Aiming to reset the immune system to transform immunology

Immune-mediated diseases affect millions of people worldwide,¹ causing chronic pain, fatigue and disabilities that can be life-limiting and are detrimental to patients’ quality of life.^2,3 The prevalence of these conditions continues to grow,⁴ yet despite significant treatment advances over recent decades, remission and cure remain out of reach for many patients.⁵

At AstraZeneca, we are developing transformative medicines across the natural history of immune-mediated diseases to potentially make remission, and one day cure, a reality. These include novel biologics for patients with moderate-to-severe disease, through to advanced modalities such as T-cell engagers and cell therapies for refractory patients.

Cell therapies form a key part of our immunology ambition and have the potential to provide complete remission – a functional cure – with a single administration for certain patients who do not respond to and remain underserved by current therapies.

The urgent need for new treatment approaches

For many years, before the approval of the first biologic in the late ‘90s, the only available treatment for patients with immune-mediated diseases – some of which are known as autoimmune diseases – were high doses of immunosuppressants, which are associated with significant side effects.^6,7 Today’s biologics help to control symptoms for patients, however, because they do not stop or reverse the root cause of disease, they must be administered indefinitely.⁵ These treatments have improved the lives of many, however, a large proportion of people with immune-mediated diseases still struggle to control their disease: for example, in Crohn’s disease up to 50% of patients do not respond to currently available treatments, and less than 20% achieve remission. Remission rates also remain low in other diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).^9,10

Aiming to reset the immune system with cell therapy

Chimeric antigen receptor T-cell (CAR T) therapy has been successful in targeting and eliminating malignant B-cells in certain haematological cancers. Autoreactive B‐cells also drive immune-mediated diseases such as SLE, RA, systemic sclerosis (SSc), myositis and multiple sclerosis (MS)^12,13,14 suggesting CAR T therapy could work for these diseases too.

In immune-mediated diseases, CAR T therapy aims to fully deplete autoreactive B-cells throughout the body, and allow the immune system to repopulate with new, healthy B-cells – effectively “resetting” the immune system. Early data have shown the capacity of CAR T therapy to induce long-lasting, drug-free remission in people with SLE.^15,16

Building on this foundation, at AstraZeneca we are leveraging our deep understanding of disease drivers to explore cell therapy applications in SLE as well as a broader spectrum of immune-mediated diseases, particularly those involving B-cell dysfunction. By targeting overlapping disease pathways, we are applying a B-cell depleting CAR T approach to diseases such as RA, myositis, SSc and MS to further expand the potential impact of these innovative therapies.

Developing cell therapies for a range of immune-mediated diseases

At AstraZeneca, our cell therapy strategy in immunology is focused on accelerating the development of two pioneering approaches, CAR T and CAR T regulatory (CAR Treg) cells.

CAR T-cells:

• We are developing dual-targeting autologous CAR Ts directed at proteins expressed on B-cells throughout their lifecycle: from autoreactive B-cells, through to long-lived plasma cells that drive multiple immune-mediated diseases.¹⁷
• This approach could provide increased effectiveness compared to CAR T-cells with a single target, because of the breadth of B-cell depletion.¹⁷ By doing so, we may be able to deliver therapies with the potential for long-lasting, drug-free remission. The effectiveness of this approach is being assessed in clinical stage trials.

CAR-Treg cells:

• We are also looking beyond B-cell-mediated diseases: diseases driven predominately by autoreactive T-cells, such as type 1 diabetes (T1D) and inflammatory bowel disease (IBD), are another key focus area for us.
• Regulatory T cells (Tregs) are a T-cell subtype that can suppress other cells in the immune system and are critical to the prevention of an overactive immune response. In certain IMDs, impaired function or number of Tregs can result in them losing the ability to suppress the overactive immune cell activity driving disease.¹⁸
• CAR Treg cells can be directed to specific tissues or antigens, providing localised immune regulation in affected organs.

With our partners, Quell Therapeutics, we are aiming to re-engineer patients’ own Tregs locking them into a stable suppressive phenotype and directing them to specific targets in the body with the use of a specific CAR. This could allow us to restore immune tolerance for the long-term in chronic immune-mediated diseases.

Enabling improved cell therapy uptake and access

To accelerate our transformative technologies, we are addressing current adoption challenges, such as complex manufacturing and scalability, so more people with immune-mediated disease may access these potentially life-changing treatments. For example, our FasTCAR platform significantly shortens the lengthy manufacturing period of autologous CAR T-cells,¹⁹ therefore reducing the time patients spend waiting to receive the therapy while it is produced.

We’re also exploring exciting new technologies beyond autologous cell therapies. We believe in the need for a diverse, multi-modal approach which is why we are pioneering off-the-shelf cell therapies such as allogeneic CAR Ts – created from a healthy donor’s immune cells – and in vivo CAR Ts – which deliver genetic instructions and engineer cells directly inside the patient. Both approaches could overcome some of the most complex elements of the cell therapy process limiting access today.

Building world-leading capabilities and expertise to realise the full potential of cell therapy

Cell therapy is a rapidly advancing field with the potential to deliver life-changing treatments to patients. To realise its full potential, we are enhancing our existing expertise through collaborations and investments in new technology and infrastructure. We are building world-leading capabilities and expertise for cell therapy to remain at the forefront of research and ensure these potentially transformative treatments reach as many patients as possible. Our efforts cover four key areas:

I. Harnessing decades-long discovery expertise in target biology, viral vectors, gene editing and biologics engineering to deliver next-generation cell therapies that could more precisely and effectively target disease and are scalable.

II. Investing in manufacturing sites to address anticipated future growth and deliver cell therapies at the scale needed globally.

III. Strategic partnerships and acquisitions to bring in new technologies and expertise that complement in-house capabilities.

IV. Reimagining how cell therapy centres deliver therapies to help build the infrastructure required to bring cell therapies to patients globally.

At AstraZeneca, we are committed to transforming the care of patients with immune-mediated diseases by moving beyond symptom control and progressing towards a potential cure. We are developing a diverse pipeline of novel therapies, utilising platforms such as T-cell engagers, complex biologics and cell therapies. By targeting the root cause of immune-mediated diseases, we believe we can deliver potentially curative therapies to patients who need them most.

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