Introduction
Cancer remains one of the most challenging diseases to treat due to its complexity, heterogeneity, and ability to evade the immune system. Classical therapy options currently include chemotherapy or radiation, harsh methods that can cause significant organ damage. In contrast to these classical options, cell therapies based on genetically engineered immune cells are emerging as a revolutionary approach.. However, these therapies suffer from on-target off-tumor toxicity (OTOT), where healthy cells expressing similar markers can be mistakenly targeted, leading to adverse effects (Flugel et al., 2023). Additionally, they may cause other complications, such as the cytokine release syndrome, where large amounts of inflammatory cytokines are rapidly released into the bloodstream, often triggered by overactive immune cells (Luo & Zhang, 2024). Furthermore, approved cell therapies, such as CAR-T cell therapy, are restricted to blood cancers due to the diverse and complex nature of solid tumors (Albelda, 2024). To address these challenges, we aim to harness the power of our immune system itself: a highly sophisticated and adaptable network capable of identifying and eliminating threats. Yet, even this complex system can be manipulated or overwhelmed by tumors that deploy numerous evasion strategies. Our approach is to build synthetic immune cells in a bottom-up fashion, designing them to incorporate the beneficial features of natural T-cells—such as targeted recognition and controlled activation—while minimizing the risks of toxicity and overstimulation. Our cells allow for flexible input and output configurations, enabling adaptation to different tumor types and clinical contexts. Rather than trying to simply overpower the tumor, as many current therapies do, our goal is to outsmart it through precise sensing, decision-making, and response mechanisms that are tailored to the tumor’s unique microenvironment. In doing so, we want to bridge the gap between foundational research and oncology to open new avenues for safer, more effective, and highly personalized cancer treatments.
Project Outline
Input
Similarly to endogenous immune cells, our synthetic cells are able to sense different inputs using an innovative receptor architecture. Different inputs, both novel and well established, can be detected using highly specific and newly computed affinity domains as well as translated into ON- and OFF-signals.
Processing
At the heart of the Phoenics cell is our intracellular processing unit. Based on protein-protein interactions, it is able to incorporate signals from the receptor units and quickly identify the cellular environment and steer the cells' response. This makes our system react significantly faster compared to typical genetic circuits.
Output
Following the integration of its environmental cues, our cells can act accordingly, which leads to the desired effector function only in the tumor microenvironment. As a result, they can reactivate the exhausted immune system or directly target the tumor tissue, while ensuring minimal on-target-off-tumor activity.
DryLab
To complement our wetlab efforts and enhance the versatility of our synthetic immune cell platform, we have developed a digital modeling tool designed to support generalized application across a broad spectrum of cancer types. Our drylab model functions as a digital twin of the synthetic immune system, combining mathematical modeling, physics-based simulations, and machine learning methods to accurately simulate the interactions.
The model accepts user-defined inputs, such as the specific tumor ligands to be targeted and desired properties of the synthetic switch. These, for example, can be the activation thresholds for the input layer or sensitivity of our switch. Based on these parameters, the digital twin computes and proposes optimal circuit architectures that balance efficient tumor targeting and minimized off-tumor effects through ratio tuning of circuit components. This approach not only accelerates the design process but also broadens the applicability of our platform to diverse tumor indications, providing a valuable resource for the future development of modular, patient-tailored cell therapies.
Human Practices
In our Human Practices work, we strongly emphasized education by developing creative ways to make complex scientific topics engaging and comprehensible to diverse audiences. One central theme of our outreach was addressing the regulatory challenges in the field of cell and gene therapies, raising awareness among scientific colleagues and the public about how policy shapes innovation. In the scope of that we organized a panel discussion for young scientists on the European regulatory landscape and encouraged critical reflection on this important topic. To inspire the next generation of scientists, we designed a comprehensive program for pupils including a lecture series, summer school lab practical in collaboration with the DKFZ, and an online learning platform offering independent use of experiment-based materials adaptable by teachers and other iGEM teams. Interactive school workshops further brought our project into classrooms, creating initial interest in synthetic biology and its real-world applications. To also reach the broader public, we hosted an information booth and published a local newspaper article, making our project and regulatory issues relevant and accessible to everyday life.
Application
To explore the broad applicability of our system across different cancer types, we conducted extensive literature research and consulted a wide range of experts, from synthetic biologists to clinical oncologists, to identify tumor-specific inputs and design parameters. Additionally, solid tumors, such as pancreatic cancer, present particularly challenging microenvironments that limit the effectiveness of conventional immune therapies. Features like dense fibrotic stroma, abnormal vasculature, and immunosuppressive signaling create physical and biochemical barriers that hinder immune cell infiltration and impair their cytotoxic function. Moreover, the high mutation rates and heterogeneity of many solid tumors enable them to adapt and escape immune pressure over time, further complicating treatment. To overcome these obstacles, we designed our synthetic immune system to incorporate targeted sensing and adaptive response mechanisms that allow for a better infiltration of the tumour microenvironment.
By decoupling our system from patient-derived cells, we enable the development of off-the-shelf therapeutic products that are readily available, scalable, and more cost-effective. This approach not only bypasses the complex and time-consuming process of harvesting and engineering autologous cells, but also allows for broader accessibility and rapid clinical deployment across diverse patient populations and tumor types.