLT3 are detected, driving the immune cells to target malignant cells. The combination of these two markers helps improve the recognition of leukemia blasts and leukemic stem cells (LSCs), which are often responsible for relapse and disease progression.

Meanwhile, the “brake” mechanism, in the form of an inhibitory receptor targeting endomucin (EMCN), ensures that healthy cells remain unharmed even if the healthy cells express CD33 and/or FLT3, since EMCN is generally found higher on healthy cells compared to AML cells. This balancing act between activating and inhibiting signals is a key feature of SENTI-202, enabling the therapy to target cancer cells effectively while safeguarding normal tissue. “You really need a balance of these two receptors in order to give you this type of selectivity,” said Dr. Lu.

Gene Circuit Technology Powers SENTI-202’s Precision in Targeting Diseases Through Dynamic Cellular Programming

Senti Bio used its proprietary Gene Circuit programming platform to design and optimize the logic gates in SENTI-202. The technology enables the engineering of cells that can respond dynamically to their environments, making them more adaptable and capable of achieving complex therapeutic goals.

“We can engineer cells with logic gates such as AND, NOT, or OR gates,” said Dr. Lu. “These logic gates allow the cell to sense the environment and respond appropriately, whether that means turning on or off a therapeutic gene, or activating or inhibiting killing.” This allows Senti’s therapies to potentially achieve greater precision, limiting off-target effects and improving safety and efficacy profiles.

SENTI-202 incorporates a NOT logic gate to help distinguish between cancerous and healthy cells. “We’re able to incorporate a NOT logic gate, and that basically takes advantage of a healthy marker such that if a target cell has that healthy marker, our circuit says, ‘Don’t kill that cell,’” Dr. Lu explained.

Navigating AML Treatment Challenges Including Drug Resistance and Age-Related Conditions

Despite promising technologies, treating AML remains extremely challenging. “It’s a difficult disease to address,” Dr. Rajangam admitted. “Not only because leukemia itself can be resistant to therapy, but also because this is a disease of the elderly, so a lot of patients have other illnesses like cardiac problems or infections, which makes it difficult to give them the drugs they need.” This reality presents logistical, clinical, and ethical challenges when designing treatment regimens.

Another major hurdle is scaling patient enrollment while maintaining safety. As with any Phase 1 trial, SENTI-202 began with small patient cohorts, gradually expanding to ensure safety at every step. “When you start a new therapy, you need to start slow,” Rajangam explained. “The first year, a lot of the data you’re getting is from really small numbers, so only when you’re able to increase patient numbers can you make meaningful conclusions.” This strategy helps ensure that researchers do not miss any critical safety signals. “There’s no shortcut to building a therapy that works. We believe the work done prior to dosing patients is as important, if not more important, than what happens after,” she stated.

However, one aspect of their approach reduces uncertainty: the use of well-validated targets. “Both CD33 and FLT3 are important drivers of AML,” Dr. Lu pointed out. “We know that inhibiting CD33 works for AML. We know that turning off the FLT3 pathway works for AML. So from that perspective, these targets are well-understood in the field.” This not only reassures regulators and clinicians but also gives confidence in the biological rationale behind the therapeutic approach.

One of the most remarkable stories from the SENTI-202 Phase 1 trial involves multiple patients with AML who remain alive and disease free well beyond the median survival rate of just five months. According to Dr. Rajangam, these cases have offered inspiration and real-world validation of their technology. “These patients’ continued Complete Remissions are not only medically meaningful, they’re personal for our team. It reinforces why we took the extra time before the clinic to ensure our gene circuit was fine-tuned to spare healthy cells,” she noted.

Company Hopes to Expand Gene Circuit Platform into Solid Tumors and Regenerative Medicine

Looking ahead, the company is now exploring its proprietary gene circuit platform for use in solid tumors and even non-oncology applications. “We have implemented and designed the technology to work in CAR-T cells as well,” Dr. Lu shared, noting active ongoing research into using the platform to create new solid tumor therapeutics. “The company is also advancing non-oncology applications such as regenerative medicine and gene therapy,” Dr. Lu confirmed. “We can repeat the same process that we went through to design SENTI-202 to address the outstanding problems in these diseases.”

While oncology remains a key focus due to its high unmet need, Senti Bio remains open to partnerships that could bring the gene circuit platform into broader therapeutic areas. “Our key driver at this point is really to develop products that can be FDA approved and commercialized for patients,” stated Dr. Rajangam. With validated targets like CD33 and FLT3 providing a strong scientific foundation, and early patient data reinforcing the platform’s logic, Senti Bio is positioning itself for long-term impact.

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Denisse Sandoval