The importance of T cell fitness in cancer immunotherapy

The advent of immunotherapies has revolutionized cancer treatment. However, the efficacy of these therapies can vary among patients, with a range of factors influencing treatment effect.

One of these factors is T cell fitness (TCF), which we explore in this article, assessing how it may influence the outcomes of cancer immunotherapy. We’ll review the latest findings from our clinical trials in this area, highlighting the association between a gene expression signature of T cell fitness and treatment benefit with ImmTAC (Immune Modulating Therapies Against Cancer) therapies. 

T cell fitness: an overview

T cell fitness has primarily been defined in the context of CAR T cell therapy, where it has been described as the ability of T cells to generate an effective immune response capable of eliminating malignant cells and providing durable protection against the recurrence of a disease.^[1]

There are several characteristics that appear to affect T cell fitness, including:^[1]

·       Age: Advanced age is associated with reduced T cell function and altered populations of T cells.

·       Disease burden: Chronic disease and inflammation can lead to reduced T cell fitness.

·       Treatment burden: Some cancer treatments can negatively impact T cell fitness, meaning patients who have experienced several lines of treatment may have reduced T cell fitness.

Beyond these characteristics, there are numerous gene signatures and cell-surface markers being explored, such as markers of naïve and stem cell memory T cells, which have been investigated in numerous research papers looking at CAR T cell products.^[1]

Assessing T cell fitness can help to explain variations in patient responses to immunotherapies. Furthermore, determining T cell fitness before therapy could help clinicians to anticipate treatment effect, tailor treatment strategies and improve patient outcomes.

We are exploring how T cell fitness – as defined by the capacity of T cells to self-renew, proliferate, find tumor cells and differentiate into active effector T cells – can impact the anti-tumor activity of ImmTAC therapies.^[2]

Blood T cell fitness and ImmTAC therapy

We have found compelling evidence supporting the impact of T cell fitness on the clinical activity of our ImmTAC therapies. 

Data we have presented so far have shown that a T cell fitness signature in blood, measured prior to therapy, is strongly associated with clinical benefit of ImmTAC therapy in different cancers.

Observations in the data included that patients with higher expression levels of the T cell fitness genes had significantly longer median progression-free survival, a higher disease control rate, and a higher overall response rate compared to patients with a low TCF signature. This association was observed in trials of two different ImmTAC therapies, initially in patients with metastatic uveal melanoma before the observations were replicated in patients with ovarian cancer and patients with cutaneous melanoma.^[2]

From the accumulating data, a T cell fitness signature has emerged as an important determinant of therapeutic effectiveness for two of our molecules, across different tumor types.

So if T cell fitness can be associated with clinical benefit of ImmTAC therapy, attention must also turn to whether anything can be done to boost a patient’s T cell fitness before treatment.

At the 2026 ASCO Annual Meeting, data was presented on the effect of rhIL7 on T cell fitness. Although early, the data is intriguing and demonstrates that it may be possible to convert low TCF patients into high TCF status^[3], which is likely to become a growing area of research across the industry.

Our aim is not only to improve the lives of patients with cancer, infectious diseases, or autoimmune diseases, but also to deepen our understanding of how tumors respond to this new wave of immunotherapies.

As we gather more data from each trial, we explore ways to evaluate the effectiveness of our treatments and incorporate factors such as T cell fitness. These learnings can be taken back into the lab and embedded in ongoing and future clinical trials, as we develop new therapies and continue to push the boundaries of immunotherapy. 

References

^[1] Mehta P, et al. Front Immunol. 2021; 12:780442. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658247/

^[2] Sacco JJ, et al. Abstract #66O. ESMO 2024. Available at: https://www.sciencedirect.com/science/article/pii/S092375342401593X

^[3] J Clin Oncol 44, 2026 (suppl 16; abstr 2662)