Looking Back: How Etcembly's ETCh Study is Uncovering New Cancer Targets from Survivors
Despite advances in medical science, finding a cure for cancer remains an elusive goal. Currently, only half of all people diagnosed with cancer survive for ten years or more, and treatment efficacy varies significantly across cancer types. Moreover, many cancer drugs fast-tracked through regulatory approval have failed to demonstrate significant clinical benefit in practice. Even immunotherapies—treatments designed to leverage the immune system to fight cancer—have been limited in their success, often failing to work universally and sometimes accompanied by significant side effects.
Etcembly, an Oxford-based techbio company, is taking a novel approach to this challenge through its ETCh study. This research initiative is designed to search for new immunotherapy targets by analyzing the immune responses of people who have survived cancer for more than three years. Unlike conventional methods that search for therapeutic targets within tumors, Etcembly’s study focuses on working backward—from the immune systems of cancer survivors who have already beaten the disease—to identify new avenues for treatment.
The Potential of TCR-Based Therapies
T cells and their receptors (TCRs) play a key role in the immune system’s ability to combat pathogens and cancer cells. In recent years, therapies based on these T cells, including CAR-T cell therapy, have shown promise in oncology. CAR-T therapies work by engineering T cells to target cancer cells using synthetic antibodies. However, there is growing interest in developing therapies directly from TCRs themselves, as these immune components offer unique advantages.
TCRs can recognize a broader range of cancer cell targets, including protein fragments displayed on a cancer cell's surface by molecules known as HLA complexes. This allows them to trigger an immune response against cells that might otherwise evade detection. Still, to develop effective TCR-based immunotherapies, new cancer-specific targets must be identified—an area where current research has struggled.
Challenges in Target Discovery
In the early days of TCR research, advances in technology, particularly mass spectrometry, brought the promise of uncovering new targets for biotherapeutics and cell therapies. Many companies, including those working on TCR therapies, invested heavily in these technologies, resulting in large volumes of data on potential targets. However, turning these findings into reliable blockbuster therapeutics has been a challenge.
"The drugs being developed today are still mostly targeting the same old suspects," says Nick Pumphrey, Chief Scientific Officer at Etcembly. Molecules like MAGEA4, MAGEA1, NYESO1, and gp100 have been known targets for years, long before the advent of mass spectrometry validation. Although some new leads have emerged, these targets remain largely unvalidated in clinical settings, underscoring the need for novel approaches.
Etcembly’s lead program, ETC-101, aims to break through these limitations. It represents the world’s first generative AI-designed bispecific T cell engager with picomolar affinity and targets PRAME, one of the few older targets that is highly expressed across multiple cancer types. While PRAME remains a well-established target, the company’s broader ambition is to develop a pipeline of TCR therapeutics that can address previously unidentified or underutilized targets within cancer cells.
“Our goal is to develop a pipeline of TCR therapeutics that take aim at new targets within cancer cells,” says Pumphrey. “We don't want to go about finding these new targets in the same ways that have had limited success before. Instead, we’re trying a different approach.”
Etcembly l-r Scott Cuthill CBO - Michelle Teng CEO - Jacob Hurst CTO - Nick Pumphrey CSO
Working Backward: From TCR to Target
Etcembly's ETCh study adopts a reverse approach to the challenge of finding new cancer targets. By focusing on T cells that have already proven effective in cancer survivors, the company hopes to identify targets that have demonstrated their ability to fight cancer in real-world scenarios.
One early breakthrough in this field was achieved through tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting T cells from a patient's tumor, expanding them in the lab, and then reintroducing them to the patient to help combat the cancer. This approach, pioneered by researchers like Professor Andy Sewell from Cardiff University and Professor Inge Marie Svane at Denmark’s Centre for Cancer Immune Therapy (CCIT), has become a well-established treatment for melanoma and other cancers.
In further studies, the team looked into the immune response of patients who had received TIL therapy, aiming to identify the specific T cells that recognized and attacked their tumors. They sought to determine whether any of these T cells could also target cancers in other patients. This research revealed T cell reactivity to both traditional melanoma and transplant targets, as well as novel, unexpected targets. This method of tracing T cells back to the targets they recognize is known as "de-orphanisation."
Etcembly is applying a similar "de-orphanization" method—identifying TCRs and tracing them back to the cancer targets they recognize. By analyzing TCRs from long-term cancer survivors, the ETCh study aims to identify new molecular targets that could become the foundation for next-generation immunotherapies.
Advanced Techniques in the ETCh Study
The ETCh study uses a range of techniques to analyze the immune system:
- Single-cell sequencing: Etcembly’s proprietary microfluidics technology enables sequencing of the TCR and antibody repertoires from each participant. This technique provides insights into how immune responses vary across different cancer types and patients.
- Paired TCR analysis: Most immune databases contain single TCR chains, but TCRs function as pairs (alpha and beta chains). Etcembly’s technology sequences both chains together for a more complete view of how TCRs recognize and attack cancer cells.
- Computational modeling: EMLy, Etcembly’s AI platform, analyzes immune repertoires to predict which TCRs hold the greatest potential for targeting new molecules within tumors. The AI also helps identify commonalities across cancer types, which could inform more broadly applicable treatments.
- Laboratory validation: Promising TCRs identified through sequencing and computational analysis are tested in the lab to assess their effectiveness. This iterative process refines the AI models, ensuring that selected TCRs have high specificity and affinity for their targets.
Why Participate in the ETCh Study?
Participants in the ETCh study will contribute to research that could underpin the development of powerful new cancer treatments. Cancer survivors who take part will provide critical insights into how their immune systems responded to their illness, helping researchers identify new therapeutic targets that may benefit future patients.
Additionally, the study will offer financial compensation of £20 per visit to cover participants' time and travel costs, with the option to donate this payment to charity. Blood samples collected during the study will be stored securely and could be used for future research, provided participants give their consent. The samples will be kept for up to 15 years and may contribute to ethically approved studies beyond the scope of the ETCh project.
Etcembly takes privacy seriously, ensuring that all data handling complies with GDPR regulations. Participants’ personal data will remain anonymized in published research, and samples can be withdrawn at any point during the study.
New Targets, New Possibilities
Etcembly’s approach to TCR-target identification might uncover more precise and broadly applicable cancer treatments than conventional methods. By focusing on T cells that respond to common antigens across multiple cancer types, the company hopes to find targets that could be used to develop therapies for a wider range of patients.
Additionally, by including newly diagnosed patients and tracking their immune responses over time, the study will provide insights into how the immune system interacts with cancer from the point of diagnosis through treatment.
Looking ahead, Etcembly’s long-term vision is to develop "in silico" TCR de-orphanization, using AI to predict a TCR’s target antigen based solely on its DNA sequence.
Topics: Novel Therapeutics
