T-cell engagers: Reawakening T-cells to fight cancer

The immune system is a magnificent design. One of its many superpowers is the ability to detect and destroy cancer cells. Our goal is to harness that potential using new therapeutic modalities, such as so-called ‘T-cell engagers’, to stimulate the immune response against hard-to-treat cancers. At Boehringer Ingelheim, we have made a generational commitment to transforming cancer care, with the ultimate goal of curing a range of cancers.

Thymus-derived lymphocytes, or T-cells, are key members of the immune system. They are highly specialized to identify and kill infected and abnormal cells that could pose a threat to the body. However, cancer cells can develop strategies to escape the immune system and continue to multiply. Eventually this can lead to the lack of T-cells within tumors, characterizing them as “cold” tumors. These tumors are known to respond poorly to immune checkpoint inhibitors – a type of immunotherapy that releases the “brakes” from T-cells, keeping them functional¹.

Our commitment to advancing immuno-oncology

We are exploring new ways of directing and boosting the immune system against cancer cells and investing in multiple platform technologies to deliver meaningful advances in areas of high unmet patient need.

T-cell engagers are promising targeted immunotherapeutics, which can reactivate T-cells, potentially resulting in the selective killing of cancer cells by the body’s own immune system. Alongside therapeutic cancer vaccines, oncolytic viruses and immune/stromal modulators, this is one of our approaches to improve responsiveness to immunotherapy and extend its benefits to more people.

Lamine Mbow, Global Head of Cancer Immunology and Immune Modulation at Boehringer Ingelheim, shares our approach to immuno-oncology, highlighting our T-cell engagers platform and how we are driving innovation in this space to unlock the next wave of targeted immunotherapies.

A new perspective in the treatment of DLL3-positive tumors

Delta-like ligand 3 (DLL3) is a protein that has been found to be highly expressed on the cell surface of up to 85% of small cell lung cancer (SCLC) tumors and approximately 77% of other neuroendocrine carcinomas (NECs)^2,3. In normal tissues, DLL3 is minimally expressed, making it a compelling therapeutic target.

SCLC is the most aggressive subtype of lung cancer and represents about 13% of all lung cancer cases worldwide. NECs are also highly aggressive cancers occurring in multiple organs including the gastrointestinal tract, skin, bone, prostate and pericardium. Chemotherapy has been the standard of care for decades, and the introduction of immune checkpoint inhibitors as frontline treatment of SCLC has yielded only limited benefit⁴. There is an urgent need for better targeted immunotherapeutics for people living with SCLC and NEC.

We developed a novel Immunoglobin G (IgG)-like bispecific T-cell engager designed to bind concomitantly to DLL3 on tumor cells and CD3 on T-cells⁵. By creating a physical link between T-cells and tumor cells, the T-cell engager can activate T-cells against DLL3-expressing tumor cells, potentially resulting in their destruction. Activated T-cells can indirectly stimulate other immune cells to broaden the immune response against the tumor tissue. Our DLL3/CD3 T-cell engager is currently being evaluated clinically for the treatment of people living with relapsed SCLC and extrapulmonary NEC.

A glimpse from the Lab: “T-cell engagers in action”

Scientists from our Cancer Immunology and Immune Modulation department in Vienna share images of tumor cells (blue, oblong-shaped) being destroyed by T-cells (red, small dots) upon treatment with a T-cell engager - while fibroblasts (green, spindle-shaped), which are non-cancerous cells, remain undisturbed. Note how, in contrast to the “T-cell engager treated” condition, in the “untreated” condition the amount of tumor cells increases over time. These images were captured via fluorescence microscopy: a technique that allows the visualization of cells stained with fluorescent dyes.

Together we can change lives

Our purpose is to transform lives for generations. Our curiosity, creativity and passion for science lead us to take the paths scientifically less travelled and the courage to face challenging journeys as we relentlessly pursue the next generation of breakthrough therapies. This is only possible with the support of our exceptional people and global family of partners, who share the same passion for science and enjoy working together to deliver breakthroughs.

Join us to grow, collaborate, innovate and transform lives for generations.

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References

1.   Bonaventura, P. et al. Cold tumors: A therapeutic challenge for immunotherapy. Front. Immunol. 10, 1–10 (2019).
2.   Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci. Transl. Med. 11, (2019).
3.   Rojo, F. et al. International real-world study of DLL3 expression in patients with small cell lung cancer. Lung Cancer 147, 237–243 (2020).
4.   Caliman, E. et al. Challenges in the treatment of small cell lung cancer in the era of immunotherapy and molecular classification. Lung Cancer 175, 88–100 (2023).
5.   Hipp, S. et al. A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer. Clin. Cancer Res. 26, 5258–5268 (2020).