From Cancer to Infectious Diseases: TCR Therapies Broaden Immunotherapeutic Horizons

My first job post-PhD was at Avidex, the predecessor of Immunocore. It was exciting to think that the science I was contributing to in the lab could one day help patients with cancer or infectious diseases. We were laying the foundations for technology with huge potential to make a massive difference for patients.

It still blows my mind that the therapeutic proteins we engineer, refine, and manufacture can harness the power of the human immune system to fight diseases. 

As a resident doctor in the 1990s, I was profoundly affected by looking after, often very young, people who had undergone a bone marrow transplant as cancer treatment or who had acquired HIV, a newly identified virus for which there was no treatment. I gained firsthand experience in managing the serious illnesses that can develop when the immune system is severely compromised. This sparked a desire to understand how the immune system works, how it interacts with infectious pathogens, and how we can apply science to develop new immune-based therapies.

Immunocore’s therapies are “off-the-shelf,” making manufacturing more straightforward than other therapies such as CAR T, where the patients’ cells are harvested and re-engineered as a personalized medicine.

There are other manufacturing advantages. For example, to produce KIMMTRAK® (tebentafusp), we use a process that is relatively cost-effective but has some batch-size limitations. Despite this, the overall yield still enables a global drug supply.

TCR-based therapies are incredibly precise in how they target diseased cells. This is very important in the infectious disease context, as the patients we are trying to help are generally healthy despite having a chronic infection, so the bars for safety and efficacy are high.

Also, viral proteins that are typical targets of antibody therapies are, for a variety of reasons, not necessarily the best drug targets. TCR-based therapies can target a wide range of peptides displayed by human leukocyte antigen (HLA) proteins on the cell surface. This provides an opportunity to hit the virus where it hurts most.

When we started this journey back in 2000, it was clear that antibodies could become powerful therapeutics. However, they have an inherent limitation: their natural ligands are only surface proteins, which represent a small fraction of the proteome (10–20%). In contrast, TCRs can access a far broader landscape by recognizing peptides derived from virtually any cellular protein, presented on the cell surface via peptide-HLA complexes. This difference sets TCR-based approaches apart from antibody-based modalities.

By expanding the target space, TCRs enable the selection of antigens that are truly cancer-specific, potentially improving therapeutic precision and reducing off-tumor toxicity.

Finally, TCR-based bispecifics offer a key distinction from other immunotherapies. By leveraging CD3-mediated T-cell redirection, they do not require pre-existing tumor-specific T cells. This is a key advantage for tumors with low mutational burden—so called “cold” or “immune desert” tumors—where endogenous anti-tumor immunity is limited.

In terms of limitations, the primary trade-off is HLA restriction: TCR therapies are limited to patients expressing specific HLA alleles, necessitating patient stratification and testing. However, HLA typing is routine and supported by well-established methodologies.

Immunotherapies were pioneered in oncology, so there are several decades’ worth of experience there that we don’t yet have. Still, we are fortunate to build on this and apply the most relevant lessons from oncology to infectious diseases.

The major challenge for infectious diseases such as HIV and hepatitis B virus (HBV) is that a functional cure—long-term disease control without the need for standard of care antiviral therapy—is a high bar. Achieving this likely depends on therapies driving a profound reduction in the number of virally infected cells in the body, i.e., a much greater therapeutic effect than would be expected for a cancer treatment.

There is only so much that can be learned from preclinical studies as to how effectively our mechanism of action can address the underlying disease biology, so we have to figure this out empirically through a clinical trial.

The core principle of using a TCR to target abnormal cells with a high level of specificity is inherently versatile and can be applied to other disease types. Adapting our oncology focused platform for infectious diseases was a logical next step. The discovery and manufacturing processes, as well as the mechanism of action are broadly similar.

However, expansion into autoimmune therapies required a more significant strategic evolution. Unlike oncology or infectious diseases, where the goal is cytotoxicity, autoimmunity requires a protective approach to shield healthy tissue from immune attack. This shift necessitated the development of entirely new effector functions to fuse to the TCR, alongside different manufacturing processes.

While infectious and autoimmune diseases present unique considerations, they are not necessarily more challenging; they represent a natural evolution and expansion of the platform.

In our clinical trials, we are testing our TCR therapies in combination with existing antiviral drugs. This is crucial because antivirals put the brakes on the disease, providing the safest environment to test a new approach.

As lifelong antiretroviral therapy is standard of care in HIV treatment, it will almost certainly be a component of any curative therapy, at least for a defined period of time. For a functional cure approach to be transformational, it must be finite. For other infectious diseases such as HBV, where individuals exhibit different levels of natural immune control, a standalone treatment might be possible in some circumstances.

It has been so exciting to take an entirely novel concept from an idea, through preclinical testing, and into clinical trials in people living with HIV and HBV. We are just getting started in terms of understanding how TCR therapies work in infectious diseases, but to see that the drug behaves in a predictable way is incredibly gratifying.

The next 5–10 years will be a steep learning curve, but we are already designing and building the next generation of therapies.

The early development of the ImmTAX platform was driven by foundational concepts and theory, but we have now entered a new, evidence-based, era.

What is truly exciting now is that, by interrogating how our molecules behave in the clinic, we are deriving key insights into their mechanism of action in patients. This feedback loop is helping us focus on parameters that correlate with clinical success, guiding us toward the next generation of molecules.

The application of immunotherapy to treat autoimmune diseases is in early stages, but has incredible potential. I believe this area will see the next wave of innovation, and I am very excited that our first autoimmune program, for type 1 diabetes, is entering the clinic this year.