Written by:
Gordon Moody
Senior Director, Cell Therapy, Oncology R&D, AstraZeneca
Cell therapy plays a pivotal role in our ambition to eliminate cancer as a cause of death. At AstraZeneca, we are advancing multiple strategies aimed at improving the precision and effectiveness of cell therapies for cancer, extending their potential benefit to solid tumours, and overcoming challenges related to scalability and accessibility.
Our goal is to broaden the transformative impact of next-generation T cell therapies to reach more people living with cancer. To achieve this, we are focussing on three key areas:
1. Chimeric antigen receptor T-cell therapies (CAR-T)
2. T-cell receptor therapies (TCR-T)
3. Off-the-shelf, patient-ready cell therapies
We aspire to be at the cutting-edge of science, and we are building industry-leading capabilities through strategic internal and external investment. This is helping us harness the latest innovations in gene editing and manufacturing, unlocking new ways to build better therapeutic T cells.
Advancing today’s cell therapies and developing tomorrow’s cancer breakthroughs
We are in an exciting era where scientists can reprogramme a patient’s own T cells—the immune system’s first line of defence—to create ‘living drugs’ targeting their specific tumour.1 Since the first such medicines, known as CAR-T, were approved in 2017, the field has grown exponentially.2 Today, it is recognised as one of very few modalities capable of curing certain cancers.1 Currently, CAR-Ts are used to treat certain blood cancers such as lymphoma and multiple myeloma.1,2
However, there are barriers that prevent the widespread adoption of cell therapies in cancer treatment:
1. Limited efficacy in solid tumours
2. Issues of accessibility
3. Challenges related to scalability
In order to make cell therapy a mainstay of future cancer treatment regimens, we need to go beyond today's innovations to solve challenges in scalability and accessibility, and to expand their potential to solid tumours.
Bringing cancer cell therapy to solid tumours
Building better therapeutic T cells: Our DIAL framework
Regardless of how potent a cell therapy is, its activity will be limited if it cannot locate, infiltrate, accumulate and persist in the target tumour. It is well established that the hostile solid tumour micro-environment (TME) can hamper the infiltration, function, and expansion of T cell therapies.3
Our DIAL framework—which stands for Distribution, Infiltration, Accumulation, and Longevity—is designed to account for these factors, maximising the insights gained from preclinical models to comprehensively understand the T cell’s journey, aiding in the design of more effective cell therapies for cancer.4
Armoured CAR-Ts: equipping cell therapies to resist the immunosuppressive TME
Advances in our understanding of immune function in suppressive conditions are informing novel ways to manipulate T cells genetically, so that we can improve their activity and persistence with the goal of providing longer-lasting anti-tumour immunity.5
Our researchers are developing armouring molecules designed to resist immunosuppression and prevent immune exhaustion. Leveraging promising preclinical results achieved by blocking the activity of TGFβ in the TME,6 we are advancing a pipeline of armoured CAR-Ts targeting hard-to-treat solid tumours, including gastric, prostate and hepatocellular cancers, some of which are being co-developed in China in collaboration with AbelZeta.7 In some cases, these investigational therapies are designed to target antigens that have never been targeted before in human clinical trials.
CAR-T cell therapy: Learn more about how our researchers engineer CAR-Ts to overcome barriers that limit their effectiveness against solid tumours in this video:
Beyond CAR-Ts - T cell receptor targeting
Complementing our efforts in CAR-Ts, we have expanded into T cell receptor therapies (TCR-T), through our acquisition of Neogene Therapeutics. While CAR-Ts target antigens on the surface of cancer cells, TCR-Ts can identify intracellular proteins, unlocking new treatment opportunities in cell therapy.8 TCR-Ts therefore have potential as new treatments directed against solid tumours, and have already entered clinical trials.
‘Off-the-shelf’ cancer cell therapies: addressing scalability and accessibility
Current approaches in oncology predominantly focus on ‘autologous’ CAR-Ts, where T cells are isolated from a patient and genetically modified to recognise antigens specific to their cancer.1,9 Although these can be highly effective, each product is made for a single patient, which is complex and time-consuming. Additionally, the need for a specialised infrastructure limits the accessibility of these medicines to dedicated treatment centres at specialist hospitals.
Delivering off-the-shelf therapies, also known as allogeneic cancer cell therapies, using cells from healthy donors rather than individual patients, could overcome these challenges.10
There is an urgent need to make cancer cell therapies more scalable and accessible. Our vision is to develop a library of ‘off-the-shelf’ therapies to achieve this.
However, there are challenges associated with allogeneic therapy. One challenge is preventing graft-versus-host disease, a life-threatening condition where donor T cells attack the recipient’s non-cancerous tissue.10 Mismatch between the donor’s cells and recipient patient’s immune system may also lead to rejection, rendering the treatment ineffective.10 At AstraZeneca, we are researching innovative ways to engineer donor cells, mitigating these immune reactions to create effective new treatments.
Accelerating our cell therapy expertise through internal and external innovation
Having the right discovery and manufacturing capabilities is pivotal to overcoming the complexities that prevent the widespread adoption of cell therapy in cancer treatment.
Our growing in-house expertise and capabilities are complemented by strategic investments and collaborations, including the recent acquisition of Gracell Biotechnologies, which accelerates our haematology cell therapy ambition and introduces differentiated manufacturing technology.
Through our partnership with Cellectis, we are complementing our in-house CRISPR expertise with state-of-the-art TALEN editing technology, creating a gene-editing toolkit with the capacity to edit a broader range of genes with greater precision and sophistication. This could enable us to build better therapeutic T cells, with improved tumour targeting and persistence, and to address challenges in host rejection of allogeneic therapies.
Join us: Developing the next wave of cell therapies to target cancer
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.
