Accelerating innovation to transform cancer care - AstraZeneca
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cell therapy
We are also looking for new ways to enhance <anchor>cell therapy</anchor> through combinations with other agents in our portfolio and via strategic research collaborations. Evidence suggests that targeting more than one pathway may combat multiple tumour escape mechanisms, potentially allowing for greater anti-tumour activity than with one pathway alone10,11,12, and we are exploring a number of IO combination strategies for these synergistic effects.
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# Harnessing the power of cell therapy

### Cell therapy is a promising, rapidly advancing field with the potential to transform treatment across disease areas with significant unmet needs.

## What is cell therapy?

Cell therapy refers to the transfer of new cells, or cells that have been modified in a laboratory to achieve particular characteristics, into the body to prevent or treat a disease.1

### Such therapeutic cells are designed to: 2-4

- Remove diseased or dysfunctional cells
- Restore or modulate the function of the patient’s cells, through expression of factors or direct cell–cell interaction

### Cell therapies can be classified based on their origin: 1

- Autologous cell therapy means cells are isolated and removed from the patient, modified outside of the body, and reinfused as a medicine
- Allogeneic cell therapy means cells are derived from a separate donor, whose cells can be unmodified or modified (for example to specifically recognise a patient’s cancer)

### Jump to section:

## Our ambition in cell therapy

Our ambition is to realise the transformative potential of cell therapies for people living with debilitating diseases around the world, including cancer, autoimmune conditions and rare diseases. To achieve this, we are building world-class cell therapy capabilities, including advancing our understanding of disease biology, and driving innovation in gene editing, biologics and cell engineering.

Today, cell therapies are already driving meaningful benefit for some patients living with blood cancer5 and are showing early potential for future use in solid tumours and autoimmune diseases. However, there are significant barriers that prevent more widespread adoption in terms of access, manufacturing, and scale. We are working to find innovative solutions to address these and bring cell therapy to more patients and expand their use.

## Latest updates in cell therapy

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## Advancing next-generation cell therapies for cancer treatment

Adoptive cell therapy (ACT), also known as cellular immunotherapy, uses immune cells to target cancer.

Cell therapy is pivotal to our ambition to eliminate cancer as a cause of death and we are exploring the promise of T cell therapies in cancer treatment.

T cell therapies are created by isolating T cells (a type of immune cell) from the patient or healthy donors' blood, and genetically modified so that they can recognise and kill cancer cells. These modified cells are then grown in the laboratory and given to the patient by infusion.6

Chimeric antigen receptor T cell therapies (CAR-Ts) are genetically modified to express a chimeric antigen receptor (CAR) that recognises a specific, cancer-associated protein on the surface of tumour cells.6

T cell receptor therapies (TCR-Ts) are created by engineering a patient’s own T cells to express a T cell receptor (TCR) that recognises intracellular targets, including tumour-specific mutations expressed by cancer cells.7 The TCR is found on the surface of T cells and recognises targets bound to the major histocompatibility complex (MHC) on antigen presenting cells.7

We are advancing a diverse pipeline of preclinical and clinical stage innovative CAR-Ts and TCR-Ts across hard-to-treat solid tumours and haematological malignancies.

## Transforming care of haematological cancers with cell therapies

Autologous CAR-Ts have been hugely successful in treating some types of blood cancer.8 Our goal is to build on this work, and we have expanded our haematology pipeline through our acquisition of Gracell Biotechnologies. Together, we are advancing novel CAR-Ts designed using their rapid manufacturing process, with the potential to treat haematological malignancies.

## Expanding cell therapies to solid tumours

Extending the success of cell therapies to solid tumours has proved challenging for the scientific community as a whole.9 Unlike blood cancers, where cancerous cells are more freely accessible to targeting with cell therapies, the tumour microenvironment (TME) in solid tumours provides a physical and immunological barrier that limits their effectiveness.8

We have developed innovative strategies to ‘armour’ our cell therapies so they can resist the immunosuppressive effects of TGFβ, a cytokine that is highly expressed in many solid tumours and that limits the activity of immune cells. We are using genetic engineering for our TCR-Ts and CAR-Ts to reduce immunosuppressive signalling, thereby enhancing the potential activity of cell therapy in solid tumours.

Our growing pipeline of CAR-Ts utilise our novel armouring platform and target hard-to-treat solid tumours. This includes therapies reaching targets in gastric and pancreatic cancer, prostate cancer and hepatocellular carcinoma. Complementing our global development programmes, we are collaborating with Chinese biotech AbelZeta Pharma, to co-develop our CAR-T solid tumour portfolio in China and accelerate the development of potential new medicines for patients.

We aspire to be at the forefront of innovations in cell therapy, and our acquisition of TCR-T pioneers, Neogene Therapeutics in 2023 accelerated our work with this new modality. With their expertise, we are leveraging TCR-Ts to target intracellular proteins and develop personalised therapies engaging specific tumour drivers. We already have three TCR-Ts in clinical development: two targeting common tumour-driver mutations ( p53 and KRAS) as well as a fully individualised, multi-specific TCR-T. Each of these approaches has exciting potential to broaden the scope of cell therapies in solid tumours.

Discover more about CAR-T cell engineering in the below video:

Learn more about how TCR-Ts differ from CAR-Ts and their potential to help target solid tumours in this video:

## Developing cell therapies for autoimmune, chronic and rare diseases

Our advancing capabilities in immunology and cell engineering also have applications beyond oncology.

Immune system conditions arise when the carefully programmed immune cells, responsible for protecting the body from bacteria and other threats, malfunction.10 This can cause inappropriate inflammation.

CAR-Ts are able to reduce inflammation and could help transform the therapy for many chronic diseases with an immune component.11 This includes autoimmune conditions driven by loss of immune regulation, or chronic kidney disease which involves considerable inflammation.11 Our ultimate aim is to advance the next generation of cell therapies, with the potential to stop and reverse disease progression in autoimmune conditions and rare disease, as well as in cancer.

Building on our existing experience, we are investigating the potential of CAR-T therapies in refractory systemic lupus erythematosus (SLE). In SLE, removing pathogenic B cells has the potential to reset and normalise immune function, changing the outlook for patients with this life-altering and hard-to-treat condition.

Learn more about CAR-T cell therapy in immunology and chronic kidney disease in this video:

Beyond CAR-Ts, our research in immune-mediated diseases aims to stabilise regulatory T cells (Tregs); this is a T cell subtype that can suppress other cells, to prevent an overactive immune response.12 This could transform the treatment of a wide range of immune-mediated diseases, including type 1 diabetes, inflammatory bowel disease, and potentially rare genetic conditions.

Our aim is to stabilise and expand Treg cells in the lab, then reinfuse the new cell population, restoring immune control—potentially a permanent solution. Our partnership with Quell Therapeutics is enabling us to develop multiple engineered Treg therapies, beginning by targeting type 1 diabetes and inflammatory bowel disease. We aim to bring these potentially curative therapies to the clinic within ten years.

## Bringing cell therapies to more patients

To have the most positive impact for patients, we need to overcome barriers that prevent the widespread adoption of cell therapy, such as complexities in manufacturing and the limited number of specialist treatment centres. We are committed to finding innovative solutions to improve the access and scalability of cell therapies.

### Scaling our manufacturing and supply

Manufacturing cell therapies requires specialised capabilities, and having the right technology, expertise and infrastructure is critical for translating research into effective cell therapy medicines. As we accelerate our capacity for next-generation cell therapy discovery, development, and deployment, we have expanded our manufacturing footprint with our recent investment in a state-of-the-art facility in Rockville, Maryland, US, that will focus on manufacturing for critical cancer trials. This is in addition to our facility in Gaithersburg, Maryland, US, and those operated by Neogene (located in the US and the Netherlands) and Gracell (located in China).

One of the most pressing challenges with autologous CAR-T is the lengthy manufacturing timelines that can lead to suboptimal T cell quality and activity, and delays in treatment. We are exploring new ways to shorten these timelines. Our acquisition of Gracell brought in their differentiated rapid manufacturing platform, FasTCAR, that aims to deliver less exhausted and potentially more effective CAR-T’s to patients faster.

### Off-the shelf cell therapies

Looking to the future, we are working to engineer cell therapies made from healthy donor blood cells. Our goal is to develop ‘off-the-shelf’ allogeneic cell therapies to significantly increase the availability of, and access to, these innovative therapies. This would help overcome challenges of scalability, time-intensive personalised manufacturing requirements, and the need for specialist treatment centres. Ultimately our vision is for a future where physicians could select from libraries of patient-ready therapies matched to their disease.

## Technology platforms underpinning our pipeline

Our scientists are at the cutting edge of genetic engineering cell therapies and we are expanding our gene editing toolkit to enable more sophisticated editing of a wider range of therapeutic genes. Our in-house capabilities in CRISPR gene editing allow us to selectively modify DNA at certain sites in the genome. This versatile and efficient method targets RNA–DNA interactions and is widely used, offering fast results and easy delivery to cells.13 Complementing our in-house expertise in CRISPR, our collaboration with Cellectis brings an opportunity to harness their differentiated gene-editing expertise with their proprietary TALEN technology. TALEN has the potential for even greater specificity than CRISPR in some circumstances, and the ability to target all sites in the genome.14

We are also researching the potential of stem cells for creating more predictive translational models, to bridge the gap between pre-clinical and clinical studies. We can direct the differentiation of stem cells into precursors of heart muscle cells, and into cells that form the ‘scaffold’ of multiple tissues. Using such ‘organoid’ models could give us a far greater understanding of the risks and benefits of new treatments before entering human trials.

## Driving cell therapy innovation forwards: our partnerships and acquisitions

We are building exciting partnerships and collaborations with leading scientific and medical institutions and commercial partners around the world to address key challenges in cell therapy and drive innovation and progress.

### AbelZeta Pharma

Our collaboration with global clinical-stage biopharmaceutical company AbelZeta aims to accelerate the development of our innovative armouring CAR-Ts for solid tumours in China.

### Cellectis

Our collaboration with Cellectis, a clinical-stage biotechnology company, brings in differentiated gene-editing and cell therapy discovery expertise and manufacturing capabilities. Together we will design novel cell and gene therapy products to accelerate the development of next generation therapeutics in areas of high unmet need, including oncology, immunology and rare diseases.

### Medical Research Council (MRC)

We are co-funding a postdoctoral fellowship scheme with the MRC to support research into key topics relating to cell therapy including patient safety, delivery in the human body and interactions with the immune system.

### Quell Therapeutics

Our collaboration with Quell is focused on type 1 diabetes and inflammatory bowel disease using Quell’s proprietary multi-modular T-regulatory (Treg) cell engineering.

### Acquisitions

Our acquisitions have brought in new expertise and strengthen our ambition to transform outcomes for patients.

### Neogene Therapeutics

Our acquisition of Neogene Therapeutics, a global clinical-stage biotechnology company, in 2023, brought in expertise in the discovery, development and manufacturing of next-generation TCR-Ts that offer a novel cell therapy approach for targeting cancer.

### Gracell Biotechnologies

Acquired by AstraZeneca in 2024, Gracell is a global clinical-stage biopharmaceutical company developing innovative cell therapies for the treatment of cancer and autoimmune diseases, and pioneering a differentiated manufacturing process, helping to further our cell therapy ambition.

### Open Innovation

Through our Open Innovation programme, we share compounds, tools, technologies and expertise with the scientific community to advance drug discovery and development. We now have over 400 R&D collaborations—and counting, including collaborations in cell therapy.

## Join us: Working together to advance cell therapy

We welcome committed, talented cell therapy scientists to join us on what promises to be one of the most exciting, stimulating and rewarding journeys in 21st-century medicine. We are proud of our progress, prepared for the challenges that lie ahead, and confident that, in the next five to 10 years, cell therapy will help improve the outlook for patients with some of today’s most serious and life-limiting diseases.

References:

1. American Society of Cell and Gene Therapy. Cell Therapy Basics [Last Accessed: May 2024]. Available from: https://patienteducation.asgct.org/gene-therapy-101/cell-therapy-basics.

2. Chua CYX, Jiang AY, Eufrásio-da-Silva T, et al. Emerging immunomodulatory strategies for cell therapeutics. Trends Biotechnol. 2023;41(3):358–73.

3. Lu J, Jiang G. The journey of CAR-T therapy in hematological malignancies. Mol Cancer. 2022;21(1).

4. Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current progress in CAR-T cell therapy for hematological malignancies. J Cancer. 2021;12(2):326–34.

5. Banerjee R, Poh C, Hirayama A V., et al. Answering the “Doctor, can CAR-T therapy cause cancer?” question in clinic. Blood Adv. 2024;8(4):895–8.

6. Rutgers University. CAR T-Cell Therapy [Last accessed: May 2024]. Available from: https://cinj.org/patient-care/car-t-cell-therapy.

7. Zhao L, Cao YJ. Engineered T Cell Therapy for Cancer in the Clinic. Front Immunol. 2019;10.

8. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4).

9. Hawkins ER, D’souza RR, Klampatsa A. Armored CAR T-cells: The next chapter in T-cell cancer immunotherapy. Biologics. 2021;15:95–105.

10. Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev Nephrol. 2023;19(8):509–24.

11. Yang Z, Liu Y, Zhao H. CAR T treatment beyond cancer: Hope for immunomodulatory therapy of non-cancerous diseases. Life Sci. 2024;344.

12. Goswami TK, Singh M, Dhawan M, et al. Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders–Advances and challenges. Hum Vaccin Immunother. 2022;18(1).

13. Uddin F, Rudin CM, Sen T. CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front Oncol. 2020;10.

14. Bhardwaj A, Nain V. TALENs—an indispensable tool in the era of CRISPR: a mini review. Journal of Genetic Engineering and Biotechnology. 2021;19(1).

Veeva ID: Z4-65393

Date of preparation: June 2024

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Veeva ID: Z4-46798

Date of next review: August 2024

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