Taking T cell engagers to the next level

At PEGS 2024, I presented the first preclinical data on AstraZeneca’s novel Target Induced T cell Activating Nanobody (TITAN) platform, a CD8+ selective T cell engager (TCE). Marking an important point in our journey to develop the next generation of immunotherapies, this moves us towards delivering potentially more selective and better tolerated TCE therapies. Here, I discuss current approaches with TCEs and the science behind our new platform.

TCEs: the evolving cancer treatment landscape

TCEs are driving real clinical impact in oncology by providing a mechanism to generate a completely new immune response against cancer. Importantly, this has extended the potential benefit of immunotherapy to patients who are not expected to respond to other modalities that rely on the presence of existing anti-tumor immunity.

Despite their promise, the TCE field is not without obstacles. One of the biggest challenges is that TCEs can generate a diverse immune response, causing unwanted effects, such as cytokine release syndrome, that limits the amount of drug that can be given.

Researchers and physicians across the industry are exploring a number of approaches that attempt to solve these problems. Scientists are designing the next wave of TCEs with improved therapeutic index in mind, for example by fine tuning CD3 binding affinity to attenuate the immune response, and exploring ‘conditional activation’ to restrict their activity to the tumor microenvironment. And innovation in clinical development has seen the emergence of novel ‘step-up-dosing’ strategies designed to gradually prime the immune system, while different routes of administration such as subcutaneous formulations are being explored for their potential to optimize pharmacokinetics.

Addressing TCE selectivity challenge: AstraZeneca’s novel CD8+ selective T cell engager platform

Imagine having the ability to activate the immune system against cancer with exquisite selectivity. This is what my colleague Corinne Cayatte and I set out to do, resulting in the creation of the TITAN platform, a concept that was brought to fruition by scientists at AstraZeneca.

Our rationally designed TITAN platform is a new class of TCE that has the potential to increase the specificity of the anti-cancer immune response, by selectively engaging CD8+ T cells. Only a fraction of T cells express the CD8 receptor, and these have a critical role in fighting cancer. In contrast, CD4+ cells, which are more abundant in the body, have more diverse functions and their activation can lead to unwanted effects.

By engaging only those T cells that have the ability to kill tumor cells, our hope is that TITAN TCEs will deliver a more targeted immune response against cancer, potentially overcoming some of the most pressing challenges in the field.

Delving deeper into the science behind TITAN, our platform uses a modular structure, with two ‘nanobody’ domains targeting the T cell via CD8 and the T-cell receptor, and an additional domain targeting a specific cancer-related antigen. Our preclinical data indicate that not only do TCEs designed using this platform preferentially engage with CD8+ T cells .vs. CD4+ T cells, but there is also evidence that T cells are activated only while the TCE is bound to a cancer cell. Biophysical analyses are ongoing into the precise mechanism behind this, but my working hypothesis is that a conformational change induced by the binding of the molecule to the cancer target could be behind this specificity.

What’s next for the platform?

The disclosure of preclinical data at PEGS 2024 is an important first step in a journey we hope will eventually lead to effective therapies for people living with cancer, and with potential in other immunological diseases. We’re excited about the progress we’ve made so far, and I look forward to sharing more preclinical data soon.