Written by:
Executive Director, Head of IO Discovery, AstraZeneca
Executive Director, Head of Immune Engagers, AstraZeneca
Senior Director, R&D Oncology, AstraZeneca
Immuno-oncology has grown exponentially over the last decade and is transforming outcomes for patients. At AstraZeneca, we are exploring innovative ways to empower the body’s immune system to fight cancer, such as novel multispecific antibodies and next-generation immune cell engagers, including our pioneering trispecific CD8+ selective T-cell engager platform.
The expansion of immuno-oncology
The first wave of immunotherapies has been transformative - potentially curative - for some patients, but they aren’t effective for everyone.1 Some cancers do not respond to immunotherapy, while others develop resistance over time.1
There are many factors that influence the effectiveness of immunotherapy treatment, such as the state of the patient’s immune system and the tumour microenvironment, both of which can be manipulated by cancer cells to suppress immune responses.2
At AstraZeneca, our scientists are exploring sophisticated approaches to support the patient’s own immune responses against cancer. These include novel ways to generate a synthetic immune response in patients whose immune system cannot recognise cancer and to overcome the immunosuppressive nature of the tumour microenvironment that limits the effectiveness of immunotherapy in some patients.
It all leads to our ultimate goal of extending the impact of immunotherapy to more patients and overcoming mechanisms of resistance to immunotherapy treatments to help achieve our ambition of eliminating cancer as a cause of death.
Find out how next-generation immunotherapies, such as multispecific antibodies and immune cell engagers, can harness the body's immune system to target cancer cells in this video:
The evolution of multispecific antibodies
Some of the most promising immunotherapies include multispecific antibodies that bind to multiple different antigens, either on the same or different cells.3
Bispecific antibodies can be used to generate new biological responses by targeting two molecules simultaneously. For example, they can be designed to target two different immune checkpoints on the same T cell, combining the potential benefits of two drugs in a single molecule.4 Alternatively, multispecifics can be engineered to increase the potency and selectivity of a molecule, for example, by using one arm of the antibody to ‘guide’ the binding of the other arm to another receptor.4 Moreover, they can be engineered to deliver novel biology either through triggering non-canonical signalling cascades inside the target cell or by causing cells to interact in new ways.5
The emergence of immune cell engagers
The first generation of immunotherapies work by releasing the ‘brakes’ that control T cell function, allowing them to attack tumour cells.6 But this relies on the presence of a pool of T cells that can recognise the abnormal antigens expressed on the surface of cancer cells.6
Immune cell engagers are a class of multispecific antibodies that bypass this requirement for antigen-specific T cells.7 One arm of the antibody binds to a target on the surface of a cancer cell, while the other binds to a receptor on the surface of an immune cell such as a T cell and brings the two into close proximity.7 This forms a synthetic synapse between them, activating the T cell to attack the cancer.7
This exciting modality offers a novel way to boost the patient’s immune system by tapping into a larger pool of immune cells than traditional immunotherapies. They could even be designed to recruit other immune cells to attack the cancer.7 By generating a new response these approaches have potential benefits in patients with a weak or absent anti-tumour response.
The first generation of immune cell engagers are bispecific, and have achieved considerable success in engaging the wider immune system by targeting CD3, which is expressed by all T cells.8 We are advancing our novel trispecific CD8+ selective T-cell engager platform, which includes several T-cell engagers that preferentially engage CD8+ T cells, a sub-group of T cells with important roles in the prevention and elimination of cancer. Additionally, these T-cell engagers are only active when bound to cancer cells, meaning unwanted effects are minimised.
Developing the next generation of immunotherapies
We have invested heavily in our diverse oncology portfolio, which spans many different treatment modalities. This lets us design and test novel combination therapies that can synergise with our multispecific antibody and immune cell engager candidates.
For example, we are exploring the use of antibody-drug conjugates (ADCs) and small molecules that can selectively kill cancer cells, and combine with immunotherapies to initiate an anti-tumour response.9 This means that we can come at cancer from multiple angles to hit the tumour smarter and drive deeper and more durable responses.9
As we look to the future, we are continually advancing our understanding of how the immune system recognises and engages with tumour cells, to inform new ways to amplify the body’s natural defences against all types of cancer. One key tool in our arsenal is our advanced oncology data platform, which organises our vast data reserves and uses artificial intelligence to guide the development of novel therapeutics and strategies in oncology.
We’re just getting started
We are living through an era where immunotherapy has moved to the forefront of cancer treatment. We are tirelessly working to discover novel cancer treatments and look forward to a time when we are able to apply these innovative approaches to transform outcomes for more patients worldwide.
